Deterioration of specific aspects of gait during the instrumented 6-min walk test among people with multiple sclerosis.

Prolonged walking is typically impaired among people with multiple sclerosis (pwMS), however, it is unclear what the contributing factors are or how to evaluate this deterioration. We aimed to determine which gait features become worse during sustained walking and to examine the clinical correlates of gait fatigability in pwMS. Fifty-eight pwMS performed the 6-min walk test while wearing body-fixed sensors. Multiple gait domains (e.g., pace, rhythm, variability, asymmetry and complexity) were compared across each minute of the test and between mild- and moderate-disability patient groups. Associations between the decline in gait performance (i.e., gait fatigability) and patient-reported gait disability, fatigue and falls were also determined. Cadence, stride time variability, stride regularity, step regularity and gait complexity significantly deteriorated during the test. In contrast, somewhat surprisingly, gait speed and swing time asymmetry did not change. As expected, subjects with moderate disability (n = 24) walked more poorly in most gait domains compared to the mild-disability group (n = 34). Interestingly, a group × fatigue interaction effect was observed for cadence and gait complexity; these measures decreased over time in the moderate-disability group, but not in the mild group. Gait fatigability rate was significantly correlated with physical fatigue, gait disability, and fall history. These findings suggest that sustained walking affects specific aspects of gait, which can be used as markers for fatigability in MS. This effect on gait depends on the degree of disability, and may increase fall risk in pwMS. To more fully understand and monitor correlates that reflect everyday walking in pwMS, multiple domains of gait should be quantified.

A new approach to quantifying the EEG during walking: Initial evidence of gait related potentials and their changes with aging and dual tasking.

BACKGROUND: The electroencephalogram (EEG) can be a useful tool to investigate the neurophysiology of gait during walking. Our aims were to develop an approach that identify and quantify event related potentials (ERPs) during a gait cycle and to examine the effects of aging and dual tasking on these gait related potentials (GRPs). METHODS: 10 young and 10 older adults walked on a treadmill while wearing a wireless 20-channels EEG and accelerometers on the ankles. Each heel strike extracted from the accelerometers was used as an event to which the electrical brain activity pattern was locked. The subjects performed usual and dual task walking that included an auditory oddball task. GRPs amplitude and latency were computed, and a new measure referred to as Amplitude Pattern Consistency (APC) was developed to quantify the consistency of these GRP amplitudes within a gait cycle. The results were compared between and within groups using linear mixed model analysis. RESULTS: The electrical pattern during a gait cycle consisted of two main positive GRPs. Differences in these GRPs between young and older adults were observed in Pz and Cz. In Pz, older adults had higher GRPs amplitude (p = 0.006, p = 0.010), and in Cz lower APC (p = 0.025). Alterations were also observed between the walking tasks. Both groups showed shorter latency during oddball walking compared to usual walking in Cz (p = 0.040). In addition, the APC in Cz was correlated with gait speed (r = 0.599, p = 0.011) in all subjects and with stride time variability in the older adults (r = -0.703, p = 0.023). CONCLUSIONS: This study is the first to define specific gait related potentials within a gait cycle using novel methods for quantifying waveforms. Our findings show the potential of this approach to be applied broadly to study the EEG during gait in a variety of contexts. The observed changes in GRPs with aging and walking task and the relationship between GRPs and gait may suggest the neurophysiologic foundation for studying walking and for developing new approaches for improving gait.

Age-associated changes in obstacle negotiation strategies: Does size and timing matter?

INTRODUCTION: Tripping over an obstacle is one of the most common causes of falls among older adults. However, the effects of aging, obstacle height and anticipation time on negotiation strategies have not been systematically evaluated. METHODS: Twenty older adults (ages: 77.7±3.4years; 50% women) and twenty young adults (age: 29.3±3.8years; 50% women) walked through an obstacle course while negotiating anticipated and unanticipated obstacles at heights of 25mm and 75mm. Kinect cameras captured the: (1) distance of the subject's trailing foot before the obstacles, (2) distance of the leading foot after the obstacles, (3) clearance of the leading foot above the obstacles, and (4) clearance of the trailing foot above the obstacles. Linear-mix models assessed changes between groups and conditions. RESULTS: Older adults placed their leading foot closer to the obstacle after landing, compared to young adults (p<0.001). This pattern was enhanced in high obstacles (group*height interaction, p=0.033). Older adults had lower clearance over the obstacles, compared to young adults (p=0.007). This was more pronounced during unanticipated obstacles (group*ART interaction, p=0.003). The distance of the leading foot and clearance of the trailing foot after the obstacles were correlated with motor, cognitive, and functional abilities. CONCLUSIONS: These findings suggest that there are age-related changes in obstacle crossing strategies that are dependent on the specific characteristics of the obstacle. The results have important implications for clinical practice, suggesting that functional exercise should include obstacle negotiation training with variable practice of height and available response times. Further studies are needed to better understand the effects of motor and cognitive abilities.

Triple paternal contribution to a normal/complete molar chimeric singleton placenta.

A comprehensive study of unusual cases of placental pathology may provide insight into mechanisms of normal human fertilization and early embryonic development by examining the exception to the rule. A gravida three para two 39-year-old woman was monitored by ultrasound from 16 weeks of gestation for cystic placenta. A female newborn was born at 36 weeks gestation. Pathologic examination of the partially cystic placenta revealed a singleton placenta comprised of 2/3 normal placenta and 1/3 complete hydatidiform mole, largely degenerated. Immunostaining for p57 was negative in stromal cells of the molar villi. Chromogenic in-situ hybridization revealed diploidy in both normal and molar parts. A total of 16 microsatellites were studied by short tandem repeat analysis, 11 of which were informative. The analysis revealed bipaternal molar tissue of dispermic origin. The paternal monospermic contribution to the normal part was different from that in the molar part, thus resulting in tripaternal contribution to the conceptus. A chimera is a single organism composed of two or more different populations of genetically distinct cells that originated from different zygotes (tetragametic) whereas mosaic is a mixture of two cell lines in one organism originating from one zygote. The possible mechanisms leading to the formation of chimeric/mosaic placenta in our case (one of the components being complete hydatidiform mole), including twinning, fusion at an early embryonic stage and diploidization of triploids, are discussed.

Naphthoquinone-tyrptophan reduces neurotoxic Aß*56 levels and improves cognition in Alzheimer's disease animal model.

An increasing body of evidence indicates a role for oligomers of the amyloid-ß peptide (Aß) in the neurotoxicity of this peptide and the pathology of Alzheimer's disease (AD). Several neurotoxic oligomeric forms of Aß have been noted ranging from the larger Amyloid ß-Derived Diffusible Ligands (ADDLs) to smaller trimers and dimers of Aß. More recently a dodecameric form of Aß with a 56 kDa molecular weight, denoted Aß*56, was shown to cause memory impairment in AD model mice. Here, we present for the first time a potential therapeutic strategy for AD that targets the early stages in the formation of neurotoxic Aß*56 oligomers using a modified quinone-Tryptophan small molecule N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-L-Tryptophan (Cl-NQTrp). Using NMR spectroscopy we show that this compound binds the aromatic recognition core of Aß and prevents the formation of oligomers. We assessed the effect of Cl-NQTrp in vivo in transgenic flies expressing Aß(1-42) in their nervous system. When these flies were fed with Cl-NQTrp a marked alleviation of their Aß-engendered reduced life span and defective locomotion was observed. Finally, intraperitoneal injection of Cl-NQTrp into an aggressive AD mouse model reduced the level of the Aß*56 species in their brain and reversed their cognitive defects. Further experiments should assess whether this is a direct effect of the drug in the brain or an indirect peripheral effect. This is the first demonstration that targeted reduction of Aß*56 results in amelioration of AD symptoms. This second generation of tryptophan-modified naphthoquinones could therefore serve as potent disease modifying therapeutic for AD.

Living related liver transplant following bone marrow transplantation from same donor: long-term survival without immunosuppression.

We report long-term (seven yr) immunological tolerance in a 16-yr-old boy, to a liver allograft donated by his father following a bone marrow transplant at age 2.5 yr from the same donor. The bone marrow transplant was complicated by severe GVHD leading to liver failure and the ensuing need for a liver transplant, performed under planned avoidance of immunosuppression. At one wk post-transplant, although a liver biopsy was histologically compatible with acute rejection, favorable clinical and biochemical evolution precluded initiating immunosuppressive therapy, thus highlighting the need for caution when interpreting early histological changes so that administration of unnecessary immunosuppression can be avoided. Induction of tolerance in transplant recipients remains an elusive goal. In those patients who had received conventional bone marrow transplants and had endured the consequences of GVHD, development of macrochimerism may allow immunosuppression-free solid organ transplantation from the same donor.

Patterned arrays of ordered peptide nanostructures.

Methods for the deposition of ordered nanostructures on various substrates are a key factor in nanotechnological devices. There is a special interest in the development of methods for the organization of organic nanostructures that are not compatible with some of the conventional fabrication methods. The unique chemical and physical properties of the peptide nanotubes make them excellent component in various devices and the useful application were already demonstrated in the case of biosensors. Here we demonstrate the ability to deposited aromatic dipeptide nanotubes using electron beam treatment of surfaces to control their wettability. The use of a low energy electron irradiation results in the formation of pre-defined surfaces with controlled level of wettability. This treatment allows the precise patterning of the organic tubular assemblies at high resolution. The differential wettability of the surface resulted in organization of the peptide assemblies according to the properties of the different areas of the surface. In the current work, we describe the use of wettability patterned surfaces for the control patterning of horizontal peptide nanotubes and nanospheres. Furthermore, lift-off lithography is used to make patterned arrays of peptide nano-forests, vertically aligned peptide nanotubes. In summary, the novel patterning techniques together with the unique properties of the peptide nanostructures represent an important step in the integration of these assemblies into functional nanosystems and devices.

A survey of laboratory-confirmed isolates of invasive listeriosis in Israel, 1997-2007.

During the 11-year period from 1997 to 2007, 321 isolates of Listeria monocytogenes from sporadic cases of invasive listeriosis were reported to the national reference laboratory in Israel. Of these isolates, 113 (35%) were identified from perinatal cases, and 208 (65%) from non-perinatal cases. The prevalent serovars were 4b, 1/2b, 1/2a and 4c. Serovar 4b was identified in 80.5% of the perinatal isolates (P=0.0162), while the number of 1/2b and 1/2a strains increased in the > or = 60 years old group (P=0.0285). Resistance to tetracycline was found in eight 4b isolates. The seasonal distribution showed that 206 isolates (64.2%) were submitted during the hot season (May-October). The estimated morbidity for the study period was 4.4 per million. The incidence of invasive listeriosis was higher in the perinatal group (5.6/100 000), than in individuals aged > or = 60 years (1.5/100 000).

HLA-G levels in serum and plasma.

Soluble human leukocyte antigen (HLA)-G levels are in most cases higher in the plasma than in the serum obtained from the same individual. This is probably due to trapping of the protein during clot formation. In studies where soluble HLA-G is quantified, it is therefore recommended that plasma or serum levels should be compared with the same blood product, namely, serum to serum and plasma to plasma. Because of possible gender differences in HLA-G levels it is also recommended that this should be considered in the construction of a control group especially in studies where there is a preponderance of one of the sexes.

Evidence for blood chimerism in dizygotic spontaneous twin pregnancy discordant for Down syndrome.

BACKGROUND: A monochorionic-diamniotic placenta (MCDAP) is rare in dizygotic (DZ) twinning. All reported cases have been documented in pregnancies achieved by the induction of ovulation alone or during the IVF cycle. METHODS AND RESULTS: We report a spontaneous pregnancy in a 39-year-old patient with evidence of MCDAP in DZ twins, discordant for trisomy 21. The first and second-trimester sonographic scans indicated male twins with MCDAP. Amniocentesis, performed because of advanced maternal age, revealed a normal karyotype in one fetus, and trisomy 21 in the other. Molecular studies, performed in order to confirm the zygosity and chorionicity, demonstrated that the fetuses were DZ. In order to identity the affected twin, a detailed sonographic examination was repeated, but no abnormal findings associated with Down syndrome were demonstrated in any of the fetuses. Therefore, umbilical cord blood samples were obtained from both fetuses. Chromosomal analysis revealed in both fetuses two cell lines: a normal cell line of 46,XY and a 47,XY,+ 21 cell line, in 65 and 80% of the cells, respectively. This result was independently confirmed by both FISH and G-banding. DNA extracted from both cord blood samples demonstrated an admixture of two distinct genotypes in each sample. CONCLUSIONS: We propose that this case represents a monochorionic-dizygotic twin pregnancy with blood chimerism. The most plausible mechanism underlying this phenomenon is placental fusion early in pregnancy, resulting in an architecturally single placenta originating from two distinct zygotes. The newly formed blood vessels created anastomoses between the DZ twins and allowed reciprocal blood chimerism between the normal and the trisomic twin.

HLA-G levels in serum and plasma.

HLA-G belongs to the non-classical HLA class-I family of genes presently designated as class-Ib genes. There are four membrane-bound (HLA-G1 to -G4) and three soluble forms (HLA-G5 to -G7) generated by alternative splicing of the primary transcript. HLA-G in the soluble form is found in the plasma, amniotic fluid, and cord blood of healthy individuals. Quantitative determination suggested that HLA-G levels are genetically controlled. While quantifying soluble HLA-G by ELISA, we observed that when plasma and serum levels were measured for the same individual, HLA-G plasma values were almost invariably higher than those from serum. Our results suggest that HLA-G is trapped and/or consumed during clot formation. The amount trapped within the clot is variable and inconsistent. To obtain values which reflect the true biological levels, it is therefore recommended that HLA-G should be determined in the plasma. If serum levels are determined, they should be compared with matched control sera. It should always be borne in mind that conclusions concerning sera levels might be erroneous, because the true plasma level of the protein can be significantly higher.

Feto-feto-fetal transfusion syndrome in monozygotic monochorionic triamniotic triplets: vascular evaluation by a cast model.

A unique cast model of the placenta in a rare case of feto-feto-fetal triplet transfusion syndrome (FFFTTS) allowed the demonstration of why the transfusion syndrome developed in one fetus and not in the other two in that single placenta. The vasculature anatomy of a monochorionic triamniotic triplet placenta with FFFTTS of three healthy infants (one donor, two recipients) born in the 35th week of gestation was cast by means of dental casting materials. After the cast hardened, the tissue was corroded, revealing the cast blood vessels. The diameters and lengths of the chorionic blood and intraplacental vessels of the cast placenta were measured with a digital caliper. The cast revealed two artery-artery (A-A) anastomoses on the chorionic plate between the two recipients and the donor. Seven artery-vein (A-V) deep anastomoses connected only the arteries of the donor and the veins of the two recipients. The blood vessel connections among the fetuses allowed the evaluation of a pathologic case with its own control in a single placenta. From the vascular appearance, we speculate that the A-A anastomoses between the two fetuses protected them from developing blood transfusions, but that the A-V anastomoses contributed to their development.

Common ancestral origin of pemphigus vulgaris in Jews and Spaniards: a study using microsatellite markers.

Pemphigus is a group of autoimmune blistering diseases of the skin and mucous membranes. The association of pemphigus with human leukocyte antigen (HLA) is widely accepted. It was described in many ethnic groups and in most countries of the world. Studies showed that the associated HLA haplotype in Jewish pemphigus vulgaris (PV) patients is HLA-B38, DRB1*0402, and DQB1*0302; or HLA-B35, DRB1*0402, and DQB1*0302. Similar associations with class II genes were found in Spanish non-Jewish PV patients. As Jews lived in Spain for hundreds of years and many converted to Christianity, the presence of the same HLA haplotype in the Jewish and Spanish PV suggests that they may share the same founder. Microsatellite markers which span the entire major histocompatibility complex (MHC) locus were used as genetic probes. They were utilized to dissect the MHC region in the search for possible common haplotypes, besides HLA, which may provide an answer to this question. It was found that in both cohorts, in addition to HLA class II genes, there are probably genes in the class I region which are associated with PV. Alleles belonging to the associated markers were used to construct haplotypes and to estimate genetic distances. The distance between the two PV cohorts is relatively short, but the distance between the Jewish patients and the Jewish controls is greater compared to the distance between Spanish patients and Spanish controls. In both PV populations, the same microsatellite haplotypes in addition to a common class II haplotype were found, suggesting that both patient populations originated from the same genetic stock and, therefore, share the same ancestral disease gene.

Different phenotypic expression in monozygotic twins with Huntington disease.

Monozygotic (MZ), 46-year-old, male twins, carrying the same Huntington disease (HD) mutation, presented with a different clinical course. In one of the twins, the disease process started at the age of 32 years with chorea, dysarthria, and a depressed mood. Over 14 years, the disease progressed to total functional dependence. The second twin presented at age 35 with gait disturbances. His behavior became aggressive with an obsessive pattern, whereas the motor features included hypokinesia, rigidity, gait unsteadiness, and dysarthria. This is the first report of genetic identity associated with different age of disease onset as well as a different motor and behavioral phenotype. Postzygotic events are a likely explanation for the observed differences of phenotype in these genetically identical twins.

NQO2 gene is associated with clozapine-induced agranulocytosis.

Clozapine is a dibenzodiazepine neuroleptic with atypical pharmacological and clinical profiles. Treatment with this drug may be complicated with agranulocytosis (AGR). It is likely that defective oxidative mechanism may be the cause of AGR. A candidate gene, dihydronicotinamide riboside (NRH) quinone oxidoreductase 2 (NQO2), which is involved in detoxification of drugs, was selected. This gene has been mapped to the short arm of chromosome six. The gene was studied by single-strand conformation polymorphism analysis and direct sequencing in 98 schizophrenic patients that were treated with clozapine. Eighteen of these patients developed AGR. Ten polymorphisms in the coding regions, in intron 1, and in the promoter region were found, two of which were novel. Comparisons of the polymorphisms in the first intron in AGR patients and controls suggested that this site might be connected with AGR. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the level of NQO2 mRNA is low in AGR patients compared with the control group. Such a reduction in message suggests that the NQO2 gene may be involved in the development of clozapine-induced AGR.

Effect of stabilization splint therapy on pain during chewing in patients suffering from myofascial pain.

Masticatory myofascial pain (MFP) condition is a musculoskeletal disorder that compromises the functional capacities of the masticatory system. As such, the incorporation of an intensive chewing test as a discriminatory exercise for the diagnosis of this condition and evaluation of treatment success has considerable potential. Various splint designs have been used successfully, which have posed a question of whether the therapeutic effect of the splint is a placebo or has some other curative properties. The purpose of this study was to evaluate the efficacy of the stabilization appliance to reduce signs and symptoms in MFP patients and to compare the pain experience during the chewing test between two groups of patients, with and without splints. Myofascial pain patients (n = 37) who reported exacerbation of pain in function participated in the study. Patients perfomed a 9-min chewing test, followed by 9-min rest and marked their pain intensity on a visual analogue scale every 3 min. Of the 37 patients, 21 received a stabilization flat occlusal splint for night use and 16 were equally monitored clinically without a splint. At the end of 8 weeks, a second clinical examination and chewing test were performed. Student's t-test was used to analyse differences between study groups. Analysis of variance and covariance (ancova) with repeated measures was applied to analyse the effect of treatment. Level of pain at baseline prior to the chewing test (P0) was introduced as a co-variant. At baseline both groups showed relatively high scores of pain intensity and did not show any significant differences among the collected variables. At the end of the experiment, the splint group had a statistically significant reduction in pain intensity, in mean muscle sensitivity to palpation and in the pain experience during the chewing test compared with no change in the controls. A stabilization splint has a therapeutic value beyond its placebo effects. Thus, it should be an integral part of the treatment modalities in MFP disorder patients. An intensive chewing test is an effective tool to evaluate the treatment modality efficacy in MFP patients.

Further experience with intravenous immunoglobulin in women with recurrent miscarriage and a poor prognosis.

PROBLEM: Women with three or more unexplained miscarriages have a 60% chance of a subsequent live birth. Intravenous immunoglobulin (IVIG) has not been conclusively shown to improve this prognosis. This study assessed the effect of IVIG in patients expected to have a poor outcome if untreated, i.e. women with five or more abortions, who have aborted after paternal leukocyte immunization or who continue to abort despite expressing anti-paternal complement dependent antibody. METHODS: Seventy-six women received IVIG in a dose of 400 mg/kg body weight, in one day (total 30-45 g) in the follicular phase of a cycle in which pregnancy was planned. A booster dose was administered when pregnancy was diagnosed. Their results were compared to an untreated control group of 74 women. RESULTS: Thirty-five (49%) pregnancies in treated women have resulted in live births or passed their previous stages of abortion compared to 23 (31%) in control patients (P = 0.04). CONCLUSIONS: These figures indicate that IVIG may prevent further miscarriages in this poor prognosis population. These figures are especially significant considering the doubt concerning the efficacy of IVIG in patients with three miscarriages and therefore a relatively good prognosis.

Breast augmentation with fresh-frozen homologous fat grafts.

The purpose of this report is to present a patient who underwent breast augmentation with fresh-frozen fat homografts in Russia 10 years ago, despite the publication of major complications following this procedure.

Cephalometric and polysomnographic analyses of functional magnetic system therapy in patients with obstructive sleep apnea.

The therapeutic effect of a functional magnetic system on obstructive sleep apnea and the system's operating mechanism have not been examined. Two hypotheses are postulated: a functional magnetic system increases the size of the oral cavity airway passage, or it increases the pharyngeal space. Twenty-eight patients with mild-to-moderate obstructive sleep apnea were examined; 10 patients (9 men and 1 woman; aged, 50.5 +/- 2.6 years) met the study criteria. After baseline nocturnal polysomnography and daytime tiredness self-evaluation, a functional magnetic system was inserted. The functional magnetic system is a mandibular repositioning appliance that uses a pair of attractive magnets (Sm2Co17), placed opposite each other in the jaws, which results in an advancement-to-opening ratio of 1:2. After 8 weeks of functional magnetic system treatment, polysomnography, daytime tiredness, and nighttime snoring were evaluated, and cephalogram radiographs with and without the appliance were taken. It was found that the respiratory disturbance index decreased significantly; minimal oxygen saturation increased significantly, reaching a normal value; day time tiredness improved; snoring declined; the oral cavity anterior region increased significantly, and the pharyngeal airway passages did not change. Reduction in the respiratory disturbance index and enlargement of the anterior oral cavity area were highly and significantly correlated. In conclusion, the functional magnetic system is a reliable mandibular repositioning appliance that has no apparent adverse effects. A functional magnetic system operates by increasing the anterior region of the oral cavity, mainly vertically, with no change in the posterior oral cavity region and pharyngeal airway passages.

Analysis of the minimal amyloid-forming fragment of the islet amyloid polypeptide. An experimental support for the key role of the phenylalanine residue in amyloid formation.

The development of type II diabetes was shown to be associated with the formation of amyloid fibrils consisted of the islet amyloid polypeptide (IAPP or amylin). Recently, a short functional hexapeptide fragment of IAPP (NH(2)-NFGAIL-COOH) was found to form fibrils that are very similar to those formed by the full-length polypeptide. To better understand the specific role of the residues that compose the fragment, we performed a systematic alanine scan of the IAPP "basic amyloidogenic units." Turbidity assay experiments demonstrated that the wild-type peptide and the Asn(1) --> Ala and Gly(3) --> Ala peptides had the highest rate of aggregate formation, whereas the Phe(2) --> Ala peptide did not form any detectable aggregates. Dynamic light-scattering experiments demonstrated that all peptides except the Phe(2) --> Ala form large multimeric structures. Electron microscopy and Congo red staining confirmed that the structures formed by the various peptides are indeed amyloid fibrils. Taken together, the results of our study provide clear experimental evidence for the key role of phenylalanine residue in amyloid formation by IAPP. In contrast, glycine, a residue that was suggested to facilitate amyloid formation in other systems, has only a minor role, if any, in this case. Our results are discussed in the context of the remarkable occurrence of aromatic residues in short functional fragments and potent inhibitors of amyloid-related polypeptides. We hypothesize that pi-pi interactions may play a significant role in the molecular recognition and self-assembly processes that lead to amyloid formation.