PURPOSE OF REVIEW: This review presents research published over the last year examining use of urate-lowering therapy (ULT) as well as trends over time in adherence to this class of agents. Additionally, it explores factors associated with nonadherence to ULTs for chronic gout and interventions to improve chronic gout management.
RECENT FINDINGS: New literature suggests prescriptions of ULTs for prevalent and incident gout patients remains lower than expected based on the burden of the disease in the population. Overall ULT adherence remains suboptimal, in part related to inadequate patient education and copayment costs; although one study demonstrated improvement in adherence over a 15-year study period. Finally, interventions that include patient education and medication titration based on laboratory results successfully lowered serum urate levels to less than 6 mg/dl in the majority of patients.
SUMMARY: Gout remains a prevalent disease that is poorly managed despite effective treatments. Recent research suggests that ULTs are underutilized and even when prescribed are not well adhered to. Patient-centered interventions that focus on education about pharmacologic therapy and lifestyle modifications with medication titration have resulted in a greater proportion of patients achieving recommended serum urate levels.
BACKGROUND: This study explores the current patterns of reproductive health service use among young women in the USA and the changing influence of socio-demographic factors on the types of services used over time.
METHODS: The study population, drawn from the two last cycles of the National Survey of Family Growth, consists of women aged 15-24 (n = 2543 in 1995, n = 2157 in 2002). We examined trends in use of 'contraceptive services' and 'other reproductive health services for preventive care' and tested for changes in the patterns of use of these services over time. Logistic regression models were used to further clarify the factors associated with the use of the two types of services in 2002.
RESULTS: Results show no difference in the overall use of reproductive health services in the past year but did reveal changes in the type of service sought. Use of services for contraception increased by 10 percentage points (39.3% in 1995 to 49.7% in 2002, P < 0.001), although the use of other services remained stable (53.2% in 1995, 50.2% in 2002, P = 0.14). The patterns of use varied over time, exhibiting growing social disparities. In 2002, the use of contraceptive services depended on women's age, number of partners, personal and mother's level of education, and menstrual problems. The use of other reproductive health services for preventive care varied across women's socio-economic background.
CONCLUSION: This study demonstrates increasing social differentials in the use of reproductive health services for preventive care among young women in the USA between 1995 and 2002, a finding which calls for careful monitoring in the context of limited resources.
PURPOSE: The purpose of this study was to compare inflammatory responses, tissue integration, and strength of the acellular dermal collagen matrices AlloDerm((R))* Regenerative Tissue Matrix, Permacol**Surgical Implant (Permacol), and CollaMend*** Implant in a rat model for ventral hernia repair.
METHODS: Rats were randomized into four groups and abdominal wall defects repaired with an inlay graft of AlloDerm, Permacol, or CollaMend. Rats were sacrificed at six time points and the defect area was removed and analyzed for tissue integration and physical strength.
RESULTS: Variable cell infiltration was seen for the three implant groups. At of the all time points examined, cellular infiltration was most rapid in the AlloDerm implants and slowest for CollaMend. At 14 days, significant cell infiltration along with putative blood vessel formation was observed for AlloDerm, while Permacol implants exhibited a moderate level of infiltration. Very few cells penetrated CollaMend implants at 2 weeks. Cells had reached the center of the Permacol implants by 1 month, whereas CollaMend implants were encapsulated with a loose coat of disconnected cells, with very few cells infiltrating past the surface. At 6 months, AlloDerm and Permacol had evidence of cell penetration throughout the implants, while the CollaMend samples exhibited limited infiltration. Animals for each implant developed seromas: AlloDerm 40%, Permacol 33%, and CollaMend 83%. Mechanical testing revealed that AlloDerm at 6 months showed the lowest tensile strength, CollaMend the highest, and Permacol an intermediate level.
CONCLUSIONS: The three biologics exhibited different patterns and rates of cellular and vascular permeation in our rat model. AlloDerm implants exhibited the most rapid and extensive cellular infiltration, followed by Permacol. However, on gross examination, the AlloDerm implants thinned significantly by 6 months. In contrast, the Permacol and CollaMend implants appeared to be largely intact.
Prostate carcinoma and radiation therapy: therapeutic treatment resistance and strategies for targeted therapeutic intervention
Adenocarcinoma of the prostate remains a significant public health problem and a prevalent cancer in men. Prostate-specific antigen used as a biomarker has established a clear migration of patients towards earlier-stage disease at presentation. However, in spite of process improvements in traditional therapies including surgery, radiation therapy, and hormone management, there remains a significant cohort of patients with intermediate- to high-risk features for poor outcome in spite of optimal use of traditional management. This paper focuses on future treatment strategies integrating new therapeutic options with traditional management, specifically to pinpoint new radiation therapy strategies.
BACKGROUND and OBJECTIVES: India carries approximately 50 per cent of the global burden of visceral leishmaniasis and majority of patients from the poor, rural communities of Bihar State. Zinc is an essential trace element and its relevance for proper functioning of the entire immune system is already well documented. Though low serum zinc levels have been reported in many parasitic diseases, limited information is available regarding zinc status in human leishmaniasis. We investigated to define the relationship between zinc level in visceral leishmaniasis (VL) patients in endemic and non-endemic regions. METHODS: Venous blood was collected from 88 patients, 16 parasitologically confirmed VL, 35 healthy controls from endemic area (Bihar) and 37 healthy urban controls from non-endemic area, Delhi. In all the three groups, levels of serum albumin, total protein (markers of nutritional status) and zinc were estimated by colorimetric methods. RESULTS: Serum zinc levels were found to be significantly lower (P<0.001) in VL patients than non-endemic controls. The serum zinc levels in VL endemic controls were also significantly lower (P < 0.001) than non- endemic controls, but these values were not statistically significantly different from VL patients. However, all samples from Bihar (VL patients and controls) had lower serum zinc levels than non-endemic controls from Delhi. INTERPRETATION and CONCLUSION: Low serum Zn levels, in healthy subjects from Bihar and more significantly in VL patients of this region, are possibly associated with vulnerability and endemicity of visceral leishmaniasis in the region. Further studies need to be done to assess the role of oral zinc supplementation in better management and prevention of VL, particularly in endemic areas.
Standardizing the method of measuring by echocardiogram the diameter of the ascending aorta in patients with a bicuspid aortic valve
Serial echocardiographic follow-up of patients with a bicuspid aortic valve (BAV), in addition to providing assessment of valve dysfunction, can help identify those at risk of aortic complications. However, currently there is no standardized echocardiographic method for measuring the ascending aorta. We examined the echocardiograms of 45 patients with a BAV and 45 matched controls to understand the effects of the measurement location (1, 2, and 3 cm above the sinotubular junction) and the point in the cardiac cycle (end-diastole, mid-systole, and end-systole) at which the ascending aortic measurements are made. A greater length of aorta could be measured in end-systole than in end-diastole, presumably because of aortic recoil. Using the control data for comparison, we found that more dilated ascending aortas were detected by measuring 3 cm above the sinotubular junction in the patients with a BAV (56%) than at 1 cm (42%). The increases in size between 1 and 2 cm were greater than those between 2 and 3 cm. In conclusion, we propose that all transthoracic echocardiograms should include the proximal aorta at least 2 cm and preferably 3 cm above the sinotubular junction and suggest that for standardization and optimal visualization the measurements be done at end-systole in all patients.
PURPOSE: To report the visual resolution of multiple cell and vascular "layers" in the cat retina using MRI.
MATERIALS AND METHODS: T2- and diffusion-weighted MRI at 4.7 Tesla was performed. Layer-specific thickness, T2, spin density, apparent diffusion coefficient perpendicular (ADC(perpendicular)) and parallel (ADC(parallel)) to the retinal surface were tabulated. T1-weighted MRI was acquired before and after intravenous administration of Gd-DTPA and subtraction images were obtained. Histology was performed for validation.
RESULTS: Three distinct "layers" were observed. The inner strip nearest to the vitreous (exhibiting large T2, ADC, spin density with Gd-DTPA enhancement) overlapped the ganglion cell layer, bipolar cell layer, and the embedded retinal vascular layer. The middle strip (exhibiting small T2, ADC, spin density without Gd-DTPA enhancement) overlapped the photoreceptor cell layer and the inner and outer segments. The outer strip (exhibiting large T2, ADC, spin density with Gd-DTPA enhancement) overlapped the tapetum and choroidal vascular layer. T2, spin density, ADC(perpendicular) and ADC(parallel) of different "layers" were tabulated. The inner strip was slightly thicker than the other two strips. The total thickness, including neural and nonneural retina, was 358 +/- 13 microm (N = 6) by MRI and 319 +/- 77 microm (N = 5) by histology.
CONCLUSION: MRI provides a noninvasive tool to study the retina with laminar specificity without depth limitation.
BACKGROUND: Extragastrointestinal stromal tumors (eGISTs) are rare mesenchymal-derived tumors arising outside of the GI tract. eGISTs are often histologically confused with leiomyosarcoma. Distinction between eGIST and leiomyosarcoma is critical because of the unique responsiveness of eGISTs to the molecularly targeted agent imatinib.
CASE: A woman presented with a history of tubal spindle cell tumor that was initially diagnosed and treated as a leiomyosarcoma. Because of minimal response to sarcoma directed chemotherapy, the possibility that the tumor was in fact an eGIST was investigated and supported by immunohistochemical and mutational analyses of the c-Kit receptor tyrosine kinase. The patient currently has stable disease control on imatinib for the last 18 months.
CONCLUSIONS: The possibility of eGIST should be considered in the differential diagnosis of tumors with a spindle cell morphology in the gynecologic tract especially when involving the ovary, fallopian tube, or uterine serosa.
Comparative effects of unfractionated heparin and low molecular weight heparin on vascular endothelial cell tissue factor pathway inhibitor release: a model for assessing intrinsic thromboresistance
OBJECTIVES: The purpose of our study was to characterize tissue factor pathway inhibitor (TFPI) release from human vascular endothelial cells following daily exposure to varying concentrations of unfractionated heparin (UFH) and low molecular weight heparin (LMWH).
BACKGROUND: A "rebound" increase in ischemic/thrombotic events, including myocardial infarction and cardiovascular death, has been observed after the abrupt cessation of UFH. In a single center pilot study of patients with acute coronary syndromes (ACS) we reported that thrombin generation was evident within one (1) hour of UFH cessation, increased progressively over the subsequent 24 hours, correlated directly with factor VII activity and inversely with TFPI (concentration and activity). METHODS: Human umbilical vein endothelial cells were grown to confluence and incubated with varying concentrations of UFH or dalteparin, a low molecular weight haparin, for up to 144 hours. Daily samples of the cells supernatant were obtained and assayed for TFPI. Cellular reserve and responsiveness to recombinant endothelial cell growth factor (rEGF) stimulation were determined at 168 hours.
RESULTS: In low concentrations (0.5 U/mL) UFH caused a progressive rise in TFPI concentration with a peak level of 6.36 +/- 0.5 ng/10(5) cells at 24 hours. By 72 hours of daily exposure, the levels declined to below control values and TFPI release following rEGF stimulation was reduced by approximately 60% compared to control (1.93 +/- 0.42 vs 4.3 +/- 0.78 ng/10(5) cells; p = 0.001). Initial endothelial cell release and rate of decline were more robust with high concentrations of UFH (5.0 U/ml). TFPI levels were above control values at each sampling time point up to 120 hours and cellular responsiveness to stimulation was preserved with dalteparin (compared to UFH) (p < 0.001).
CONCLUSIONS: Thrombin generation and clinical events that occur during treatment with UFH and following its abrupt cessation may represent an acquired state of transiently impaired thromboresistance to the tissue factor-VIIa complex. The differing effects of UFH and LMWH on vascular endothelial cell TFPI synthesis, release and reserve with prolonged administration require further investigation.
PURPOSE: To evaluate the percent of the prescribed radiation dose to the breast delivered to the axillary tissue and to evaluate the volume of the axilla receiving 95% of the prescribed dose with normal and with high tangential fields.
METHODS AND MATERIALS: Computed tomographic scan images with 5-mm sections were retrospectively analyzed for 35 patients who had undergone three-dimensional (3D) planning for whole-breast radiation. The axillary nodal region was identified and divided into Levels I to III and Rotter's nodes (RN). Digitally reconstructed radiographs were created, and two plans were developed: (a) the standard clinical opposed tangential irradiation fields and (b) the high-tangential irradiation fields. Axillary coverage was examined by use of dose-volume histograms (DVH), and the average coverage for the four nodal groups was obtained.
RESULTS: The data show that with the standard tangential irradiation fields, the average dose delivered to Levels I, II, III, and RN is 66% (standard deviation, or SD = 13%), 44% (SD = 18%), 31% (SD = 20%), and 70% (SD = 19%) of the prescribed dose, respectively. The coverage increases to 86% (SD = 9%), 71% (SD = 19%), 73% (SD = 17%), and 94% (SD = 8%) of the prescribed dose, respectively, for Levels I, II, III, and RN when the high tangential irradiation fields are used. 51% of Level I, 26% of Level II, and 15% of Level III receive 95% of the prescribed dose with normal tangents. The volume increases to 79%, 51%, and 49% of Levels I, II, and III, respectively, with high tangents.
CONCLUSION: The tangential fields designed to treat only the breast do not adequately cover the axillary region and, therefore, cannot be relied upon for prophylactic therapy of the axilla. The high tangential irradiation fields increase the dosages received by the axillary region, but the average dosages received by the lower axillary regions are still less than 90% of the prescribed dose.
Mammalian hibernation is mediated by humoral agonists of the delta opioid receptor (DOR). Moreover, transfer of either humoral or synthetic DOR agonists to non-hibernators reportedly induces a state of improved myocardial ischemic tolerance.
OBJECTIVE: To determine whether the DOR agonist D-Ala 2, D-Leu 5, enkephalin (DADLE) similarly elicits protection in noncardiac-i.e., mesenteric-tissue.
METHODS: In Protocols 1 and 2, the authors developed and characterized an in vitro model of mesenteric ischemia/reperfusion in isolated rabbit jejunum by documenting the effect of increasing ischemic duration (0 to 120 minutes) and the relative importance of glucose and/or oxygen deprivation on the evolution of jejunal injury. In Protocol 3, jejunal segments were randomized to receive either no treatment (controls) or 15 minutes of pretreatment with 1 microM DADLE, followed by 60 minutes of simulated ischemia and 30 minutes of reperfusion. Jejunal injury was quantified by repeated, time-matched assessment of peak contractile force evoked by 1 microM acetylcholine (all protocols) and delineation of tissue necrosis (Protocol 1).
RESULTS: Development of significant jejunal injury required combined oxygen/glucose deprivation. Moreover, there was a direct relationship between ischemic duration and tissue injury, and a significant inverse correlation between reperfusion contractile force (% of baseline) and the extent of smooth muscle necrosis (r(2) = 0.87; p < 0.01). Most notably, mesenteric ischemia/reperfusion injury was attenuated by DADLE: reperfusion contractile force was 47 +/- 5% versus 36 +/- 5% in DADLE-treated versus control segments (p < 0.01).
CONCLUSIONS: Treatment with the delta opioid agonist DADLE increases ischemic tolerance of isolated rabbit jejunum.
Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS)
Astrocytic proliferation and hypertrophy (astrogliosis) are associated with neuronal injury. However, neither the temporal nor the spatial relationship between astrocytes and injured neurons is clear, especially in neurodegenerative diseases. We investigated these questions in a mouse amyotrophic lateral sclerosis (ALS) model. The initial increase in astrogliosis coincided with the onset of clinical disease and massive mitochondrial vacuolation in motor neurons. After disease onset, astrogliosis increased further in parallel with the number of degenerating motor neurons. Examination of individual astrocytes by three-dimensional reconstruction revealed that astrocytes extended their processes toward, wrapped around, and sometimes penetrated vacuoles derived from neuronal mitochondria. These results show a close temporal correlation between the onset of neuronal degeneration and the beginning of astrogliosis in this neurodegenerative disease and reveal a novel spatial relationship that is consistent with the view that astrocytes play an active role in the neuronal degeneration process.
The human retinal pigment epithelium (RPE) is a potential target tissue for directed transfer of candidate genes to treat age-related macular degeneration (AMD). The RPE is uniquely suited to gene therapy protocols that use liposome-mediated DNA transfer because of its high intrinsic phagocytic function in vivo. In these studies, we examined the efficacy of human RPE cell uptake and expression of the green fluorescent protein (GFP) and neomycin resistance marker genes by polyplex-mediated gene transfer in vitro. The effects of varying DNA and polyplex concentration and ratios on GFP transgene expression were examined. A narrow range of experimental conditions were found to maximize transgene expression; most important were the DNA concentration and the DNA:polyplex ratio. The transfection efficiency for human RPE cells was reproducibly 20% in vitro by this method and reached a maximum level of expression after 48 h. There was a rapid decline in gene expression over 2 weeks following polyplex-mediated gene transfer, but stable integration does occur at low frequencies with and without selection.
Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction
HYPOTHESIS: Intravenous patient-controlled analgesia (IV PCA) meperidine hydrochloride can be used with a reasonable margin of safety. DESIGN: A retrospective review was performed of 355 medical records of patients receiving IV PCA meperidine treatment. Four groups of patients were defined, based on daily meperidine dose and the presence or absence of central nervous system excitation adverse effects. Use of more than 600 mg/d of meperidine hydrochloride was considered a high dose. SETTING: University tertiary care hospital. PARTICIPANTS: Postoperative patients from general, orthopedic, neurosurgical, gynecological, and urologic procedures receiving IV PCA. INTERVENTIONS: If patients were judged to have consumed significant amounts of meperidine, the analgesic regimen was modified to (1) discontinue meperidine therapy, (2) substitute hydromorphone hydrochloride, or (3) decrease the use of meperidine by adding oral methadone hydrochloride or transdermal fentanyl citrate to the regimen. MAIN OUTCOME MEASURES: Patients who received less than 10 mg/kg per day of IV PCA meperidine hydrochloride therapy were unlikely to experience central nervous system excitatory adverse effects and maintain adequate analgesia. RESULTS: The mean meperidine hydrochloride consumption for those patients classified as high dose, asymptomatic was 13.3 mg/kg per day (95% confidence interval, 12.1-14.4 mg/kg per day). This differed statistically significantly (P<.05) from the mean meperidine hydrochloride dose in patients classified as high dose, symptomatic, which was 16.9 mg/kg per day (95% confidence interval, 14.7-19.2 mg/kg per day). The duration of meperidine use did not differ among the 4 patient groups. The incidence of a central nervous system toxic reaction associated with IV PCA meperidine therapy was 2%. CONCLUSIONS: We recommend 10 mg/kg per day as a maximum safe meperidine hydrochloride dose by an IV PCA device for no longer than 3 days. Daily patient evaluation is mandatory. Care must also be taken when using this dose to ensure the absence of renal dysfunction or enhanced hepatic metabolism of meperidine.