"Time Saved" Calculations to Improve Decision-Making in Progressive Disease Studies.

BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

Vacuum-assisted closure in the treatment of a 9-year-old child with severe and multiple dog bite injuries of the thorax.

The vacuum-assisted closure (VAC; KCI International, San Antonio, TX) device is a negative pressure dressing, which we have used in the treatment of wounds with devitalized or infected tissues. Although introduced in plastic and reconstructive surgery, its use has extended to orthopedic and cardiothoracic surgical practice in the treatment of infected joint replacement and sternal wound infections, respectively. Although the VAC is becoming more widely used in surgical practice, only a small number of case reports exist in addition to the original case series by Argenta and Morykwas in 1997. Previously, the device was described in treating single wounds in adult patients. We report a case where it was successfully used to treat multiple dog bite injuries in a 9-year-old child.

Pamidronate decreases tumor-induced osteoclastogenesis in osteopetrotic mice.

Recent studies indicate that the bisphosphonate pamidronate reduces skeletal complications caused by tumor osteolysis. In this investigation, the cellular mechanism through which pamidronate affects tumor-induced osteoclastogenesis is studied in osteopetrotic mice. A unique animal model is employed which studies the effect of pamidronate on a tumor (2472 sarcoma) which induces osteoclastogenesis in osteoclast-deficient mice (oplop). This model provides opportunity to specifically study effects on osteoclast formation and findings suggest that pamidronate decreases the number of osteoclasts at sites of 2472 tumor by decreasing the number of osteoclast precursor cells at the level of myeloid precursors.

Metabolism of benzo(a)pyrene by duck liver microsomes.

The metabolism of benzo(a)pyrene [BP], a model carcinogenic PAH, by hepatic microsomes of two duck species, mallard (Anas platyrhynchos) and common merganser (Mergus merganser americanus) collected from chemically-contaminated and relatively non-contaminated areas was investigated. The rate of metabolism of BP by liver microsomes of common merganser and mallard collected from polluted areas (2,650 +/- 310 and 2,200 +/- 310 pmol/min per mg microsomal protein, respectively) was significantly higher than that obtained with liver microsomes of the two species collected from non-polluted areas (334 +/- 33 and 231 +/- 30 pmol/min per mg microsomal protein, respectively). The level of cytochrome P-450 1A1 was significantly higher in the liver microsomes of both duck species from the polluted areas as compared to the ducks from the non-polluted areas. The major BP metabolites, including BP-9, 10-diol, BP-4, 5-diol, BP-7, 8-diol, BP-1, 6-dione, BP-3, 6-dione, BP-6, 12-dione, 9-hydroxy-BP and 3-hydroxy-BP, formed by liver microsomes of both duck species from polluted and non-polluted areas, were qualitatively similar. However, the patterns of these metabolites were considerably different from each other. Liver microsomes of ducks from the polluted areas produced a higher proportion of benzo-ring dihydrodiols than the liver microsomes of ducks from the non-polluted areas, which converted a greater proportion of BP to BP-phenols. The predominant enantiomer of BP-7,8-diol formed by hepatic microsomes of the two duck species had an (-)R,R absolute stereochemistry. The data suggest that duck and rat liver microsomal enzymes have different regioselectivity but similar stereoselectivity in the metabolism of BP.

Photodegradation of polychlorinated dibenzo-p-dioxins and dibenzofurans in aqueous solutions and in organic solvents.

Aqueous solutions of selected polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) were prepared using a generator column and exposed to UV (300 nm) light in the laboratory and to sunlight in an outdoor environment. In the laboratory, additional exposures were also carried out using 60% acetonitrile/water solutions. At 300 nm di- and tetra PCDDs had higher first-order photodegradation rate constants in 60% acetonitrile/water than in pure water. The solvent effect was reversed for PCDFs. These results may be a reflection of the higher polarity of PCDFs compared to PCDDs. In both the indoor and outdoor exposures photodegradation rates decreased with increasing concentrations of chlorination. However, OCDF exposed to 300 nm light in 60% acetonitrile/water and to sunlight in pure water photodegraded more rapidly than tetra CDF. Photolysis rates in sunlight were considerably slower (t(1/2) of 6.4-23 h) than photolysis rates at 300 nm in the laboratory (t(1/2) of 4.3-680 min), reflecting the lower intensity of sunlight in the 300 nm region of the UV/Vis spectrum. The extent of dechlorination of the PCDDs/PCDFs was less than 20% and reductive dechlorination does not appear to be a major process in the photodegradation of PCDDs/PCDFs in aqueous solutions.

Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord.

Bone cancer pain is common among cancer patients and can have a devastating effect on their quality of life. A chief problem in designing new therapies for bone cancer pain is that it is unclear what mechanisms drive this distinct pain condition. Here we show that osteoprotegerin, a secreted 'decoy' receptor that inhibits osteoclast activity, also blocks behaviors indicative of pain in mice with bone cancer. A substantial part of the actions of osteoprotegerin seems to result from inhibition of tumor-induced bone destruction that in turn inhibits the neurochemical changes in the spinal cord that are thought to be involved in the generation and maintenance of cancer pain. These results demonstrate that excessive tumor-induced bone destruction is involved in the generation of bone cancer pain and that osteoprotegerin may provide an effective treatment for this common human condition.

Perforation of the right ventricle by a suction drain.

Suction drains can be used as alternatives to conventional underwater seal drains following cardiac surgery, and may be advantageous under some circumstances. The authors present a case where a suction drain eroded into the right ventricle causing near-fatal haemorrhage following coronary artery surgery. Caution should be exercised in taking the decision to use suction drains, the material from which they are manufactured should be chosen carefully, and close attention paid to their positioning within the mediastinum.

Antiestrogenicity of environmental polycyclic aromatic hydrocarbons in human breast cancer cells.

The total concentration of 14 polycyclic aromatic hydrocarbons (PAHs) was determined to be 3400-fold greater in a sediment sample from an industrial site on the St. Lawrence River (SLR), NY, than in a sediment sample from a non-industrial site on the Kinderhook Creek (KC), NY. PAH fractions from extracts of the two environmental samples and two reconstituted mixtures as well as the 14 individual PAHs were examined for their toxic, estrogenic, and antiestrogenic activities using MCF-7 focus, recombinant human estrogen receptor (ER) binding, whole-cell ER binding, and 17beta-estradiol (E2) metabolism assays. PAH fractions from the KC and SLR were antiestrogenic; they significantly inhibited the formation of foci elicited in MCF-7 breast cancer cells by 1 nM E2. Eight of the 14 individual PAHs, and the reconstituted mixtures were also antiestrogenic. Results from the whole-cell ER binding assay and the radiometric analysis of E2 metabolism indicate that the PAHs detected in the KC and the SLR environmental samples induce antiestrogenic responses in metabolically intact human breast cancer cells through at least two mechanisms: one involving competition for the ER by a PAH metabolite and the other involving depletion of E2 through induction of metabolism.

Effective oral ganciclovir prophylaxis against cytomegalovirus disease in heart transplant recipients.

The presented data show the combined sequential use of i.v. G for 14 days followed by PO G for 90 days is a much more effective prophylaxis for CMVD after heart transplantation than use of i.v. G for 14 days followed by PO A for 90 days. A need for hospitalization due to CMVD is significantly reduced by this new strategy. The follow-up in group II is shorter than in group I but is now at least 6 months in group II, without any new cases in the first 6 months after cardiac transplantation. Some currently unknown adverse effect of prolonged PO G, which may be present, is not identified in this analysis.

Pericardial substitution after cardiopulmonary bypass surgery: a trial of an absorbable patch.

Primary closure of the pericardium affords some protection against adhesion formation and the consequent hazards of resternotomy. However, its completion may be impractical and hazardous, and therefore the pursuit of an ideal pericardial substitute has prompted much research. Twenty calves were divided into 3 groups for the study. All animals underwent right posterolateral thoracotomy. The test group (group X), consisting of 6 animals, received a poly-beta-hydroxybutyrate patch (PHB) to close the pericardium following cardiopulmonary bypass (CPB). In group Y (9 animals) the pericardium was left open following CPB. Group Z (5 animals) also had their pericardium left open but did not undergo CPB (non-CPB). The plasminogen activating activity (PAA) of homogenates of pericardial tissue samples were measured in 5 animals in group X, and 5 in group Z. Samples were taken at three time points from the time of pericardiotomy, and at reoperation 4 weeks later. In group X (CPB) there was a significant reduction in the PAA during the operation with some recovery at reoperation. The reduction in the pericardial PAA of group Z (non-CPB) animals did not reach significance. For both group X and group Z the progress of mesothelial damage, compared with that at zero time, showed a significant increase. In addition, their pericardial inflammatory features became more apparent in the later samples but more significantly in group Z. This study demonstrated no significant short-term differences in adhesion formation or postoperative coronary anatomy visibility between any of the groups. At reoperation the patch material contained pronounced macrophage activity but no regenerative mesothelium. There were no infective episodes in any of the animals studied. Furthermore, this study suggests that CPB in comparison to non-CPB has a significant affect on pericardial PAA.

Separation of extracts from biological tissues into polycyclic aromatic hydrocarbon, polychlorinated biphenyl and polychlorinated dibenzo-p-dioxin/polychlorinated dibenzofuran fractions prior to analysis.

A low-pressure liquid chromatography method is presented for separating polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDDs/PCDFs) from biological tissue extracts. After removing lipid from extracts, the PAHs are separated from PCBs and PCDDs/PCDFs on a deactivated 13-24 microns silica gel column. The PCBs are subsequently separated from PCDDs/PCDFs by collecting the first fraction from an automated three column cleanup procedure for PCDDs/PCDFs. The complete method has been used to obtain high recoveries of the three compound classes for analysis by GC-electron capture detection (PCBs) or GC-MS (PAHs and PCDDs/PCDFs).

Participatory analysis for redefining health delivery in a Bombay slum.

BACKGROUND: This paper explores the application of participatory methods in a Bombay slum of 33 households, Budh Mandir, to establish the local women's perception of their health status. METHOD: Six participatory meetings were conducted alongside informal interviews with key informants. The meetings were structured with health ranking, mapping and seasonal mapping exercises. RESULTS: The participatory exercises expose the differences in perceptions between professional health deliverers and the women of Budh Mandir, as well as providing data at a household scale about the incidence of disease and important differences in the interpretation of health problems. CONCLUSIONS: Differences in the perception between local women and health professionals are noted, which, it is argued, have important implications in redefining health delivery. Some methodological problems are identified and solutions are offered. It is argued that participatory methods can act as a process through which slum dwellers can demand appropriate health care for themselves and their families. In so doing, they can redefine their health needs in order that health intervention can be directed more appropriately.

PIP: Siddharth Nagar is an extensive slum in Bombay. Budh Mandir is a part of that slum, comprising 33 brick and concrete dwellings. Participatory methods were applied in Budh Mandir to establish local women's perception of their health status. Six participatory meetings were held together with informal interviews with key informants. The meetings were structured with health ranking, mapping, and seasonal mapping exercises. The perceptions of professional health care providers differ from those of the women of Budh Mandir. Data were also provided at a household scale on the incidence of disease and important differences in the interpretation of health problems. These differences in perception have important implications in redefining health delivery. Some methodological problems are identified and solutions offered. Participatory methods can act as a process through which slum dwellers can demand appropriate health care for themselves and their families. In so doing, they can redefine their health needs to better direct health interventions.

Polychlorinated dibenzofurans and dibenzo-p-dioxins in subsurface soil, superficial dust, and air extracts from a contaminated landfill.

Extracts of soil, dust and air from a National Priorities List Landfill have been found to contain distinct profiles of polychlorinated biphenyls (PCBs). The different extracts show subtle differences in toxicities and the soil extract has been shown to cause both Ah receptor mediated effects and Ah receptor independent effects in immature female rats. Evidence of open burning at the site dictated quantitation of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) for a more accurate tabulation of dioxin equivalencies. High volume air sampling on XAD-2 resin cartridges captured trace amounts of PCDFs and no detectable PCDDs. Acetone:Hexane (1:1) extracts of soil and dust contained 762 microg/ml and 250 microg/ml PCDFs, respectively, and less than 10% as much PCDD. Subsequent benzene:methylene chloride (1:1) extracts were enriched in coplanar compounds relative to total PCBs. PCDF:PCB ratios in all extracts were higher than in the rice oils contaminated with heated PCBs in the Yusho and Yu-Cheng incidents. No 2,3,7,8-TCDD was detected, and total PCB+PCDD+PCDF toxic equivalencies were dominated by the high proportions of PCDFs.