Foot and leg problems are important determinants of functional status in community dwelling older people

Purpose.?To determine whether foot and leg problems are independently associated with functional status in a community sample of older people after adjusting for the influence of socio-demographic, physical and medical factors.

Method.?Data were analysed from the Health Status of Older People project, a population-based study involving a random sample of 1000 community-dwelling people aged 65?–?94 years (533 females, 467 males, mean age 73.4 years?±?5.87). A structured interview and brief physical examination were used to investigate the associations between self-reported foot and leg problems and functional status. Functional status was assessed using: (i) timed ‘Up & Go’ test, (ii) self-reported difficulty climbing stairs, (iii) self-reported difficulty walking one kilometer, (iv) self-reported difficulty performing instrumental activities of daily living (IADLs), and (v) self-reported history of one or more falls in the previous 12 months. These associations were then explored after adjusting for socio-demographic, physical and medical factors.

Results.?Thirty-six percent of the sample reported having foot or leg problems. Univariate analyses revealed that people with foot and leg problems were significantly more likely to exhibit poorer functional status in all parameters measured. After adjusting for socio-demographic, physical and medical factors, foot and leg problems remained significantly associated with impaired timed ‘Up & Go’ performance (OR?=?2.15, 95%CI 1.55?–?2.97), difficulty climbing stairs (OR?=?3.33, 95%CI 1.98?–?5.61), difficulty walking one kilometer (OR?=?3.13, 95%CI 2.09?–?4.69), and history of falling (OR?=?1.73, 95%CI 1.26?–?2.37).

Conclusions.?Foot and leg problems are reported by one in three community-dwelling people aged 65 years and older. Independent of the influence of age, gender, common medical conditions and other socio-demographic factors, foot and leg problems have a significant impact on the ability to perform functional tasks integral to independent living.     

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).     

Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein- 1 alpha

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha with improved solution properties. We show here that it mobilizes stem cells into the peripheral blood. We investigated the mobilizing effects of BB-10010 on the numbers of circulating 8-day spleen colony-forming units (CFU-S8), CFU-S12, and progenitors with marrow repopulating ability (MRA). A single subcutaneous dose of BB-10010 caused a twofold increase in circulating numbers of CFU-S8, CFU-S12, and MRA 30 minutes after dosing. We also investigated the effects of granulocyte colony-stimulating factor (G- CSF) and the combination of G-CSF with BB-10010 on progenitor mobilization. Two days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA progenitors by 25.7-, 19.8-, and 27.7-fold. A single administration of BB-10010 after 2 days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA even further to 38-, 33-, and 100- fold. Splenectomy resulted in increased circulating progenitor numbers but did not change the pattern of mobilization. Two days of treatment with G-CSF then increased circulating CFU-S8, CFU-S12, and MRA by 64-, 69-, and 32-fold. A single BB-10010 administration after G-CSF treatment further increased them to 85-, 117-, and 140-fold, respectively, compared with control. We conclude that BB-10010 causes a rapid increase in the number of circulating hematopoietic progenitors and further enhances the numbers induced by pretreatment with G-CSF. BB- 10010 preferentially mobilized the more primitive progenitors with marrow repopulating activity, releasing four times the number achieved with G-CSF alone. Translated into a clinical setting, this improvement in progenitor cell mobilization may enhance the efficiency of harvest and the quality of grafts for peripheral blood stem cell transplantation.     

Surface antigens on malignant Sezary and T-CLL cells correspond to those of mature T cells

Tumor cells from eight adult patients with T-cell chronic malignancies were investigated with a series of monoclonal antibodies recognizing T- cell differentiation antigens. This series allowed definition of discrete subpopulations of mature T cells with functional specialization. All six patients with Sezary syndrome and one patient with T-chronic lymphocytic leukemia had cells with the same phenotype as normal helper/inducer T cells, whereas the other patient with T- chronic lymphocytic leukemia had cell with the same phenotype as normal cytotoxic/suppressor T cells. Some clinical manifestations observed in these patients may reflect retention of functional activities by their malignant cells.     

Doppler velocimetry in prolonged pregnancy

Eighty-two patients at 287 days' gestation or longer were tested by nonstress test (NST), amnioscopy, ultrasound assessment of amniotic fluid volume, and Doppler velocimetry. Several maternal and fetal arteries were analyzed: uterine, umbilical, descending thoracic aorta, renal, and middle cerebral. During the study, other maternal-fetal functional indices were recorded: hPL, estriol, hematocrit, platelets, mean platelet volume, and uric acid. No abnormalities were found in the uterine, umbilical, middle cerebral, thoracic descending aorta, and renal artery velocimetry in post-dates gestations. However, a significant reduction of the time-averaged mean velocity in the descending thoracic aorta was associated with an increased incidence of oligohydramnios, meconium-stained fluid, abnormal NST, and cesarean delivery for fetal distress. The present study suggests that serial Doppler flow measurements of mean velocity of the fetal descending thoracic aorta may be a simple and rapid technique for identifying prolonged pregnancies at increased risk for perinatal complications.     

Sleeping position and sudden infant death syndrome (SIDS): effect of an intervention programme to avoid prone sleeping

The proportion of prone sleeping among sudden infant death syndrome (SIDS) victims and infants in general, and the rate of SIDS were prospectively studied in the county of Hordaland, Norway, three years before (1987–89) and three years after (1990–92) a campaign to discourage prone sleeping. Before the campaign, 64% of random reference infants were put prone versus 8% after (p < 0.0001). Concurrently, the rate of SIDS decreased from 3.5 to 1.6 per 1000 live births (63 infants before and 30 after the campaign, p = 0.0002). Prone sleeping was not considered a statistically significant risk factor for SIDS before (OR 2.0,95% CI 0.8–4.5), but was highly significant (OR 11.3,95% CI 3.6–36.5) after the campaign. Prone sleeping is an important risk factor for SIDS, but the association may be missed in epidemiological studies if prone is the predominant sleeping position. Behaviour with regard to sleeping position may be changed rapidly by means of a simple campaign.     

Acute rejection in the elderly recipient: Influence of age in the outcome of kidney transplantation

Since the immune response in older recipientsis weaker they should be less likely to rejecta transplanted organ and should need lessaggressive immunosuppressive treatment. Our aimwas to record the incidence and severity ofepisodes of acute rejection (AR), estimate theinfluence of these events on graft survival ofelderly recipients (60) and to comparethese with that in younger ones.We performed 363 kidney transplants between1/94 and 12/98, and recorded clinical andimmunological data, incidence-severity of ARand cause of graft loss. Patients were dividedinto two groups, according to the age attransplantation: A (<60, n = 281/77.4%) and B( 60, n = 82/22.6%). The percentage ofaging recipients and mean age of donors andrecipients increased throughout the period.Although the incidence of ATN was higher in theolder group (29% vs.19%, p < 0.0001) thenumber of graft biopsies was equal in bothgroups. The incidence of AR was similar, 33.4%vs. 26.8%, pNS. The number of AR episodes perpatient was 0.44 and 0.41 respectively. Theseverity of AR was: Banff grade I: A (40.3%)/B (45.7%) pNS; grade II: A (44.1%)/B(48.57) pNS; grade III: A (15.5%)/B (5.7%)pNS. Younger recipients presented a higherlevel of panel-reactive antibodies (PRA) (4.3%vs. 2.07%, p = 0.01). One-year patient survivalwas 96%/91% (p<0.05) and graft survivalwas 81%/78% (pNS) respectively.The age of recipient does not seem to haveinfluenced the incidence-severity of AR or thegraft survival. Thus immunosuppression shouldbe individualised for each patient and shouldnot depend on the age at transplantation.     

Enhanced phagemid particle gene transfer in camptothecin-treated carcinoma cells

Engineered phage-based vectors are an attractive alternative strategy for gene delivery because they possess no natural mammalian cell tropism and can be genetically modified for specific applications. Genotoxic treatments that increase the transduction efficiency of single-stranded adeno-associated virus were tested on cells transfected by single-stranded phage. Indeed, green fluorescent protein transgene expression by epidermal growth factor-targeted phagemid particles increased with heat shock, UV irradiation, and camptothecin (CPT) treatment. CPT resulted in transduction efficiencies of 30-45% in certain human carcinoma cell lines and reduced the minimal dose needed to detect green fluorescent protein-expressing cells to as low as 1-10 particles/cell. Targeted phage transduction was effective in many tumor cell lines and in prostate tumor xenografts with CPT treatment. Taken together, these data suggest the feasibility of using phage-based vectors for therapeutic gene delivery to cancer cells.     

Identification of the key amino acids of gliai cell line-derived neurotrophic factor family receptor alpha 1 involved in its biological function

Glial cell line-derived neurotrophic factor （GDNF） plays a critical role in neurodevelopment and survival of midbrain dopaminergic and spinal motor neurons in vitro and in vivo. The biological actions of GDNF are mediated by a two-receptor complex consisting of a glycosylphosphatidylinositol-linked cell surface molecule, the GDNF family receptor alpha 1 （GFR alpha 1）, and receptor protein tyrosine kinase Ret. Although structural analysis of GDNF has been extensively examined, less is known about the structural basis of GFR alpha 1 function. In this study, based on evolutionary trace method and relative solvent accessibility prediction of residues, a set of trace residues that are solvent-accessible was selected for site-directed mutagenesis. A series of GFR alpha 1 mutations was made, and PC12 cell lines stably expressing different GFR alpha 1 mutants were generated. According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNF- GFR alpha 1-Ret interaction assay, residues 152NN153, Arg259, and 316SNS318 in the GFR alpha 1 central region were found to be critical for GFR alpha 1 binding to GDNF and eliciting downstream signal transduction. The single mutation R259A in the GFR alpha 1 molecule simultaneously lost its binding ability to GDNF and Ret. However N152A/N153A or S316A/N317A/ S318A mutation in the GFR alpha 1 molecule still retained the ability to bind with Ret. These findings suggest that distinct structural elements in GFR alpha 1 may be involved in binding to GDNF and Ret.