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A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of 'Withdrawn' patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n = 232) patients received ≥ 1 GA dose since 1991; 'Ongoing' patients (n = 108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to ∼ 1 relapse/5 years; median time to ≥ 1 EDSS point increase was 8.8 years; mean EDSS change was 0.73 ± 1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.50 ± 1.65; 62% were stable/improved; and 24, 8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.24 ± 1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients. [ABSTRACT FROM AUTHOR]

The article presents a study examining the dental prosthetic restorations used by patients in the U.S. Navy. The relative absence of detailed quantitive data on dentures worn by patients in the U.S. is noted, mentioning that the study provides information useful for the creation of more accurate budget estimates and supports the emphasis on the man-hour costs for rendering prosthodontic treatment.

The aim of this study was to assess the long-term safety and efficacy of glatiramer acetate (GA) for patients with multiple sclerosis (MS) who received active treatment versus those on placebo for approximately 30 months (24-35 months) before receiving GA during a six-year organized, prospective open label study. Entry required two relapses in the previous two years and an Expanded Disability Status Scale (EDSS) score of 0-5. Patients (251) were equally randomized to daily subcutaneous GA, 20 mg, or to placebo. After approximately 30 months, 208 patients continued in an open label study: 101 continued on GA and 107 switched from placebo to active drug. Groups were well matched at randomization and entry to the open label study. Patients always on GA showed a steady decline in relapses: a mean of 1.5 per year at entry, a mean of 0.42 over the entire six years (95% CI = 0.34-0.51), a 72% reduction (P = 0.0001). They averaged a relapse every four + years (yearly rate 0.23 in year six) and 26/101 remain relapse free. Patients did less well if on placebo for 30 months, but relapses then declined, and by year six the rates were similar. Of patients always on GA, 69% showed neurological improvement of > or = 1 EDSS steps or remained stable compared with 57% if GA treatment was delayed. Of relapse-free patients always on GA over six years, only three of 26 (11%) were worse by > or = 1 EDSS steps, whereas nine of 21 (43%) in the placebo/active group were worse (P < 0.03). Disability, measured every six months, showed that the group of patients always on GA was relatively stable over the six years, while the group who received placebo for the first two-and-a-half years did significantly less well. Daily injections of GA were well tolerated. This longest ever organized MS treatment trial shows that delaying therapy with GA increases the risk of neurologic disability, reinforcing the rationale for using GA as a first-line treatment early in the course of relapsing-remitting MS.

Matrix metalloproteinases (MMPs) are increased in the CSF of patients with multiple sclerosis. Devic's neuromyelitis optica (DNO) is a demyelinating syndrome that involves the optic nerve and cervical cord but differs pathologically from multiple sclerosis. Therefore, we hypothesized that the type of inflammatory reaction that causes MMPs to be elevated in multiple sclerosis would be absent in patients with DNO. CSF was collected from 23 patients with relapsing-remitting or secondary progressive multiple sclerosis, all of whom were experiencing acute symptoms, from seven patients with DNO, and from seven normal volunteers. Diagnoses were made according to current criteria on the basis of clinical manifestations, imaging results and CSF studies. IgG synthesis was increased in the CSF of multiple sclerosis patients but not in that of DNO patients. Zymography, reverse zymography and ELISA (enzyme-linked immunosorbent assay) were used to measure gelatinase A (MMP-2), gelatinase B (MMP-9) and tissue inhibitors of metalloproteinases (TIMPs). Zymograms showed that multiple sclerosis patients had elevated MMP-9 compared with DNO patients and controls (P: < 0.05). TIMP-1 and TIMP-2 levels were similar in all three groups. We conclude that multiple sclerosis patients have higher MMP-9 levels in the CSF than patients with DNO, which supports the different pathological mechanisms of these diseases.

The authors compared the frequency of paranasal sinus inflammatory changes (SIC) on brain magnetic resonance imaging (MRI) obtained from 23 patients with new onset acute optic neuritis (ON) and 48 control patients who underwent outpatient MRI of the brain for reasons other than ON. The authors found a higher frequency of paranasal SIC in patients with ON (83%) than in controls (54%) (p = 0.02). The distribution of paranasal SIC (in ON and in controls) was maxillary (83% and 52%), ethmoid (4% and 2%), frontal (9% and 14%), and sphenoid (4% and 10%). Frequency of the maxillary SIC was significantly higher (p = 0.02) in patients with ON than in controls. Further evaluation of maxillary paranasal SIC with a grading system showed the presence of thickened mucosal lining of the sinuses (grade I) in 17% (ON) and 23% (controls), mucous retention cysts within the sinuses (grade II) in 48% (ON) and 25% (controls), and severe mucosal thickening with complete or near-complete filling of the sinus or an air-fluid level within the sinus (grade III) in 17% (ON) and 4% (controls). Combined frequency of grade II and grade III SIC was significantly higher in the ON group than in controls (p = 0.005), as was the frequency of grade III SIC alone (p = 0.02). Grade I SIC did not significantly differ between the groups. There was a trend (p = 0.09) toward a higher prevalence of bilateral sinus inflammatory changes in patients with bilateral ON. These findings suggest that ON may be associated with sinus inflammatory changes.

Although maturation/M phase promoting factor (MPF) can activate autonomously in Xenopus egg cytoplasm, indirect evidence suggests that nuclei and centrosomes may focus activation within the cell. We have dissected the contribution of these structures to MPF activation in fertilized eggs and in egg fragments containing different combinations of nuclei, centrosomes, and microtubules by following the behavior of Cdc2 (the kinase component of MPF), the regulatory subunit cyclin B, and the activating phosphatase Cdc25. The absence of the entire nucleus-centrosome complex resulted in a marked delay in MPF activation, whereas the absence of the centrosome alone caused a lesser delay. Nocodazole treatment to depolymerize microtubules through first interphase had an effect equivalent to removing the centrosome. Furthermore, microinjection of isolated centrosomes into anucleate eggs promoted MPF activation and advanced the onset of surface contraction waves, which are close indicators of MPF activation and could be triggered by ectopic MPF injection. Finally, we were able to demonstrate stimulation of MPF activation by the nucleus-centriole complex in vitro, as low concentrations of isolated sperm nuclei advanced MPF activation in cycling cytoplasmic extracts. Together these results indicate that nuclei and microtubule asters can independently stimulate MPF activation and that they cooperate to enhance activation locally.

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone) reduced the relapse rate and slowed accumulation of disability for patients with relapsing - remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis. Multiple Sclerosis (2000) 6 255 - 266

Objective: To determine the relationship between neurochemical markers of brain injury and brain dysfunction associated with systemic lupus erythematosus (SLE)., Methods: Patients with SLE (n = 12) were studied using magnetic resonance spectroscopic imaging at 1.5 Tesla to determine neurochemistry and a neurocognitive testing battery to determine brain dysfunction. N-acetylaspartate (NAA), creatine (Cre), and choline (Cho) concentrations were measured in white (WM) and gray (GM) matter and expressed as the ratios NAA/Cho, NAA/Cre, and Cho/Cre. Neurocognitive testing results were expressed as a composite z score. Disease activity was quantified by SLE Disease Activity Index (SLEDAI) and disease injury by Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology Damage Index., Results: Neurochemical measures of brain injury were correlated with neurocognitive testing z scores: NAA/Cho in WM (r = 0.77, p = 0.003) and GM (r = 0.67, p = 0.017); WM Cho/Cre also correlated with total z score (r = -0.74, p = 0.006). Neurometabolite ratios and SLICC were correlated: GM NAA/Cho (r = -0.70, p = 0.011 ) and NAA/Cre (r = -0.71, p = 0.01) and WM Cho/Cre (r = 0.66, p = 0.02). Correlations between neurometabolite ratios and SLEDAI did not reach significance., Conclusion: Brain function is closely correlated with brain injury assessed noninvasively by proton magnetic resonance spectroscopy. This important finding further supports the use of magnetic resonance spectroscopy to evaluate brain injury in SLE.

Children with symptoms of schizophrenia-spectrum disorder (N = 20) were compared to controls (N = 20) matched for age and socioeconomic status. Structural brain abnormalities were assessed with magnetic resonance imaging and functional brain abnormalities with neuropsychological tests. Children with schizophrenia-spectrum disorder had smaller amygdala and temporal cortex volumes, along with reduced callosal areas and an unusual pattern of neuroanatomic asymmetries. No differences were noted in overall brain volume, ventricular volume, hippocampal volume, or frontal area. Schizophrenia-spectrum children were also characterized by deficits in all neuropsychological functions examined. Some types of verbal memory and frontal lobe skills were especially deficient. These results support the hypothesis that children with schizophrenia-spectrum disorder have significant brain abnormalities, similar in some ways to those seen in adult schizophrenics. In conjunction with recent primate studies, the current results draw attention to the role of the amygdala as one relevant factor in the pathogenesis of schizophrenia.

We have analysed the recircularisation of plasmid DNA, cut with two different endonucleases to generate non-homologous DNA ends, in extracts of unfertilised eggs and oocytes of Xenopus. We found that the capacity to join non-homologous DNA ends, generating diagnostic covalently closed monomer circles, appeared during oocyte maturation at the time of germinal vesicle breakdown. This enzyme function was post-translationally activated in oocyte extracts incubated with unfertilised egg extract containing active cdc2/cyclin B, or by incubation with purified cdc2/cyclin B. Dephosphorylation of egg proteins by alkaline phosphatase inhibited the ability to join non-homologous DNA ends. We show that most linear non-homologous DNA ends repaired to form closed-circular supercoiled monomers, are joined without loss of nucleotides. Following partial purification, the activity was inhibited by inhibitors of poly(ADP-Rib) polymerase, an enzyme that is inactive in oocytes, but phosphorylated and activated during maturation. Competitive inhibition of poly(ADP-Rib) polymerase by > 50 microM 3-aminobenzamide prevented the joining of both matched and non-homologous DNA ends. We conclude that post-translational phosphorylation provides one route by which end-joining of non-homologous DNA can be regulated.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Xenopus egg extracts, which support nuclear assembly and DNA replication, were functionally depleted of lamin LIII by inoculating them with monoclonal anti-lamin antibodies. Phase-contrast microscopy and electron-microscopy studies indicated that lamin-depleted extracts supported efficient chromatin decondensation, and assembly of double membrane structures and nuclear pores on demembranated sperm heads. Immunofluorescence microscopy suggests that lamin-antibody complexes are transported across the nuclear membrane but do not assemble into a lamina. These findings were confirmed by immunoblotting analysis of isolated nuclei. Metabolic labelling studies with either biotin-11-dUTP or [32P]dCTP, revealed that nuclei lacking a lamina were unable to initiate DNA replication and that, although such nuclei could import proteins required for DNA replication (e.g. PCNA), these proteins were apparently not organized into replicon clusters.

An animal model of central nervous system demyelination was created by injecting rat internal capsules with lysophosphatidylcholine (LPC). The resulting chemically induced demyelinating lesions were readily visible in T1-weighted spin-echo, T2 weighted spin-echo, and inversion-recovery magnetic resonance imaging (MRI) sequences. Changes in lesions were followed over 8 weeks and correlated with histopathology. Histologically, lesions were characterized initially by an acute, inflammatory phase with edema and blood-brain barrier breakdown, followed by macrophage-mediated removal of myelin debris and finally by remyelination after 3 to 4 weeks. MRI can differentiate lesion stages in the LPC model and may be useful in investigating mechanistic aspects of the demyelinating process. In addition the well-localized lesions may be amenable to study by techniques of volume-localized NMR spectroscopy.

A method is described for the enucleation and complete healing of Xenopus oocytes so that the enucleated oocytes withstand multiple injections and culture for several days. The oocytes are defolliculated and enucleated manually and allowed to heal in a potassium phosphate buffer. Oocytes enucleated in this way support RNA synthesis by injected HeLa-cell nuclei 3 days later. This method is valuable in providing a low-background system in which transcription of injected nuclei can be studied.

It has not previously been possible to label the nuclear protein modification poly(ADP-ribose) directly from NAD because of the impermeability of the cell membrane. We have overcome this important problem by micro-injection of radioactively labelled NAD into Xenopus laevis early embryos. The polymer was identified and then quantified by its insensitivity to DNAase, RNAase, and spleen phosphodiesterase and by the chromatographic mobility of the products of digestion with snake-venom phosphodiesterase. The quantity of poly(ADP-ribose) present after 25 h of development (129 ng/mg DNA) is lower than that found in fully differentiated tissue.

The NAD pools of Xenopus laevis oocytes and early embryos can be radioactively labelled by microinjection of [adenine-3H]NAD. This technique is used to study the metabolism of NAD in oocytes and during early development. The rate at which NAD is degraded in vivo has been monitored by determining the rate of transfer of adenine residues from the NAD pool into other nucleotides and polynucleotides. In oocytes, NAD turnover is extremely slow, with a half-life of about 400 h. NAD turnover increases dramatically after fertilisation, and the half-life of the compound decreases to 37 h in 5-h-old embryos and to 10 h in 40-h-old embryos. 2 mM 3-aminobenzamide, a specific inhibitor of poly(ADP-ribose) polymerase, reduces the NAD turnover rate by about 20%, whereas 5 mM isonicotinic acid hydrazide, a specific inhibitor of NAD glycohydrolase, produces no significant inhibition. This indicates that a significant fraction of the considerable NAD turnover observed involves poly(ADP-ribose) polymerase. Our results indicate that poly(ADP-ribose) polymerase is active during early development and suggest that this activity may be involved in one or more aspects of the nuclear metabolism of the embryo.

Cell cycles in early amphibian embryos are characterized by the absence of G1 and G2 phases. The simple cycle of S phase and mitosis does show similarities with other systems, particularly in the presence of cytoplasmic components advancing nuclei into DNA synthesis and mitosis. Maturation-promoting factor induces nuclear envelope breakdown and subsequent chromosome condensation. Cytoplasmic factors appear during maturation which are capable of inducing DNA synthesis, and arrest of the nuclear division cycle in metaphase (cytostatic factor). The timing of appearance of these activities is considered and their relationship in integrating DNA synthesis during early cleavage is discussed.