Cognitive frailty is a condition recently defined by operationalized criteria describing the simultaneous presence of physical frailty and mild cognitive impairment (MCI). Two subtypes for this ...clinical construct have been proposed: "potentially reversible" cognitive frailty (physical frailty plus MCI) and "reversible" cognitive frailty (physical frailty plus pre-MCI subjective cognitive decline). Here the prevalence of a potentially reversible cognitive frailty model was estimated. It was also evaluated if introducing a diagnosis of MCI in older subjects with physical frailty could have an additive role on the risk of dementia, disability, and all-cause mortality in comparison with frailty state or MCI condition alone, with analyses separately performed for inflammatory state.
In 2,373 individuals from the population-based Italian Longitudinal Study on Aging with a 3.5-year-follow-up, we operationally categorized older individuals without dementia into four groups: non-frail/non-MCI, non-frail/MCI, frail/non-MCI, and frail/MCI.
The prevalence of potentially reversible cognitive frailty was 1%, increasing with age and more represented in women than in men, and all groups were associated with significant increased incident rate ratios of dementia, disability, and mortality. A significant difference in rates of disability has been found between the MCI and non-MCI groups (contrasts of adjusted predictions: 0.461; 95% confidence interval: 0.187-0.735) in frail individuals with high inflammatory states (fibrinogen >339 mg/dL).
In older individuals without dementia and with elevated inflammation, a potentially reversible cognitive frailty model could have a significant additional predictive effect on the risk of disability than the single conditions of frailty or MCI.
We performed 31 friction experiments on glassy basalts (GB) and glass‐free basalts (GFB) at slip rates up to 6.5 m s−1 and normal stress up to 40 MPa (seismic conditions). Frictional weakening was ...associated to bulk frictional melting and lubrication. The weakening distance (Dw) was about 3 times shorter in GB than in GFB, but the steady state friction was systematically higher in GB than in GFB. The shorter Dw in GB may be explained by the thermal softening occurring at the glass transition temperature (Tg ~500°C), which is lower than the bulk melting temperature (Tm ~1250°C) of GFB. Postexperiment microanalyses suggest that the larger crystal fraction measured in GB melts results in the higher steady state friction value compared to the GFB melts. The effect of interstitial glass is to facilitate frictional instability and rupture propagation in GB with respect to GFB.
Key Points
First experiments on basalts at seismic slip rates
Interstitial glass renders the basalts more prone to frictional instabilities
Interstitial glass in basalts increases the steady‐state friction
Occupational focal upper-limb dystonia is characterized by involuntary muscle contractions that selectively interfere with the execution of specific motor tasks such as writing or playing a musical ...instrument. Occupational dystonias have a severe social impact, especially in certain professions. The available medical treatments offer little benefit.
In eight patients with idiopathic occupational focal dystonia of the upper limb, the dystonic forearm and hand were immobilized with a plastic splint for mean (+/-SD) 4.5 +/- 0.75 weeks. Before splinting (base line) and at various intervals afterwards (4, 12, and 24 weeks), the authors assessed the severity of dystonia and the patients' motor performance objectively (Arm Dystonia Disability Scale and Tubiana and Chamagne Score) and subjectively (Self-Rating Score).
Assessment 4 weeks after splint removal, when patients had regained normal voluntary movements, showed that the severity of dystonia and the patients' performance of the impaired motor task had improved; the benefit persisted unchanged at later follow-up visits (Arm Dystonia Disability Scale: base line 20.6 +/- 30.2%; after 4 weeks 83.9 +/- 23.8%, p = 0.007; after 12 weeks 83.9 +/- 23.8%, p = 0.007; after 24 weeks 79.7 +/- 29.5%, p = 0.015. Tubiana and Chamagne Score: base line 28.6 +/- 22.7%; after 4 weeks 80.0 +/- 23.1%, p = 0.015; after 12 weeks 80.0 +/- 23.1%, p = 0.015; after 24 weeks 74.3 +/- 32.1%, p = 0.031. Self-Rating Score: base line 20.6 +/- 19.3%; after 4 weeks 63.7 +/- 25.2%, p = 0.015; after 12 weeks 66.9 +/- 28.1%, p = 0.015; after 24 weeks 70.6 +/- 31.8%, p = 0.015). At the 24-week visit the improvement disappeared in one patient, was moderate in three, and marked in four.
Limb immobilization can be a simple, effective, safe, and inexpensive treatment for focal occupational upper-limb dystonia.
To study the association of estrogen-replacement therapy and other estrogen-related variables with Alzheimer's disease in postmenopausal women.
Postmenopausal estrogen use has been reported to lower ...the risk of Alzheimer's disease.
A population-based, multicenter survey was carried out in eight Italian municipalities. The sample of 2,816 women, aged 65 to 84 years, was randomly selected from the population register of each municipality and stratified in 5-year age groups. All women were screened using the Mini-Mental State Examination and interviewed concerning risk factors. Those who screened positive underwent a clinical assessment. Dementia syndrome was diagnosed according to DSM-III-R criteria, and Alzheimer's disease was diagnosed according to NINCDS-ADRDA criteria for possible and probable Alzheimer's disease.
The estimated prevalence of postmenopausal estrogen use adjusted to the 1991 Italian female population was 12.3%. The frequency of estrogen use was higher among nonpatients compared with Alzheimer's disease patients (odds ratio, 0.24; 95% confidence interval, 0.07 to 0.77). The inverse association between estrogen therapy and Alzheimer's disease remained significant after adjustment for age, education, age at menarche, age at menopause, smoking and alcohol habits, body weight at the age of 50 years, and number of children (odds ratio, 0.28; 95% confidence interval, 0.08 to 0.98).
Our data from a population-based study support the hypothesis that estrogen-replacement therapy is associated with a reduced prevalence of Alzheimer's disease in postmenopausal women. Prospective clinical trials are required to enable women and their physicians to weigh risks and benefits of estrogen-replacement therapy for the prevention of dementia.
The genes responsible for insulin resistance are poorly defined. Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance. ...We describe here a novel polymorphism in exon 4 of the PC-1 gene (K121Q) and demonstrate that it is strongly associated with insulin resistance in 121 healthy nonobese (BMI <30 kg/m2) nondiabetic (by oral glucose tolerance test OGTT) Caucasians from Sicily. Compared with 80 KK subjects, Q allele carriers (n = 41, 39 KQ and 2 QQ) showed higher glucose and insulin levels during OGTT (P < 0.001 by two-way analysis of variance) and insulin resistance by euglycemic clamp (M value = 5.25 +/- 1.38 n = 24 vs. 6.30 +/- 1.39 mg x kg(-1) x min(-1) n = 49, P = 0.005). Q carriers had higher risk of being hyperinsulinemic and insulin resistant (odds ratio CI: 2.99 1.28-7.0, P < 0.001). Insulin receptor autophosphorylation was reduced (P < 0.01) in cultured skin fibroblasts from KQ versus KK subjects. Skeletal muscle PC-1 content was not different in 11 KQ versus 32 KK subjects (33 +/- 16.1 vs. 17.5 +/- 15 ng/mg protein, P = 0.3). These results suggest a cause-effect relationship between the Q carrying genotype and the insulin resistance phenotype, and raise the possibility that PC-1 genotyping could identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes and coronary artery disease.
Sulfatides have been established recently as ligands for L-selectin, and we investigated whether they trigger transmembrane
signals through ligation of L-selectin. We found that sulfatides trigger ...the increase of cytosolic free calcium in neutrophils
and that this effect was strictly dependent on sulfation of the galactose ring, as non-sulfated galactocerebrosides were not
stimulatory. Chymotrypsin and phorbol 12-myristate 13-acetate treatment of neutrophils caused shedding of L-selectin, but
not of class I major histocompatibility complex antigens or beta 2 integrins, and blunted the capability of neutrophils to
respond to sulfatides with an increase of cytosolic free calcium. Four different anti-L-selectin antibodies (DREG-200, LAM1/3,
LAM1/6, and LAM1/10), but not four control antibodies directed against different surface molecules of neutrophils, also triggered
an increase of cytosolic free calcium. The anti-L-selectin antibodies were stimulatory both if used in a soluble form, after
cross-linking with anti-mouse F(ab')2 fragments, and immobilized to protein A of Staphylococcus aureus through the Fc fragment.
With immobilized antibodies, an increase of cytosolic free calcium was found also by plating neutrophils on antibodies bound
to protein A-coated coverslips and monitoring the increase of cytosolic free calcium by fluorescence microscopy. Both sulfatides
and anti-L-selectin antibody effects were not inhibited by pertussis toxin, thus indicating that a pertussis toxin-sensitive
GTP-binding protein was not involved in signal transduction. Sulfatides also triggered an increase of tumor necrosis factor-alpha
and interleukin-8 mRNAs in neutrophils. Also to act as stimuli of cytokine mRNA expression, sulfatides required sulfation
of the galactose ring, as non-sulfated galactocerebrosides were not stimulatory, and depended on expression of L-selectin,
as shedding of this molecules induced by chymotrypsin blunted their effects. These findings suggest that L-selectin can transduce
signals activating selective cell function.
Objective: To determine whether patients with clinically typical multifocal motor neuropathy (MMN) with or without definite or probable conduction block (CB) differ in terms of clinical presentation, ...immunological findings, or response to treatment with intravenous immunoglobulin (IVIg). Methods: 23 consecutive patients were studied with the typical clinical features of MMN, consisting of a progressive multineuropathic motor impairment with minimal or no sensory loss. In 14 patients, electrophysiological studies disclosed the presence of a definite or probable CB according to the criteria proposed by the American Association of Electrodiagnostic Medicine (AAEM) in at least one motor nerve. Six patients had possible CB, defined as a degree of CB 10% less than that required by the AAEM for probable CB, while no CB was detected in three patients. Results: Patients with possible CB did not differ from those with a definite or probable CB in terms of age at disease onset (mean 38.8 v 38.2 years, respectively), distribution and severity of limb weakness, clinical impairment (mean Rankin score 2.2 in both), and frequency of antiganglioside antibodies (33% v 29%). Patients with possible CB had a longer mean disease duration (9 v 5.9 years, p < 0.05) and a less frequent consistent response to IVIg (67% v 86%) than those with a definite or probable CB. Patients without a detectable CB had a similar frequency of antiganglioside antibodies (33%) but had a longer disease duration (20.3 years), greater impairment (Rankin score 2.7), and more frequent signs of axonal degeneration (41% of examined motor nerves) than patients with CB (13–15%, p < 0.005). Only one patient without detectable CB (33%) consistently improved with IVIg. Conclusions: Patients with possible CB were clinically and immunologically indistinguishable from those with definite or probable CB, albeit with a slightly less frequent response to IVIg. This finding suggests that failure to fulfil AAEM criteria for CB in patients with otherwise clinically typical MMN should not preclude this diagnosis and consequently a treatment trial with IVIg. Whether the longer duration and greater severity of the disease and more frequent axonal impairment in patients without detectable CB than in those with CB explain their lower response to IVIg remains to be established.
Bone marrow (BM) transplantation in mice suggests the existence of pluripotent cells able to differentiate into skeletal muscle tissue, although sustained myofiber reconstitution has not yet been ...achieved. We investigated the myogenic potential of mouse BM cells and evaluated whether a BM fraction enriched for cells expressing skeletal muscle markers would ameliorate muscle repair, when compared to whole BM, into the dystrophic
mdx mouse. We demonstrate that cells expressing striated-muscle-specific proteins are already present in the BM independently from experimentally forced myogenic conversion. We observed the presence of both markers of early myogenic program such as Pax3, Myf5, MyoD, desmin, and late myogenesis such as myosin heavy chain and α-sarcomeric actin. These myogenic cells are more represented in the early nonadherent BM fraction, which generates clones able to fully differentiate into myotubes. Transplantation in
mdx mice by intravenous injection of whole BM and a tenfold BM myogenic enriched fraction resulted in BM reconstitution and limited dystrophin restoration. Taken together, these data show that a fraction of BM cells have a definite potential for differentiation along the skeletal muscle pathway and can be recruited by muscle repair mechanisms. They also indicate that factors limiting the degree of muscle recruitment and the host stem cell competition should be assessed in order to evaluate the usefulness of BM-derived myogenic cells into the context of cell-mediated gene therapy of inherited muscle diseases.
Autosomal dominant progressive external ophthalmoplegia (adPEO) is caused by mutations in at least three different genes: ANT1 (chromosome 4q34-35), TWINKLE, and POLG. The ANT1 gene encodes the ...adenine nucleotide translocator-1 (ANT1). We identified a heterozygous T293C mutation of the ANT1 gene in a Greek family with adPEO. The resulting leucine to proline substitution likely modifies the secondary structure of the ANT1 protein. ANT1 gene mutations may account for adPEO in families with different ethnic backgrounds.
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