Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections.

The objective of this study was to document pan-European real-world treatment patterns and healthcare resource use and estimate opportunities for early switch (ES) from intravenous (IV) to oral antibiotics and early discharge (ED) in hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infections (cSSTIs). This retrospective observational medical chart review study enrolled 342 physicians across 12 European countries who collected data from 1542 patients with documented MRSA cSSTI who were hospitalized (July 2010 to June 2011) and discharged alive (by July 2011). Data included clinical characteristics and outcomes, hospital length of stay (LOS), MRSA-targeted IV and oral antibiotic use, and ES and ED eligibility according to literature-based and expert-validated criteria. The most frequent initial MRSA-active antibiotics were vancomycin (50.2%), linezolid (15.1%), clindamycin (10.8%), and teicoplanin (10.4%). Patients discharged with MRSA-active antibiotics (n = 480) were most frequently prescribed linezolid (42.1%) and clindamycin (19.8%). IV treatment duration (9.3 ± 6.5 vs. 14.6 ± 9.9 days; p <0.001) and hospital LOS (19.1 ± 12.9 vs. 21.0 ± 18.2 days; p 0.162) tended to be shorter for patients switched from IV to oral treatment than for patients who received IV treatment only. Of the patients, 33.6% met ES criteria and could have discontinued IV treatment 6.0 ± 5.5 days earlier, and 37.9% met ED criteria and could have been discharged 6.2 ± 8.2 days earlier. More than one-third of European patients hospitalized for MRSA cSSTI could be eligible for ES and ED, resulting in substantial reductions in IV days and bed-days, with potential savings of €2000 per ED-eligible patient.

Of Guinea pigs and gratitude: the difficult discourse of clinical trials from the cancer patient perspective.

In an ongoing longitudinal qualitative cohort study of cancer patients' needs and preferences across the cancer journey, we harvested a subset of accounts pertaining to conversations between patients and their clinicians around clinical trials. Recognising these conversations as a departure from the more routine discourses of clinical care, in that they enter into new dimensions of investment and motivation on the part of clinicians, we engaged in both secondary analysis of banked data and focussed interviewing of cancer patients to better understand how cancer patients describe communications in relation to decisions pertaining to clinical trials participation. Using constant comparative techniques informed by the interpretive description approach to applied qualitative methodology to guide a systematic analysis of this set of data, we documented patterns and themes across patient accounts. The resulting thematic depiction of clinical trials discourses from a patient perspective contrasts with assumptions apparent in the professional literature relating to the clinical advantage of trials participation, and illuminates aspects of patient-clinician interaction that are particularly amenable to disruption within this delicate and nuanced discourse. Findings from this study have implications for our understanding of the complexities of cancer communication at the delicate intersection of patient care and knowledge generation.

Association between drug tolerability and medical resource use in prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplant.

OBJECTIVES: To conduct a retrospective analysis of the association between drug tolerability and potential economic impact measured by medical resource utilization (MRU) for prophylaxis of invasive antifungal infections (IFI) after allogeneic hematopoietic stem cell transplantation (alloHCT). METHODS: An open-label, multi-center study (IMPROVIT) included patients (≥12-years old) who were randomized to receive oral voriconazole (VOR) or oral itraconazole (ITR) from the alloHCT day for at least 100 days and up to 180 days. Trial data on discontinuation and MRU for the first 100 days were analyzed. RESULTS: Two hundred and twenty-four patients were in VOR and 241 in ITR, with similar demographic distributions (average age of 43 years, 58% male, 92% Caucasian). All-cause and study drug intolerance discontinuations were less frequent with VOR than ITR (50% vs 63%, p = 0.0137; 7% vs 22%, p < 0.0001). VOR patients had longer study drug exposure (median = 96 vs 68 days, p < 0.0001; mean = 68 vs 60 days, p = 0.0044). ITR patients were 2-times more likely (p = 0.0110) to use other antifungals vs VOR patients. Controlling for treatment and key baseline variables, longer IFI prophylaxis was associated with fewer hospital days (p < 0.0001) and less other antifungal use (p < 0.0001). Patients who discontinued prophylaxis during the first 100 days incurred 10 more hospital days (p < 0.0001) and 17 more other antifungal days (p < 0.0001) compared to their counterparts. Eight more prophylaxis days were associated with ∼1 less hospital day and 3.6 less other antifungal days (p < 0.0001). Key limitation: MRU data collection was limited to the first 100 days post-transplant, which may not fully capture the real-world utilization and outcomes. CONCLUSIONS: Patients' ability to tolerate and continue their antifungal prophylaxis after alloHCT is associated with less use of MRU such as other antifungals and hospital days. In the current resource-constrained healthcare environment, it is important to consider the potential economic impact of the tolerability of antifungal prophylaxis.

Clinical, quality of life, and economic value of acromegaly disease control.

Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998-2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 µg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease.

Cost-effectiveness of zoledronic acid in the prevention of skeletal-related events in patients with bone metastases secondary to advanced renal cell carcinoma: application to France, Germany, and the United Kingdom.

BACKGROUND: The use of zoledronic acid (ZOL) has recently been shown to significantly reduce the risk of new skeletal-related events (SREs) in renal cell carcinoma (RCC) patients with bone metastases. The present exploratory study assessed the cost-effectiveness of ZOL in this population, adopting a French, German, and United Kingdom (UK) government payer perspective. MATERIALS AND METHODS: This cost-effectiveness model was based on a post hoc retrospective analysis of a subset of patients with RCC who were included in a larger randomized clinical trial of patients with bone metastases secondary to a variety of cancers. In the trial, patients were randomized to receive ZOL (n = 27) or placebo (n = 19) with concomitant antineoplastic therapy every 3 weeks for 9 months (core study) plus 12 months during a study extension. Since the trial did not collect costs or data on the quality-adjusted life years (QALYs) of the patients, these outcomes had to be assumed via modeling exercises. The costs of SREs were estimated using hospital DRG tariffs. These estimates were supplemented with literature-based costs where possible. Drug, administration, and supply costs were obtained from published and internet sources. Consistent with similar economic analyses, patients were assumed to experience quality of life decrements lasting 1 month for each SRE. Uncertainty surrounding outcomes was addressed via multivariate sensitivity analyses. RESULTS: Patients receiving ZOL experienced 1.07 fewer SREs than patients on placebo. Patients on ZOL experienced a gain in discounted QALYs of approximately 0.1563 in France and Germany and 0.1575 in the UK. Discounted SRE-related costs were substantially lower among ZOL than placebo patients (-€ 4,196 in France, - € 3,880 in Germany, and -€ 3,355 in the UK). After taking into consideration the drug therapy costs, ZOL saved € 1,358, € 1,223, and € 719 in France, Germany, and the UK, respectively. In the multivariate sensitivity analyses, therapy with ZOL saved costs in 67-77% of simulations, depending on the country. The cost per QALY gained for ZOL versus placebo was below € 30,000 per QALY gained threshold in approximately 93-94% of multivariate sensitivity analyses simulations. CONCLUSIONS: The present analysis suggests that ZOL saves costs and increases QALYs compared to placebo in French, German, and UK RCC patients with bone metastases. Additional prospective research may be needed to confirm these results in a larger sample of patients.

Inversion of ferromagnetic proximity polarization by MgO interlayers.

We investigate the spin-dependent reflection properties in Fe/MgO/GaAs heterostructures by optical pump-probe measurement of the ferromagnetic proximity polarization (FPP). As a function of MgO thickness, the FPP is initially enhanced (<2.0 A) and then exhibits an unexpected sign reversal at approximately 5.0 A. The identification of two competing thresholds in the intensity dependence of FPP and the observation of FPP sign reversal in Fe/Mg/GaAs suggest that the inversion of FPP is related to an interfacial bonding effect.

Economic burden of haematological adverse effects in cancer patients: a systematic review.

OBJECTIVE: Patients receiving cancer treatments commonly experience haematological adverse effects (AEs) related to chemotherapy or molecularly targeted therapies, which may be associated with high healthcare costs. The objective of this review was to summarise the published literature on the economic burden of neutropenia, thrombocytopenia and anaemia as AEs of cancer treatment. METHODS: A systematic search of the medical literature published between 1990 and 2006 was conducted using PubMed/MEDLINE, EMBASE, BIOSIS, related article links and supplemental searches. References selected for inclusion were prospective or retrospective studies specifically designed to examine the burden of illness, direct medical costs, indirect costs and/or cost drivers associated with neutropenia, thrombocytopenia and anaemia in adult cancer patients. All costs are reported as originally published and adjusted to 2006 US dollars. RESULTS: In the US, the cost of neutropenia ranged from $US 1893 (2006 value $US 2632) per outpatient episode to $US 38,583 ($US 49,917) per febrile neutropenia hospitalisation. For countries outside the US, the cost of neutropenia appeared to be lower. The cost of thrombocytopenia ranged from $US 1035 ($US 1395) to $US 5328 ($US 7635) per cycle or episode in the US. Costs attributable to anaemia ranged from $US 18,418 ($US 22,775) to $US 69,478 ($US 93,454) per year in the US. The costs of AEs for patients with haematological malignancies appeared to be up to 2-3 times higher than those for patients with solid tumours. Economic studies of the cost of haematological AEs specific to new molecularly targeted treatments for haematological malignancy have not been published. CONCLUSIONS: Chemotherapy-related haematological AEs result in a substantial economic burden on patients, payers, caregivers and society in general. Because of their burden, the frequency and severity of these toxicities should be one of the key factors in the selection of optimal treatments for patients with cancer, especially those with haematological malignancies. Future research is needed to assess the economic burden of AEs associated with new molecularly targeted treatments for haematological malignancies.

A systematic literature review of the clinical and epidemiological burden of acute lymphoblastic leukaemia (ALL).

Our goal was to identify and summarize the published literature pertaining to the incidence, prevalence, mortality, aetiology, clinical diagnosis, and management of acute lymphoblastic leukaemia (ALL). Acute lymphoblastic leukaemia represents 12% of all leukaemia cases, with a worldwide incidence projected to be 1-4.75 per 100,000 people. Italy, the United States (US), Switzerland, and Costa Rica are the countries with the highest incidence of ALL. Hereditary link, genetic defects, and possibly radiation or chemical exposures are listed amongst the most significant risk factors. Acute lymphoblastic leukaemia is predominantly a disease of childhood, but it affects adults as well. It accounts for 80% of all leukaemia cases in children. The incidence is slightly higher in men than in women and greater in white people than in black people. In 2003 in the US, there were an estimated 5800 deaths from ALL. Presenting signs and symptoms of ALL are fairly non-specific and include fever, anaemia, petechiae, and bone and joint pain. Staging of the disease and patient risk profile are routinely performed to define ALL subtypes and guide management. Chemotherapy, cranial radiation in patients with high-risk disease, and stem cell transplantation for selected patients are the prevalent therapies. Complete remission rates are high, especially amongst children (even 100%); however, long-term survival at 10 years (event-free survival) is in the range of 63% for children and 25-35% for adults. This implies that there is still a strong need for new therapies to maintain remission and prolong survival. Future treatment strategies may be driven by the patient's minimal residual disease status, a measure that more precisely defines remission, prognosis, responsiveness to therapy, and expected long-term survival.

The clinical and epidemiological burden of chronic lymphocytic leukaemia.

The purpose of this literature review was to identify and summarize published studies describing the epidemiology and management of chronic lymphocytic leukaemia (CLL). Chronic lymphocytic leukaemia represents 22-30% of all leukaemia cases with a worldwide incidence projected to be between < 1 and 5.5 per 100,000 people. Australia, the USA, Ireland and Italy have the highest CLL incidence rates. Chronic lymphocytic leukaemia presents in adults, at higher rates in males than in females and in whites than in blacks. Median age at diagnosis is 64-70 years. Five-year survival rate in the USA is 83% for those < 65 years old and 68% for those 65 + years old. Hereditary and genetic links have been noted. Persons with close relatives who have CLL have an increased risk of developing it themselves. No single environmental risk factor has been found to be predictive for CLL. Patients are usually diagnosed at routine health care visits because of elevated lymphocyte counts. The most common presenting symptom of CLL is lymphadenopathy, while difficulty exercising and fatigue are common complaints. Most patients do not receive treatment after initial diagnosis unless presenting with clear pathologic conditions. Pharmacological therapy may consist of monotherapy or combination therapy involving glucocorticoids, alkylating agents, and purine analogs. Fludarabine may be the most effective single drug treatment currently available. Combination therapy protocols have not been shown to be more effective than fludarabine alone. As no cure is yet available, a strong unmet medical need exists for innovative new therapies. Experimental treatments under development include allogeneic stem cell transplant, mini-allogeneic transplants, and monoclonal antibodies (e.g. alemtuzumab against CD52; rituximab against CD20).

Ferromagnetic imprinting of nuclear spins in semiconductors.

We examine how a ferromagnetic layer affects the coherent electron spin dynamics in a neighboring gallium arsenide semiconductor. Ultrafast optical pump-probe measurements reveal that the spin dynamics are unexpectedly dominated by hyperpolarized nuclear spins that align along the ferromagnet's magnetization. We find evidence that photoexcited carriers acquire spin-polarization from the ferromagnet, and dynamically polarize these nuclear spins. The resulting hyperfine fields are as high as 9000 gauss in small external fields (less than 1000 gauss), enabling ferromagnetic control of local electron spin coherence.

The identification and characterization of a STAT 1 binding site in the PPARgamma2 promoter.

Interferon-gamma (IFNgamma) has been shown to decrease the expression of peroxisome proliferator activated receptor-gamma (PPARgamma) in fat cells by blocking the synthesis and increasing the degradation of this transcription factor. Since IFNgamma is a potent activator of STAT 1, we searched for IFNgamma-sensitive binding sites in the PPARgamma promotors. A region of the murine PPARgamma2 promoter was identified that bound nuclear protein from adipocyte nuclei that had been acutely treated with IFNgamma. Supershift analysis revealed that STAT 1, and no other STATs present in the adipocyte nucleus, was capable of binding to this site within the PPARgamma2 promoter. NIH 3T3 and 3T3-L1 cells were transiently transfected with a PPARgamma2 promoter reporter construct, which contained the STAT 1 binding site. Treatment of these cells with IFNgamma resulted in a decrease in reporter activity, demonstrating the modulation of the PPARgamma2 promoter by IFNgamma. We also examined the ability of leukemia inhibitory factor (LIF) to regulate binding at this site. LIF, a potent activator of STAT3 and a weak activator of STAT 1 in these cells, resulted in some binding to the IFNgamma responsive element in the PPARgamma2 promoter that was mediated by STAT 1. Therefore, we examined the ability of LIF to regulate PPARgamma mRNA and observed that LIF, unlike IFNgamma, had little effect on PPARgamma expression. These results and our previous work suggest that cytokine induced STAT 1 homodimers modulate the transcriptional repression of PPARgamma2 in adipocytes.

Agouti regulates adipocyte transcription factors.

Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agouti expression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-gamma protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-gamma.

Interferon-gamma-induced regulation of peroxisome proliferator-activated receptor gamma and STATs in adipocytes.

Interferon-gamma (IFN-gamma) is known primarily for its roles in immunological responses but also has been shown to affect fat metabolism and adipocyte gene expression. To further investigate the effects of IFN-gamma on fat cells, we examined the effects of this cytokine on the expression of adipocyte transcription factors in 3T3-L1 adipocytes. Although IFN-gamma regulated the expression of several adipocyte transcription factors, IFN-gamma treatment resulted in a rapid reduction of both peroxisome proliferator-activated receptor (PPAR) protein and mRNA. A 48-h exposure to IFN-gamma also resulted in a decrease of both CCAAT/enhancer-binding alpha and sterol regulatory element binding protein (SREBP-1) expression. The short half-life of both the PPARgamma mRNA and protein likely contributed to the rapid decline of both cytosolic and nuclear PPARgamma in the presence of IFN-gamma. Our studies clearly demonstrated that the IFN-gamma-induced loss of PPARgamma protein is partially inhibited in the presence of two distinct proteasome inhibitors. Moreover, IFN-gamma also inhibited the transcription of PPARgamma, which was accompanied by a decrease in PPARgamma mRNA accumulation. In addition, exposure to IFN-gamma resulted in a substantial increase in STAT 1 expression and a small increase in STAT 3 expression. IFN-gamma treatment of 3T3-L1 adipocytes (48-96 h) resulted in a substantial inhibition of insulin-sensitive glucose uptake. These data clearly demonstrate that IFN-gamma treatment results in the development of insulin resistance, which is accompanied by the regulation of various adipocyte transcription factors, in particular the synthesis and degradation of PPARgamma.

A short-term cost-of-treatment model for type 2 diabetes: comparison of glipizide gastrointestinal therapeutic system, metformin, and acarbose.

OBJECTIVE: To compare, from a managed care perspective, the 3-year costs of 3 first-line monotherapy strategies in type 2 diabetes patients: glipizide gastrointestinal therapeutic system (GITS), metformin, and acarbose. STUDY DESIGN: A Markov model, with a Monte Carlo simulation, was developed to compare the costs to achieve full glycemic control (hemoglobin A1c of < or = 7%) with each first-line strategy. PATIENTS AND METHODS: The patient population for the model was assumed to be all newly diagnosed type 2 diabetes patients eligible for monotherapy with an oral agent. Each monotherapy could be succeeded by add-on treatments. The model included the costs of routine medical care and supplies, medication, adverse events, and treatment failures. RESULTS: Using a Monte Carlo simulation, the mean 3-year cumulative costs per patient were $4971, $5273, and $5311 for glipizide GITS, metformin, and acarbose first-line strategies, respectively. The main cost drivers were drug prices. Mean 3-year cost savings for first-line glipizide GITS were $301 over metformin and $340 over acarbose. Between 83% and 85% of all simulations showed cost savings with glipizide GITS compared with the other agents. CONCLUSIONS: The model suggests first-line monotherapy with glipizide GITS should result in desirable short-term economic benefits for managed care. Because the model incorporates recommended glycemic goals and performed well in sensitivity analyses, it should be applicable to a variety of clinical practices and useful for economic assessments of new therapies. Results of this model should be verified prospectively in typical care settings.

Regulation of signal transducers and activators of transcription (STATs) by effectors of adipogenesis: coordinate regulation of STATs 1, 5A, and 5B with peroxisome proliferator-activated receptor-gamma and C/AAAT enhancer binding protein-alpha.

We have recently demonstrated that three signal transducers and activators of transcription (STAT) family members are induced during adipocyte differentiation (Stephens et al., J. Biol. Chem. 271 (1996) 10441-10444). Since STATs 1, 5A, and 5B are induced during adipocyte differentiation, we have examined the ability of these proteins to be regulated by components of the differentiation cocktail. In addition, we have examined the effects of potent effectors of differentiation on STAT protein expression during adipogenesis. A negative effector, tumor necrosis factor-alpha (TNFalpha), and a positive effector, a thiazolidinedione, were used in these experiments. Our results demonstrate that the expression of STATs 1, 5A, and 5B is not dramatically influenced by individual components of the differentiation cocktail. However, the expression of these three STAT family members tightly correlates with lipid accumulation. Moreover, the expression of STATs 1, 5A, and 5B, but not STATs 3 and 6, are regulated in an identical fashion to both C/AAAT enhancer binding proteins alpha and peroxisome proliferator-activated receptor-gamma by TNFalpha and a thiazolidinedione. Furthermore, the expression of adipocyte-expressed JAK kinases are unaffected by effectors of differentiation. These findings suggest that three STAT family members may play a role in the regulation of adipocyte gene expression.

PPARgamma ligand-dependent induction of STAT1, STAT5A, and STAT5B during adipogenesis.

We have recently demonstrated that STAT1, STAT5A, and STAT5B are induced during adipogenesis of cultured preadipocytes in a differentiation-dependent manner. Members of the C/EBP and PPAR families of transcription factors have also been shown to be induced during adipocyte differentiation and to play a significant role in the regulation of fat-specific genes. In this investigation, we have examined the ability of C/EBPs and PPARs to contribute to STAT protein expression during conversion of non-precursor fibroblasts to functionally mature adipocytes. For this study, NIH-3T3 fibroblasts engineered to ectopically co-express C/EBPbeta and C/EBPdelta under the control of a tetracycline-responsive, inducible expression system were utilized to assess STAT expression during controlled adipogenesis. Data presented here demonstrate that STAT1, STAT5A, and STAT5B, but not STAT3 and STAT6, were induced in a tetracycline-responsive manner during the differentiation of these engineered fibroblasts. The STAT protein accumulation resulting from C/EBP expression was tightly coupled to the morphological conversion of fibroblasts to adipocytes and represents an expression profile identical to that reported for mature adipocytes in vivo. Data are also presented demonstrating that STAT protein accumulation and adipocyte conversion occurred only during controlled conditions leading to the expression of PPARgamma and that the expression of these three STATs was tightly regulated in a PPARgamma ligand dose-response fashion. These data illustrate that the cascade of transcriptional events leading to adipogenesis regulate the STAT family of transcription factors and that the differentiation-dependent upregulation of STAT protein expression is regulated downstream of PPARgamma in a ligand-dependent manner.

Walking speed on parquetry and carpet after stroke: effect of surface and retest reliability.

OBJECTIVE: At the transition stage from rehabilitation to home this study aimed to (1) investigate the effect of floor surface (carpet and parquetry) on walking speed; (2) investigate whether there was a difference between these surfaces as stroke patients voluntarily increased from comfortable to fast pace; (3) investigate whether walking speed on parquetry was a predictor of walking speed on carpet at the two paces; (4) investigate whether walking speed at a comfortable pace was a predictor of walking speed at a fast pace on the two surfaces; and (5) quantify systematic and random error in repeated measurements for fast-paced walking trials. DESIGN: Subjects walked 10 metres at comfortable and fast paces on carpet and parquetry on two consecutive days. SETTING: Inpatient rehabilitation centre. SUBJECTS: Twenty-four stroke patients. MAIN OUTCOME MEASURE: Walking speed. RESULTS: Two-way analysis of variance confirmed that patients walked more slowly on carpet than parquetry (F(1,23) = 5.3, p <0.05) at both paces; the interaction effect was not significant (p >0.05). Walking speed on parquetry was a strong predictor of walking speed on carpet at a comfortable (r = 0.92), and fast pace (r = 0.97). Walking speed at comfortable pace was a moderately strong predictor of walking speed at fast pace on parquetry (r = 0.84), and on carpet (r = 0.88). Random error in repeated measurements was higher when walking fast on carpet (7.21 m/min) and parquetry (8.32 m/min) than when walking at a comfortable pace on carpet (4.63 m/min) and parquetry (3.48 m/min). Systematic error was negligible (p <0.05). CONCLUSION: Carpet surface was more challenging than parquetry surface, as evidenced by the systematic decrease in walking speed. This may have been due to lack of familiarity. Relative to the wide range of scores in the group, stroke patients showed consistency of walking speed across both surfaces. Likewise, stroke patients retained their relative position in the group as they changed from a comfortable to a fast walking pace. The difference in random error between comfortable and fast-paced trials highlights the need to quantify error in the repeated measurement situation according to specific test conditions.

Activation of signal transducers and activators of transcription 1 and 3 by leukemia inhibitory factor, oncostatin-M, and interferon-gamma in adipocytes.

We have recently demonstrated that signal transducers and activators of transcription (STATs) 1, 3, 5A, 5B, and 6 are expressed in both cultured and native adipocytes. Our current studies have focused on the activation of STATs 1 and 3 by leukemia inhibitory factor (LIF), oncostatin-M (OSM), and interferon-gamma (IFNgamma) in 3T3-L1 adipocytes. IFNgamma is shown to be a potent activator of STAT 1 as indicated by both tyrosine phosphorylation and nuclear translocation. However, LIF and OSM, which are potent inducers of STAT 3, are less potent activators of STAT 1 as measured by both tyrosine phosphorylation and nuclear translocation. Both STATs 1 and 3 were translocated to the nucleus in a time-dependent fashion following LIF treatment. In addition, IFNgamma resulted in a time- and dose-dependent effect on STATs 1 and 3 nuclear translocation. Growth hormone, a potent activator of STATs 5A and 5B, had a minimal effect on STAT 1 and STAT 3 tyrosine phosphorylation. Preincubation with either insulin or growth hormone had no detectable effects on the tyrosine phosphorylation or nuclear translocation of STATs 1 and 3 induced by LIF, OSM, or IFNgamma. The effects of LIF and IFNgamma on STAT 1 and 3 tyrosine phosphorylation and nuclear translocation were confirmed in native rat adipocytes. In 3T3-L1 adipocytes, a low level of serine phosphorylation of STAT 3 on residue 727 was observed and was markedly enhanced by insulin, LIF, or OSM. This increase in STAT 3 Ser727 phosphorylation was dependent upon the activation of MAPK, since the MAPK kinase inhibitor (PD98059) reduced STAT 3 Ser727 phosphorylation to basal levels. The inhibition of MAPK had no effect on the ability of STATs 1 and 3 to be tyrosine-phosphorylated or translocate to the nucleus. These studies demonstrate the highly specific and quantitative activation of STATs 1 and 3 by LIF, OSM, and IFNgamma in adipocytes and indicate that STAT 3 is a substrate for MAPK in adipocytes.

Highly specific and quantitative activation of STATs in 3T3-L1 adipocytes.

We have recently demonstrated that STATs 1, 3, 5A, 5B, and 6 are expressed in adipocytes. Using the 3T3-L1 cell line, we have examined the activation of all adipocyte expressed STATs by 23 different factors which are either potent regulators of adipocyte gene expression or known STAT activators in other cell types. STAT activation was assessed by examining nuclear translocation and tyrosine phosphorylation in serum deprived, fully differentiated 3T3-L1 adipocytes. Unlike other adipocyte-expressed STATs, STAT 5A was present in the nucleus under basal conditions. Of all the activators examined, only growth hormone was capable of causing STATs 5A and 5B to translocate to the nucleus. None of the activators were capable of affecting the cellular distribution of STAT 6. Furthermore, our results indicate that there is a quantitative activation of STATs 1 and 3 by LIF, OSM, and IFN-gamma as measured by both nuclear translocation and tyrosine phosphorylation in whole cell extracts. IFN-gamma is a potent activator of STAT 1 and a weaker activator of STAT 3, whereas LIF and OSM are potent activators of STAT 3 and weaker activators of STAT 1. These studies demonstrate that STAT activation in adipocytes is highly specific, quantitative, and distinct.