An exploratory pilot study of palliative medicine compared to anesthesia-pain consultation for pain in patients with cancer

Oncologists often manage cancer-associated symptoms including pain. When symptoms are severe, anesthesia-pain medicine (APM) and/or palliative medicine (PM) can effectively treat symptoms. Nevertheless, symptom management may be suboptimal, leading to diminished quality of life (QOL). We assessed the value of PM vs. APM consultation in cancer patients referred for pain management alone. Patients referred to an APM-based Cancer Pain Clinic (CPC) over an 8-month period were evaluated by PM or APM based on the first available appointment. Symptoms and QOL were assessed by the MD Anderson Symptom Inventory and Linear Analog Self-Assessment at baseline and 4-6 weeks after initial encounter. Data were analyzed on an available-case basis. Sixty-two patients (37 PM, 25 APM) completed the initial survey, with 48 patients (31 PM, 17 APM) completing followup. Mean pain score improved from 7.97 to 5.47 in the PM group (P < 0.0001) and from 7.1 to 4.5 (P = 0.29) in the APM group. The PM group demonstrated a clinically significant improvement in 8/19 symptoms vs. 3/19 in the APM group and in 3/5 QOL parameters in the PM group vs. 1/5 in the APM group. Our small sample size weakens our power and ability to detect significant differences between the groups. Only one follow-up symptom-assessment point was obtained. PM consultation is as effective as APM in improving cancer pain but may be more effective with symptom management and improving QOL.     

Endocrine therapy, new biologicals, and new study designs for presurgical studies in breast cancer

The preoperative setting is increasingly popular for the clinical investigation of hormonal agents and new biological drugs. The effectiveness of endocrine agents is well established for estrogen receptor-positive disease, and the emphasis in preoperative studies is on their combination with agents targeted at resistance mechanisms over 3 or more months. New agents are also being assessed for early evidence of clinical efficacy in shorter-term window-of-opportunity studies. The establishment of Ki67 as an intermediate marker of treatment benefit and of long-term outcome, with endocrine drugs, provides the opportunity for new trial designs with Ki67 as the primary endpoint. The PeriOperative Endocrine Therapy for Individualizing Care (POETIC) trial is randomizing (2:1) 4000 estrogen receptor-positive patients to 2 weeks presurgical treatment with a nonsteroidal aromatase inhibitor or no presurgical treatment. It provides a unique opportunity for detailed study of the determinants of response and resistance to estrogen deprivation as well as testing the role of presurgical therapy for improved biomarker-based estimates of prognosis.     

Comparison of outcomes in patients aged <75, 75 to 84, and ≥ 85 years with ST-elevation myocardial infarction (from the ACTION Registry-GWTG)

ST-segment elevation myocardial infarction (STEMI) is common in older adults and has high age-related mortality. We describe contemporary STEMI care using the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Network Registry-Get With The Guidelines (ACTION-GWTG) database. Patients with STEMI (n = 30,188) from 285 ACTION-GWTG sites from January 1, 2007 to June 30, 2008 were grouped by age (<75, 75 to 84, and ≥ 85 years) to compare baseline characteristics, reperfusion, and in-hospital outcomes. In this population, 79.7% (24,070) were <75 years old, 14.2% (4,273) were 75 to 84 years old, and 6.1% (1,845) were ≥ 85 years old (the oldest old). Compared to younger patients, the oldest-old patients (median age 88 years, interquartile range 86 to 91) were more often women, had more hypertension, and end-organ co-morbidity (heart failure and stroke, p <0.0001 for all). More than 42% of the oldest old were also cited as having contraindications to reperfusion, but with absolute or relative contraindications noted in only 10%, and patient preference was the most common reason indicated (45%). Even in reperfusion-eligible patients, the oldest old were less likely to receive it. Although patients who received reperfusion had better outcomes than those who did not, this was significant only for younger patients (< 75 years old, odds ratio 0.58, confidence interval 0.40 to 0.84). In conclusion, > 42% of the oldest old have reported contraindications to reperfusion, with neither mortality benefit nor harm in those who receive it. Disparities in process of care and co-morbidity may explain these observational findings. Whether efforts to optimize patient selection and initiate reperfusion therapy can improve outcomes in the oldest old with STEMI is unknown.     

Evaluation of three commercially available Japanese encephalitis virus IgM enzyme-linked immunosorbent assays

We evaluated performance of three commercial Japanese encephalitis virus (JEV) IgM antibody capture enzyme-linked immunosorbent assay (MAC ELISA) kits with a panel of serological specimens collected during a surveillance project of acute encephalitis syndrome in India and acute meningitis and encephalitis syndrome in Bangladesh. The serum and cerebral spinal fluid specimens had been referred to the Centers for Disease Control and Prevention (CDC) for confirmatory testing. The CDC results and specimen classifications were considered the reference standard. All three commercial kits had high specificity (95-99.5%), but low sensitivities, ranging from 17-57%, with both serum and cerebrospinal fluid samples. Specific factors contributing to low sensitivity compared with the CDC ELISA could not be determined through further analysis of the limits and dilution end points of IgM detection.     

Cyclooxygenase-2 derived thromboxane A2 and reactive oxygen species mediate flow-induced constrictions of venules in hyperhomocysteinemia

ObjectiveHyperhomocysteinemia (HHcy) has been shown to impair the endothelial function of arterial vessels and promote thrombosis. There are no studies, however, assessing the effects of HHcy on the vasomotor function of venules. We hypothesized that HHcy activates pathophysiological mechanisms impairing flow/shear stress-dependent responses of venules.Methods and resultsChanges in diameter of isolated gracilis muscle venules (diameter: ～250 μm at 10 mmHg) of control and HHcy rats (induced by methionine diet for 5 weeks) to increases in intraluminal flow were measured. Increases in flow elicited dilations in control (at max.: 14 ± 1%), but induced constrictions in HHcy venules (at max.: ?24 ± 4%). Flow-induced constrictions in HHcy venules were converted to dilations in the presence of the thromboxane A₂ (TxA₂) receptor (TP) antagonist SQ 29,548, which were then abolished by the simultaneous administration of nitric oxide (NO) synthase inhibitor, L-NAME and non-selective cyclooxygenase (COX) blocker, indomethacin. In addition, the selective COX-2 inhibitor NS 398 reversed flow-induced constrictions to dilations, which were significantly decreased by additional COX-1 inhibitor, SC 560. Also, as compared to controls, a SOD/CAT sensitive increased ethidium bromide fluorescence was detected in HHcy small veins, indicating substantial production of reactive oxygen species (ROS) in HHcy. Correspondingly, SOD/CAT diminished flow-induced constrictions in venules of HHcy rats.ConclusionsIn hyperhomocysteinemia increases in flow/shear stress increases the production of COX-2-derived TxA₂, and reactive oxygen species – that overcome the dilator effects of NO and prostaglandins – eliciting constrictions in skeletal muscle venules; changes which can increase vascular resistance and favor thrombus formation in the venular circulation.     

Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific,high-affinity binding to CSA

Pregnancy-associated malaria (PAM) is a serious consequence of sequestration of Plasmodium falciparum-parasitized erythrocytes (PE) in the placenta through adhesion to chondroitin sulfate A (CSA) present on placental proteoglycans. Recent work implicates var2CSA, a member of the PfEMP1 family, as the mediator of placental sequestration and as a key target for PAM vaccine development. Var2CSA is a 350 kDa transmembrane protein, whose extracellular region includes six Duffy-binding-like (DBL) domains. Due to its size and high cysteine content, the full-length var2CSA extracellular region has not hitherto been expressed in heterologous systems, thus limiting investigations to individual recombinant domains. Here we report for the first time the expression of the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) from the 3D7 parasite strain using the human embryonic kidney 293 cell line. We show that the recombinant extracellular var2CSA region is correctly folded and that, unlike the individual DBL domains, it binds with high affinity and specificity to CSA (K_D = 61 nM) and efficiently inhibits PE from binding to CSA. Structural characterization by analytical ultracentrifugation and small-angle x-ray scattering reveals a compact organization of the full-length protein, most likely governed by specific interdomain interactions, rather than an extended structure. Collectively, these data suggest that a high-affinity, CSA-specific binding site is formed by the higher-order structure of the var2CSA extracellular region. These results have important consequences for the development of an effective vaccine and therapeutic inhibitors.     

Pentoxifylline inhibits replication of Japanese encephalitis virus: a comparative study with ribavirin

Several investigations have shown that pentoxifylline possesses broad-spectrum antiviral activity against a range of RNA and DNA viruses. However, its ability to inhibit Japanese encephalitis virus (JEV) replication has not yet been studied. The present study was designed to investigate the antiviral activity of pentoxifylline against JEV in vitro and in vivo. The activity of pentoxifylline against JEV was evaluated in vitro using cytopathic effect inhibition and plaque reduction assays. Pentoxifylline was able to inhibit JEV replication in a dose-dependent manner at a 50% inhibitory concentration (IC(50)) of 50.3microg/mL (0.00018microM) and a therapeutic index (TI) of 10. Experiments to study the mechanism of antiviral action of pentoxifylline using in vitro translation of viral mRNA suggested that the drug did not interfere either with early or late protein synthesis but most likely exerted its action on virus assembly and/or release. Furthermore, the in vivo study showed that pentoxifylline at a concentration of 100mg/kg and 200mg/kg body weight was able to protect completely mice challenged with 50 x 50% lethal dose (LD(50)) of JEV.