Influence of Frailty Status on Pain, Disability, and Quality of Life in Older Adults with Acute Low Back Pain: Results from the Back Complaints in the Elders (BACE-Brazil) Study.

A cross-sectional analysis was conducted using data from a prospective cohort study to investigate whether frailty is associated with pain intensity, disability caused by low back pain (LBP), and quality of life in an older population with acute non-specific LBP. Six hundred and two individuals with a mean age of 67.6 (standard deviation [SD] 7.0) years were included in the analysis. In relation to frailty status, 21.3 per cent of the sample were classified as robust, 59.2 per cent were classified as pre-frail, and 19.5 per cent were classified as frail. In the unadjusted analysis, pre-frail and frail groups showed significantly higher pain and disability scores than the robust group. Moreover, the same two groups exhibited lower scores in both physical and mental domains of quality of life than the robust group. After adjusting for socio-demographic and clinical variables, disability scores and the physical component of quality of life were significantly associated with frailty. In older adults with acute LBP, frailty is associated with more disability and worse scores in the physical component of quality of life.

Handgrip Strength Cutoff Points to Identify Mobility Limitation in Community-dwelling Older People and Associated Factors.

BACKGROUND: Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass and strength. The specific threshold of muscle weakness that leads to mobility limitations has not been identified. OBJECTIVES: To determine the best cutoff point of handgrip strength for identifying mobility limitation and to investigate the factors associated with muscle weakness and mobility limitation in community-dwelling older people. DESIGN: Transversal study. SETTING: Cities of Belo Horizonte, Barueri and Santa Cruz in Brazil. PARTICIPANTS: 1374 community-dwelling older people from the Frailty study in Brazilian older people (FIBRA Study). MEASUREMENTS: Outcomes included muscle weakness determined according to gender-specific handgrip strength cutoff points generated by Receiver Operating Characteristic curves, mobility limitation defined as a gait speed ≤ 0.8 m/s; and a combination of both muscle weakness and mobility limitation. Associated factors included socio-demographic variables, lifestyle, anthropometrics, health conditions, use of health services and disability. RESULTS: The cutoff points of handgrip strength with the best balancing between sensitivity and specificity for mobility limitation were 25.8 kgf for men (sensitivity 69%, specificity 73%) and 17.4 kgf (sensitivity 60%, specificity 66%) for women. Age and disability in instrumental activities of daily living were associated with all outcomes. Women had greater odds of mobility limitation than men. Physical inactivity, body fat, diabetes, depression, sleeping disturbances, number of medications and occurrence of falls remained as significant associated factors in the final model. CONCLUSIONS: Handgrip strength can be a useful tool to identify mobility limitation in clinical practice. Interventions to prevent or minimize impacts of sarcopenia should stimulate physical activity and improvement of body composition in addition to the management of chronic diseases and disabilities.

Decreased platelet glutamate uptake in patients with amyotrophic lateral sclerosis.

Decreased glutamate uptake and a loss of the astrocytic glutamate transporter EAAT2 (GLT-1) have been shown in spinal cord and motor cortex of patients with ALS. Because platelets express the three major glutamate transporter subtypes, including GLT-1, and possess a high-affinity glutamate uptake, the authors investigated glutamate uptake in platelets from patients with ALS and controls. A 43% reduction of high-affinity glutamate uptake rate (p < 0.0001) was observed in patients with ALS compared with normal controls and chronic neurologic disorder patients, suggesting a systemic impairment of glutamate uptake in ALS.

The imbalance of brain large-chain aminoacid availability in amyotrophic lateral sclerosis patients treated with high doses of branched-chain aminoacids.

Following the report of an increased mortality among patients with amyotrophic lateral sclerosis given high daily doses of branched-chain aminoacids, we assessed the plasma concentrations of large neutral aminoacids and glutamic acid and the large neutral aminoacid brain influx in 24 amyotrophic lateral sclerosis patients receiving placebo or branched-chain aminoacids (L-leucine 12 g, L-isoleucine 6 g, L-valine 6 g daily), in 15 untreated amyotrophic lateral sclerosis patients and in 15 healthy volunteers. The branched-chain aminoacid plasma concentrations increased three- to six-fold in the treated group compared to the patients receiving placebo or no treatment and to the healthy controls. Plasma glutamic acid concentrations in healthy volunteers were 51.59 +/- 7.53 nmol/ml while in the amyotrophic lateral sclerosis patients receiving no treatment, placebo or branched-chain aminoacids were 92.33 +/- 12.15 nmol/ml, 91.21 +/- 15.86 nmol/ml and 95.08 +/- 17.96 nmol/ml respectively. The glutamic acid concentration was significantly higher (P < 0.01) in amyotrophic lateral sclerosis patients than in healthy individuals. Plasma phenylalanine and tyrosine were lower in the amyotrophic lateral sclerosis patients than in healthy controls, regardless of treatment, whereas tryptophan levels were not significantly different. The branched-chain aminoacid brain influx of the treated group was 110-140% of that measured in the patients receiving placebo and in the healthy controls. The aromatic aminoacid brain influx was lower in the treated group than in the placebo group or healthy controls. An impairment of brain large neutral aminoacid availability might possible contribute to enhancing the progression of symptoms in patients with amyotrophic lateral sclerosis.

Glutamate transporters in the spinal cord of the wobbler mouse.

We studied the role of glutamate excitotoxicity in motor neuron degeneration in the wobbler mouse (wr/wr), a model of amyotrophic lateral sclerosis and spinal muscular atrophies. Choline acetyltransferase (ChAT) activity was decreased in the cervical spinal cord and in the muscles innervated by nerves originating in this region of wobbler mice, but no differences were found in the lumbar spinal cord and in the hindleg muscles. Glial fibrillar acid protein (GFAP), a marker of reactive gliosis, was significantly higher in the cervical spinal cord of wobbler mice aged 4 weeks than in controls and the differences were more marked at 12 weeks; no differences were found in the lumbar spinal cord. In spite of this selective degeneration of motor neurons (resulting in strong decrease in the neuronal glutamate transporter EAAC1) and reactive gliosis in the cervical spinal cord, the levels of the glial glutamate transporter proteins GLT-1 and GLAST were similar in wobbler and control mice. Plasma concentrations of excitatory amino acids were no different at any time examined. Our results exclude the involvement of decrease in glutamate GLT 1 transporter in the motor neuron degeneration in wobbler mice.

Experimental beta beta'-iminodipropionitrile (IDPN) neuropathy: neurofilament profile of sensory, motor and autonomic nerves as seen by immunocytochemistry on whole-mount preparations.

IDPN-induced changes in a variety of sensory, motor and autonomic nerves were studied by whole-mount immunocytochemistry. A full range of proximo-distal accumulations of neurofilament-like material was found, from paranuclear round bodies in perikarya to distal and preterminal axonal dilations. Conversely, both terminal areas and nodal-paranodal regions of myelinated axons showed striking, sharply localized loss of neurofilament-immunostaining. The latter change, when transport of neurofilaments is halted by IDPN, may indicate their local processing and/or differential transport at nodal-paranodal regions.

2,5-Hexanedione-induced accumulations of neurofilament-immunoreactive material throughout the rat autonomic nervous system.

In rats intoxicated with 2,5-hexanedione, nerve fibres supplying virtually all visceral organs showed large numbers of densely immunoreactive accumulations of neurofilament-like material, of fusiform, elongated, smoothly tapering morphology. In the gut, round to oval, morphologically different lesions were also present, and abnormal neurofilament-immunoreactive accumulations were revealed in oesophageal terminal end-plates. An extensive damage to autonomic nerve fibres, which are largely non-myelinated, was thus revealed in 2,5-hexanedione intoxication. The observed diversity in lesion morphology may suggest heterogeneity in cytoskeletal and/or associated proteins among autonomic neurons.

[3H](+)-pentazocine binding to rat brain sigma 1 receptors.

[3H](+)-Pentazocine binding has been characterized in the rat brain. It binds to a single population of binding sites with affinity of about 7 nM and density of 280 fmol/mg protein. [3H](+)-Pentazocine binding is not enriched in the crude synaptic membrane, being about 1/6 of what we found in the crude membrane preparation. The binding, like that for other sigma ligands, was enriched in the microsomal and nuclear fractions. The inhibition by haloperidol, proadifen and d-fenfluramine was the same in the crude synaptic membrane, nuclear and microsomal fractions, suggesting that [3H](+)-pentazocine binds to a homogeneous protein in the different subcellular fractions. Our pharmacological characterization using 45 different drugs suggests that the [3H](+)-pentazocine binding site in rat brain differs from other sigma ligands, like N-propyl-3-(3-hydroxyphenyl)piperidine ([3H](+)-3PPP), N,N'-di(o-tolyl)guanidine ([3H]DTG) and (+)-N-allylnormetazocine ([3H](+)-SKF10,047). [3H](+)-Pentazocine binding in rat brain is inhibited by sigma compounds and some cytochrome P450 ligands, like proadifen and 1-[2-[bis(4-fluoro-phenyl) methoxy]ethyl]-4-[3-phenylpropyl] piperazine (GBR 12909), although with considerably lower potency than reported for other sigma ligands. Other inhibitors are some serotonin uptake blockers or their metabolites and phenylalkylamines.

Extracellular glutamate levels in the hypothalamus and hippocampus of rats after acute or chronic oral intake of monosodium glutamate.

Using brain microdialysis we studied the effect of high doses of monosodium glutamate (MSG) on the extracellular concentration of glutamate in the hypothalamus and in the hippocampus of freely moving rats. MSG at 4 g/kg (40% solution) given by gavage caused a significant increase in plasma (5.3 +/- 0.4-fold, P < 0.01) and extracellular glutamate in the hippocampus (4.2 +/- 0.6-fold, P < 0.01) and in the hypothalamus (8.9 +/- 1.7-fold, P < 0.01) compared to control rats receiving a 40% sucrose solution (10 ml/kg). The peak increase was found within 40 min after MSG administration then declining to baseline in the next 80 min. No changes were found in glutamate tissue concentrations. Twenty-one days after ad libitum MSG intake with the diet (approximately 4 g/kg) no changes were found, in plasma, in extracellular and tissue concentration of glutamate in the hypothalamus compared to rats fed with a normal diet. Glutamate release induced by 200 mM KCl was not modified as well. Histological analysis of Nissl-stained brain tissue slices did not reveal any obvious cell loss in the hippocampus after acute or chronic MSG administration.

Spinal cord GLT-1 glutamate transporter and blood glutamic acid alterations in motor neuron degeneration (Mnd) mice.

This study characterizes for the first time neurochemical mechanisms in Mnd mice, initially described as a model of motor neuron disease and more recently proposed as a model for neuronal ceroid lipofuscinosis. A selective decrease (-30%) of [3H]glutamate uptake was found in spinal cord but not cortical synaptosomes of Mnd mice aged 28 weeks, when they show histopathological alterations, complete blindness and moderate neurological deficits. In spite of the widespread presence of stored material in neurons in many brain regions and spinal cord, the active transport of [3H]serotonin, [3H]dopamine and depolarization-induced [3H]serotonin release were not affected. Spinal EAAC1 glutamate transporter protein was significantly decreased in some but not all aged mice by 36% on average, possibly due to the loss of motor neurons. GLT-1 immunoreactivity was reduced by 34% in 28-week-old Mnd mice, while GLAST immunoreactivity was not affected. In Mnd mice aged 14 weeks, when there was no apparent alteration of motor function, the defect in the glial transporter protein GLT-1 was similar to that in 28-week-old mice (25%). Blood glutamic acid concentration was increased in Mnd mice aged 14-22 weeks. We suggest that the early decrease of GLT-1 protein might raise the extrasynaptic glutamic acid concentration, and contribute to the loss of motor neurons in affected mice, resulting in low [3H]glutamate uptake, low EAAC1 immunoreactivity and neurological deficits.

Effects of 2,5-hexanedione on the ovary and fertility. An experimental study in mice.

Sixty-day-old virgin female Swiss CD1 mice were treated with 1.5% 2,5-hexanedione in their drinking water; control mice received tap water; duration of treatment was either 4 or 6 weeks. Under these conditions the treated mice did not show any clinical symptoms although electromyography revealed some signs of polyneuropathy. Protein and DNA content per mg of ovarian tissue in treated mice were not significantly different from controls. Histological examination of ovarian sections at the light microscope level showed no significant alterations after exposure. A morphometric study revealed a statistically significant reduction in the number of growing oocytes after 6 weeks of treatment. For fertility studies three groups of 15 female mice each were treated for 0, 4 or 6 weeks as above and then permanently housed with untreated proven breeder male mice (one male per female); cages were checked daily for newly born mice. All litters appeared normal by gross examination. During the first 14 weeks of continuous mating the mean litter size (number of newborns per litter) remained about 11.4 in all groups; this number subsequently began to decrease. Control and 4-week treatment regression curves did not differ statistically, while the slope of the 6-week line was significantly steeper, indicating a faster decrease in litter size over time and a shortening of fertile life in the latter group of treated females.

Metabolism of caffeine to 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil in the isolated, perfused liver from control or phenobarbital-, beta-naphthoflavone- and 3-methylcholanthrene-pretreated rats.

Caffeine metabolism to 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil was studied in the isolated, perfused rat liver. The [2-14C]-labelled drug and metabolites were separated by thin-layer chromatography or high-pressure liquid chromatography. The chemical structure of 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil was confirmed by mass spectrometry and it was quantitatively determined by liquid scintillation counting. 6-Amino-5-[N-methylformylamino]-1,3-dimethyluracil is one of the major metabolites of caffeine found in the perfusion medium. The kinetics of caffeine elimination and of the uracil metabolite formation were studied up to 2 h perfusion time using livers from control rats and rats pretreated with phenobarbital, beta-naphthoflavone or 3-methylcholanthrene. Phenobarbital pretreatment did not modify the rate of caffeine elimination or the extent of 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil formation. In contrast, there was a highly significant inducing effect on both drug elimination and formation of the uracil metabolite in perfusions of livers from beta-naphthoflavone- and 3-methylcholanthrene-pretreated animals.

Normalization of idiopathic arterial hypertension following cancer immunotherapy with interleukin-2.

It is known that IL-2 cancer immunotherapy is associated with hypotension. The present study was performed to evaluate the influence of low-dose IL-2 subcutaneous therapy on blood pressure in cancer patients with idiopathic hypertension requiring hypotensive therapy. The study included 12 patients, who received IL-2 at 6 million IU/day for at least 4 weeks. Mean values of both systolic and diastolic pressure significantly decreased under IL-2 therapy, and the hypotensive agents were interrupted within 2 weeks in 10/12 patients. Moreover, 6 of them still showed normal blood pressure values without hypotensive therapy after a median follow-up of 6 months. This preliminary study would suggest that low-dose IL-2 subcutaneous therapy may normalize blood pressure values in cancer patients with idiopathic hypertension.

Quality problems in waters used for drinking purposes in Italy.

With a grant from the Italian Ministry of the Environment, the National Institute of Health (Istituto Superiore di Sanità) promoted and coordinated some activities aimed at determining the extent and the intensity of contamination of waters used for human consumption by some chemical agents, and describing causes and modalities of contamination and human health implications. The chemical agents examined were herbicides, nitrates, trihalomethanes, asbestos, manganese and fluoride. In this paper a first nationwide picture of these problems is reported.

Cholinesterases in blood plasma and tissues of rats treated with n-hexane or with its neurotoxic metabolite 2,5-hexanedione.

Adult male rats were subjected to 4 weeks' respiratory treatment with n-hexane (5000 ppm, 16h/day, 6 days/week); motor conduction velocity was significantly decreased in tail nerves at all weekly intervals and did not approach normal values in the 4 weeks following interruption of treatment. Plasma acetylcholinesterase (AChE) levels were significantly increased at all weekly intervals during treatment (25-40%); 2 weeks after the end of treatment they had returned to baseline. Oral treatment with 2,5-hexanedione (HD) (1% in drinking water) caused a similar increase in plasma levels; this increase was statistically significant also when compared with pair-fed (PF) control rats. A sucrose density gradient analysis showed only one peak of AChE activity at approximately 10 S (as in normal plasma). The levels of butyrylcholinesterase were unaltered in plasma of both n-hexane-and HD-treated rats. Both the fast-contracting EDL and the slow-contracting soleus muscles lost weight in HD-treated rats with respect to free-fed (AL) and PF controls. AChE levels responded differently to HD treatment in the two muscle types: in EDL total extracts, AChE activity increased considerably with respect to AL controls (+ 70%, p less than 0.001), while the levels of the 16 S and 4 S molecular forms were unaltered. The increased levels of AChE found in plasma of rats intoxicated with n-hexane or with its metabolite HD may originate from muscle and correspond to an increased secretion of this molecular form.

Determination of argininosuccinate lyase and arginase activities with an amino acid analyzer.

The measurement of argininosuccinate lyase (ASase) and arginase, both in liver and erythrocytes, was developed by using a commercial amino acid analyzer. The method is based upon the use of two different substrates, argininosuccinate and arginine for ASase and arginase, respectively, and the measurement of only one final metabolite: ornithine. The use of ornithine as a marker of biological activity of ASase is related to the fact that in the urea cycle, the specific activity of arginase is much higher than that of ASase; thus, during in vitro determinations, arginine, which is the product of ASase, is rapidly converted to ornithine. The sensitivity of the methods is very high since we were able to detect both activities using very diluted rat liver homogenates (0.10 mg protein/ml) or few microliters of human blood. In rat liver the Vmax for ASase and arginase were respectively 0.54 and 140 mumol/h/mg protein; the apparent Km values 1.25 and 13.5 mM. In human erythrocytes the Vmax for the same enzymes were 7.2 and 170 nmol/h/mg Hb and the apparent Km values were 0.66 and 9.5 mM. In 10 healthy volunteers the specific activity of ASase and arginase determined in blood were respectively 8.60 +/- 0.46 and 124.1 +/- 14.5 nmol/h/mg Hb. The results obtained from 2 patients suffering from argininosuccinic aciduria were also reported. In these latter cases while ASase was not detectable in blood, arginase activity was at the lowest end of the confidence limits determined in healthy volunteers.

Prevalência do medo de cair em uma população de idosos da comunidade e sua correlação com mobilidade, equilíbrio dinâmico, risco e histórico de quedas / Prevalence of fear of falling among a population of older adults and its correlation with mobility, dynamic balance, risk and history of falls

OBJETIVOS: Investigar a prevalência do medo de cair em uma população de idosos da comunidade e sua correlação com mobilidade, equilíbrio dinâmico, risco e histórico de quedas. MÉTODOS: Estudo transversal randomizado. Participaram do estudo 147 idosos com idades entre 60 e 92 anos, sendo 94 (65,95 por cento) mulheres e 53 (36,05 por cento) homens. O medo de cair foi avaliado usando FES-I-BRASIL (FIB), a mobilidade foi avaliada por meio do teste "Timed Up and go" (TUG), o risco de quedas, por meio do "Functional Reach Test" (FRT) e o equilíbrio dinâmico, pelo teste da Marcha Tandem (MT). RESULTADOS: Cento e trinta e três (90,48 por cento) idosos relataram medo de cair em pelo menos uma atividade, e 80 (54,42 por cento) dos idosos apresentaram histórico de quedas (HQ). A correlação de Pearson demonstrou resultado significante (p<0,001) do medo de cair com MT (r=-0,44248), FRT (r=-0,51562), HQ (r=0,54069), TUG (r=0,45738) e idade (r=0,39772). CONCLUSÕES: O presente estudo identificou alta prevalência de medo de cair nos idosos da comunidade, independente do HQ, e correlação significativa do medo de cair com mobilidade, equilíbrio dinâmico, risco e HQ.

OBJECTIVES: To investigate the prevalence of fear of falling among a population of older adults and its correlation with mobility, dynamic balance, risk and history of falls. METHODS: This was a randomized cross-sectional study. The participants were 147 older adults between the ages of 60 and 92: 94 women (65.95 percent) and 53 men (36.05 percent). Fear of falling was assessed using FES-I-BRAZIL (FIB); mobility, using the "timed up and go" (TUG) test; risk of falls, using the "functional reach test" (FRT); and dynamic balance, using the "tandem gait test"(TGT). RESULTS: One hundred and thirty-three older adults (90.48 percent) reported fear of falling in at least one activity and 80 older adults (54.42 percent) had a history of falls (HF). Pearson's correlation was statistically significant (p<0.001) between fear of falling and the TGT (r=-0.44248), FRT (r=-0.51562), HF (r=0.54069), TUG (r=0.45738) and age (r=0.39772). CONCLUSIONS: The present study identified high prevalence of fear of falling among older adults in the community, independent of their history of falls, and significant correlations between fear of falling and mobility, dynamic balance, risk and history of falls.

The clinical significance of melatonin serum determination in oncological patients and its correlations with GH and PRL blood levels.

In order to investigate the pineal function and its relation with the hypophysis in human neoplasms, melatonin and GH serum levels were determined in 63 patients, 42 affected by solid tumours and 21 by lymphoma or leukaemia. In women with breast cancer PRL was also measured. Melatonin, GH and PRL were evaluated in 52 healthy subjects acting as controls. The oncological patients showed significantly higher mean melatonin serum levels than the control subjects. Mean melatonin values were lower in patients with solid tumours who had metastases, than in cases without metastases. Chemotherapy caused an evident decrease in melatonin levels. Surgery was followed by a fall in melatonin in patients without metastases. Mean GH serum levels observed in oncological patients were similar to those in control subjects and were not influenced by therapy. PRL levels were within the normal range in women suffering from breast cancer.

Purification of the aldehyde oxidase homolog 1 (AOH1) protein and cloning of the AOH1 and aldehyde oxidase homolog 2 (AOH2) genes. Identification of a novel molybdo-flavoprotein gene cluster on mouse chromosome 1.

We report the cloning of the AOH1 and AOH2 genes, which encode two novel mammalian molybdo-flavoproteins. We have purified the AOH1 protein to homogeneity in its catalytically active form from mouse liver. Twenty tryptic peptides, identified or directly sequenced by mass spectrometry, confirm the primary structure of the polypeptide deduced from the AOH1 gene. The enzyme contains one molecule of FAD, one atom of molybdenum, and four atoms of iron per subunit and shows spectroscopic features similar to those of the prototypic molybdo-flavoprotein xanthine oxidoreductase. The AOH1 and AOH2 genes are 98 and 60 kilobases long, respectively, and consist of 35 coding exons. The AOH1 gene has the potential to transcribe an extra leader non-coding exon, which is located downstream of exon 26, and is transcribed in the opposite orientation relative to all the other exons. AOH1 and AOH2 map to chromosome 1 in close proximity to each other and to the aldehyde oxidase gene, forming a molybdo-flavoenzyme gene cluster. Conservation in the position of exon/intron junctions among the mouse AOH1, AOH2, aldehyde oxidase, and xanthine oxidoreductase loci indicates that these genes are derived from the duplication of an ancestral precursor.

Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels.

Glutamate-induced excitotoxicity is suggested to play a central role in the development of amyotrophic lateral sclerosis (ALS), although it is still unclear whether it represents a primary cause in the cascade leading to motor neurone death. We used western blotting, immunocytochemistry and in situ hybridization to examine the expression of GLT-1 in transgenic mice carrying a mutated (G93A) human copper-zinc superoxide dismutase (TgSOD1 G93A), which closely mimic the features of ALS. We observed a progressive decrease in the immunoreactivity of the glial glutamate transporter (GLT-1) in the ventral, but not in the dorsal, horn of lumbar spinal cord. This effect was specifically found in 14- and 18-week-old mice that had motor function impairment, motor neurone loss and reactive astrocytosis. No changes in GLT-1 were observed at 8 weeks of age, before the appearance of clinical symptoms. Decreases in GLT-1 were accompanied by increased glial fibrillary acidic protein (GFAP) levels and no change in the levels of GLAST, another glial glutamate transporter. The glutamate concentration in the cerebrospinal fluid (CSF) of TgSOD1 G93A mice was not modified at any of the time points examined, compared with age-matched controls. These findings indicate that the loss of GLT-1 protein in ALS mice selectively occurs in the areas affected by neurodegeneration and reactive astrocytosis and it is not associated with increases of glutamate levels in CSF. The lack of changes in GLT-1 at the presymptomatic stage suggests that glial glutamate transporter reduction is not a primary event leading to motor neurone loss.