Clinical presentation and predictors of outcome in patients with severe acute exacerbation of chronic obstructive pulmonary disease requiring admission to intensive care unit

BACKGROUND: Severe acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) is a common reason for emergency room (ER) visit about which little has been documented from India. METHODS: Prospective study of the clinical presentation and predictors of outcome in 116 patients presenting with severe AE-COPD requiring admission to the medical intensive care unit between January 2000 and December 2004. RESULTS: Their mean age was 62.1 ± 9.8 years. There were 102 males. Mean duration of COPD was 7.2 ± 5.8 years. All males were smokers (22.3 ± 11.2 pack years); 35.2% smoked cigarettes and 64.8% smoked bidis. All women were exposed to domestic fuel. Associated co-morbid illnesses were present in 81 patients (69.8%); 53(45.7%) had one co-morbid illness and the remaining 28 (54.3%) had two or more co-morbid illnesses. Evidence of past pulmonary tuberculosis (PTB) was present in 28.4% patients; 5 patients who also had type II diabetes mellitus had active PTB. Arterial blood gas analysis revealed respiratory failure in 40 (33.8%) patients (type I 17.5% and type II 82.5%). Invasive mechanical ventilation was required in 18 patients. Sixteen (13.7%) patients died. Stepwise multivariate logistic regression analysis revealed need for invasive ventilation (OR 45.809, 95%CI 607.46 to 3.009;p < 0.001); presence of co-morbid illness (OR 0.126, 95%CI 0.428 to 0.037;p < 0.01) and hypercapnia (OR 0.114, 95%CI 1.324 to 0.010;p < 0.05) were predictors of death. CONCLUSION: Co-morbid conditions and metabolic abnormalities render the diagnosis of AE-COPD difficult and also contribute to mortality. High prevalence of past PTB and active PTB in patients with AE-COPD suggests an intriguing relationship between smoking, PTB and COPD which merits further study

PDEPT: polymer-directed enzyme prodrug therapy

Polymer-directed enzyme prodrug therapy (PDEPT) is a novel two-step antitumour approach using a combination of a polymeric prodrug and polymer-enzyme conjugate to generate cytotoxic drug selectively at the tumour site. In this study the polymeric prodrug N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-Gly-Phe-Leu-Gly-doxorubicin conjugate PK1 (currently under Phase II clinical evaluation) was selected as the model prodrug, and HPMA copolymer-cathepsin B as a model for the activating enzyme conjugate. Following polymer conjugation (yield of 30–35%) HPMA copolymer-cathepsin B retained ~20–25% enzymatic activity in vitro. To investigate pharmacokinetics in vivo,125I-labelled HPMA copolymer-cathepsin B was administered intravenously (i.v.) to B16F10 tumour-bearing mice. HPMA copolymer-cathespin B exhibited a longer plasma half-life (free cathepsin B t1/2α= 2.8 h; bound cathepsin B t1/2α= 3.2 h) and a 4.2-fold increase in tumour accumulation compared to the free enzyme. When PK1 (10 mg kg−1dox-equiv.) was injected i.v. into C57 mice bearing subcutaneously (s.c.) palpable B16F10 tumours followed after 5 h by HPMA copolymer-cathepsin B there was a rapid increase in the rate of dox release within the tumour (3.6-fold increase in the AUC compared to that seen for PK1 alone). When PK1 and the PDEPT combination were used to treat established B16F10 melanoma tumour (single dose; 10 mg kg−1dox-equiv.), the antitumour activity (T/C%) seen for the combination PDEPT was 168% compared to 152% seen for PK1 alone, and 144% for free dox. Also, the PDEPT combination showed activity against a COR-L23 xenograft whereas PK1 did not. PDEPT has certain advantages compared to ADEPT and GDEPT. The relatively short plasma residence time of the polymeric prodrug allows subsequent administration of polymer-enzyme without fear of prodrug activation in the circulation and polymer-enzyme conjugates have reduced immunogenicity. This study proves the concept of PDEPT and further optimisation is warranted. © 2001 Cancer Research Campaign   http://www.bjcancer.co

Improving breast cancer services for African-American women living in St. Louis

A mixed methods, community-based research study was conducted to understand how provider-level factors contribute to the African-American and white disparity in breast cancer mortality in a lower socioeconomic status area of North St. Louis. This study used mixed methods including: (1) secondary analysis of Missouri Cancer Registry data on all 885 African-American women diagnosed with breast cancer from 2000 to 2008 while living in the geographic area of focus; (2) qualitative interviews with a subset of these women; (3) analysis of data from electronic medical records of the women interviewed; and (4) focus group interviews with community residents, patient navigators, and other health care professionals. 565 women diagnosed with breast cancer from 2000 to 2008 in the geographic area were alive at the time of secondary data analysis; we interviewed (n = 96; 17 %) of these women. Provider-level obstacles to completion of prescribed treatment included fragmented navigation (separate navigators at Federally Qualified Health Centers, surgical oncology, and medical oncology, and no navigation services in surgical oncology). Perhaps related to the latter, women described radiation as optional, often in the same words as they described breast reconstruction. Discontinuous and fragmented patient navigation leads to failure to associate radiation therapy with vital treatment recommendations. Better integrated navigation that continues throughout treatment will increase treatment completion with the potential to improve outcomes in African Americans and decrease the disparity in mortality

Predictors of mortality of patients with acute respiratory failure secondary to chronic obstructive pulmonary disease admitted to an intensive care unit: A one year study

BACKGROUND: Patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) commonly require hospitalization and admission to intensive care unit (ICU). It is useful to identify patients at the time of admission who are likely to have poor outcome. This study was carried out to define the predictors of mortality in patients with acute exacerbation of COPD and to device a scoring system using the baseline physiological variables for prognosticating these patients. METHODS: Eighty-two patients with acute respiratory failure secondary to COPD admitted to medical ICU over a one-year period were included. Clinical and demographic profile at the time of admission to ICU including APACHE II score and Glasgow coma scale were recorded at the time of admission to ICU. In addition, acid base disorders, renal functions, liver functions and serum albumin, were recorded at the time of presentation. Primary outcome measure was hospital mortality. RESULTS: Invasive ventilation was required in 69 patients (84.1%). Fifty-two patients survived to hospital discharge (63.4%). APACHE II score at the time of admission to ICU {odds ratio (95 % CI): 1.32 (1.138–1.532); p < 0.001} and serum albumin (done within 24 hours of admission) {odds ratio (95 % CI): 0.114 (0.03-0.432); p = 0.001}. An equation, constructed using the adjusted odds ratio for the two parameters, had an area under the ROC curve of 91.3%. For the choice of cut-off, sensitivity, specificity, positive and negative predictive value for predicting outcome was 90%, 86.5%, 79.4% and 93.7%. CONCLUSION: APACHE II score at admission and SA levels with in 24 hrs after admission are independent predictors of mortality for patients with COPD admitted to ICU. The equation derived from these two parameters is useful for predicting outcome of these patients

Sub-Nucleocapsid Nanoparticles: A Nasal Vaccine against Respiratory Syncytial Virus

Background: Bronchiolitis caused by the respiratory syncytial virus (RSV) in infants less than two years old is a growing public health concern worldwide, and there is currently no safe and effective vaccine. A major component of RSV nucleocapsid, the nucleoprotein (N), has been so far poorly explored as a potential vaccine antigen, even though it is a target of protective anti-viral T cell responses and is remarkably conserved between human RSV A and B serotypes. We recently reported a method to produce recombinant N assembling in homogenous rings composed of 10–11 N subunits enclosing a bacterial RNA. These nanoparticles were named sub-nucleocapsid ring structure (N SRS). Methodology and Principal Findings: The vaccine potential of N SRS was evaluated in a well-characterized and widely acknowledged mouse model of RSV infection. BALB/c adult mice were immunized intranasally with N SRS adjuvanted with the detoxified E. coli enterotoxin LT(R192G). Upon RSV challenge, vaccinated mice were largely protected against virus replication in the lungs, with a mild inflammatory lymphocytic and neutrophilic reaction in their airways. Mucosal immunization with N SRS elicited strong local and systemic immunity characterized by high titers of IgG1, IgG2a and IgA anti-N antibodies, antigen-specific CD8+ T cells and IFN-c-producing CD4+ T cells. Conclusions/Significance: This is the first report of using nanoparticles formed by the recombinant nucleocapsid protein as an efficient and safe intra-nasal vaccine against RSV

Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples

Impact of Tai Chi exercise on multiple fracture-related risk factors in post-menopausal osteopenic women: a pilot pragmatic, randomized trial

Background: Tai Chi (TC) is a mind-body exercise that shows potential as an effective and safe intervention for preventing fall-related fractures in the elderly. Few randomized trials have simultaneously evaluated TC's potential to reduce bone loss and improve fall-predictive balance parameters in osteopenic women. Methods: In a pragmatic randomized trial, 86 post-menopausal osteopenic women, aged 45-70, were recruited from community clinics. Women were assigned to either nine months of TC training plus usual care (UC) vs. UC alone. Primary outcomes were changes between baseline and nine months of bone mineral density (BMD) of the proximal femur and lumbar spine (dual-energy X-ray absorptiometry) and serum markers of bone resorption and formation. Secondary outcomes included quality of life. In a subsample (n = 16), quiet standing fall-predictive sway parameters and clinical balance tests were also assessed. Both intent-to-treat and per-protocol analyses were employed. Results: For BMD, no intent-to-treat analyses were statistically significant; however, per protocol analyses (i.e., only including TC participants who completed $\geq$ 75% training requirements) of femoral neck BMD changes were significantly different between TC and UC (+0.04 vs. -0.98%; P = 0.05). Changes in bone formation markers and physical domains of quality of life were also more favorable in per protocol TC vs. UC (P = 0.05). Changes in sway parameters were significantly improved by TC vs. UC (average sway velocity, P = 0.027; anterior-posterior sway range, P = 0.014). Clinical measures of balance and function showed non-significant trends in favor of TC. Conclusions: TC training offered through existing community-based programs is a safe, feasible, and promising intervention for reducing multiple fracture risks. Our results affirm the value of a more definitive, longer-term trial of TC for osteopenic women, adequately powered to detect clinically relevant effects of TC on attenuation of BMD loss and reduction of fall risk in this population