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Yu-Wen Chiu,1 Yu-Hsiang Kao,1 Michael J Simoff,2 David E Ost,3 Oliver Wagner,4 James Lavin,4 Richard A Culbertson,1 Dean G Smith1 1Health Policy & Systems Management, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA; 2Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, Michigan, USA; 3Department of Pulmonology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 4Intuitive Surgical, Sunnyvale, California, USACorrespondence: Dean G SmithLSU Health Sciences Center – New Orleans, School of Public Health, 2020 Gravier St., New Orleans, LA, 70112, USAEmail dgsmith@lsuhsc.eduPurpose: To describe the distribution of diagnostic procedures, rates of complications, and total cost of biopsies for patients with lung cancer.Patients and Methods: Observational study using data from IBM Marketscan® Databases for continuously insured adult patients with a primary lung cancer diagnosis and treatment between July 2013 and June 2017. Costs of lung cancer diagnosis covered 6 months prior to index biopsy through treatment. Costs of chest CT scans, biopsy, and post-procedural complications were estimated from total payments. Costs of biopsies incidental to inpatient admissions were estimated by comparable outpatient biopsies.Results: The database included 22,870 patients who had a total of 37,160 biopsies, of which 16,009 (43.1%) were percutaneous, 14,997 (40.4%) bronchoscopic, 4072 (11.0%) surgical and 2082 (5.6%) mediastinoscopic. Multiple biopsies were performed on 41.9% of patients. The most common complications among patients receiving only one type of biopsy were pneumothorax (1304 patients, 8.4%), bleeding (744 patients, 4.8%) and intubation (400 patients, 2.6%). However, most complications did not require interventions that would add to costs. Median total costs were highest for inpatient surgical biopsies ($29,988) and lowest for outpatient percutaneous biopsies ($1028). Repeat biopsies of the same type increased costs by 40– 80%. Complications account for 13% of total costs.Conclusion: Costs of biopsies to confirm lung cancer diagnosis vary substantially by type of biopsy and setting. Multiple biopsies, inpatient procedures and complications result in higher costs.Keywords: cancer, diagnosis, economics, frequency

Abstract Background Rhesus macaques (Macaca mulatta) are the primate most used for biomedical research, but phenotypic differences between Indian-origin and Chinese rhesus macaques have encouraged genetic methods for identifying genetic differences between these two populations. The completion of the rhesus genome has led to the identification of many single nucleotide polymorphisms (SNPs) in this species. These single nucleotide polymorphisms have many advantages over the short tandem repeat (STR) loci currently used to assay genetic variation. However, the number of currently identified polymorphisms is too small for whole genome analysis or studies of quantitative trait loci. To that end, we tested a combination of methods to identify large numbers of high-confidence SNPs, and screen those with high minor allele frequencies (MAF). Results By testing our previously reported single nucleotide polymorphisms, we identified a subset of high-confidence, high-MAF polymorphisms. Resequencing revealed a large number of regionally specific SNPs not identified through a single pyrosequencing run. By resequencing a pooled sample of four individuals, we reliably identified loci with a MAF of at least 12.5%. Finally, we found that when applied to a larger, geographically variable sample of rhesus, a large proportion of our loci were variable in both populations, and very few loci were ancestry informative. Despite this fact, the SNP loci were more effective at discriminating Indian and Chinese rhesus than STR loci. Conclusion Pyrosequencing and pooled resequencing are viable methods for the identification of high-MAF SNP loci in rhesus macaques. These SNP loci are appropriate for screening both the inter- and intra-population genetic variation.

Background: Chronic fatigue syndrome (CFS) in children is a controversial diagnosis with unclear aetiology, ill defined but likely increasing incidence, and debatable clinical management options. However these children experience real [...]

This is a review of the literature on osteogenesis imperfecta and a case report of an edentulous patient with osteogenesis imperfecta rehabilitated with implant-supported fixed prostheses in the maxilla and mandible. Quality and quantity of the bone is of paramount importance for establishment of osseointegration. In osteogenesis imperfecta bone is osteoporotic. There are few reported cases in the literature of implant placement and subsequent rehabilitation of patients with osteogenesis imperfecta. To our knowledge, this is the first reporting of successful short-term follow-up of an edentulous osteogenesis imperfecta patient with implant-supported fixed prostheses. [ABSTRACT FROM AUTHOR]

The functional differences between persons with amputation who are classified as Medicare Functional Classification Level (MFCL)-2 and -3 include the abilities to walk at various cadences and to negotiate environmental barriers outside the home. This study compared the effect of active microprocessor control and passive mechanical control of the prosthetic knee on function and safety in 17 subjects with transfemoral amputation (8 MFCL-2 and 9 MFCL-3). Assessed functional tasks included hill and stair descent, an attentional demand task, and an obstacle course. Self-reported measures included concentration, multitasking ability, and numbers of stumbles and falls. Active knee control was associated with significant improvements (p < 0.05) in hill and stair gait, speed (hills, obstacle course, and attentional demand task), and ability to multitask while walking for both cohorts. MFCL-2 subjects also reported a significant reduction (p < 0.01) in uncontrolled falls. Over the study, 50% of MFCL-2 subjects and 33% of MFCL-3 subjects transitioned to a higher MFCL. Results suggest that active knee control improves function and reduces the frequency of adverse events in a population that is at risk for falls. Use of active knee control may allow persons with amputation to expand their functional domain, transition to a higher MFCL, and access additional prosthetic options. [ABSTRACT FROM AUTHOR]

BACKGROUND: Not-for-profit (NFP) hospitals' accumulations of financial assets have been growing steadily over the past 10 years. Surprisingly, little is known about how much investment reserves represent and how they are handled among NFP hospitals. PURPOSE: The purpose of this study is to evaluate investment strategies in financial assets among NFP hospitals. Specifically, this article seeks to explore how NFP hospitals allocate and manage financial assets, how much risk hospitals employ in their investment strategies, and the risk and return trade-off under contrasting market conditions. METHODOLOGY/APPROACH: Using two years of survey data from the Common fund Benchmarks Study for Health Care Institutions for fiscal years 2002 and 2003, we analyze NFP hospitals' investment strategies by comparing asset size, investment management characteristics, board characteristics, asset allocation, levels of risk, and annual returns. Univariate regression analysis is used to evaluate the relationship between risk and return. FINDINGS: NFP hospitals have sizeable long-term financial assets, averaging over $558 million in 2002 and $634 million in 2003. Two thirds of these funds are invested in long-term operating funds followed by defined benefit pension funds and insurance reserves; management of these funds is primarily outsourced. NFP hospitals allocate, on average, 50% of their operating fund assets to equities. During the stock market downturn in 2002, each 1% investment in equities was significantly associated with a -0.18% decrease in annual returns. In contrast, the relationship is almost exactly opposite--consistent with the relationship typically associated with risk and return--in 2003. PRACTICE IMPLICATIONS: NFP hospitals with heavy reliance on investment income to boost total profit margins may have difficulty adjusting to periods of low performance. Evaluation of the performance and financial condition of the hospital must account for the size and composition of financial assets. [ABSTRACT FROM AUTHOR]

Background: Recent reports have suggested that functional outcomes are similar following either amputation or reconstruction of a severely injured lower extremity. The goal of this study was to compare two-year direct health-care costs and projected lifetime health-care costs associated with these two treatment pathways.Methods: Two-year health-care costs were estimated for 545 patients with a unilateral limb-threatening lower-extremity injury treated at one of eight level-I trauma centers. Included in the calculation were costs related to (1) the initial hospitalization, (2) all rehospitalizations for acute care related to the limb injury, (3) inpatient rehabilitation, (4) outpatient doctor visits, (5) outpatient physical and occupational therapy, and (6) purchase and maintenance of prosthetic devices. All dollar figures were inflated to constant 2002 dollars with use of the medical service Consumer Price Index. To estimate projected lifetime costs, the number of expected life years was multiplied by an estimate of future annual health-care costs and added to an estimate of future costs associated with the purchase and maintenance of prosthetic devices.Results: When costs associated with rehospitalizations and post-acute care were added to the cost of the initial hospitalization, the two-year costs for reconstruction and amputation were similar. When prosthesis-related costs were added, there was a substantial difference between the two groups ($81,316 for patients treated with reconstruction and $91,106 for patients treated with amputation). The projected lifetime health-care cost for the patients who had undergone amputation was three times higher than that for those treated with reconstruction ($509,275 and $163,282, respectively).Conclusions: These estimates add support to previous conclusions that efforts to improve the rate of successful reconstructions have merit. Not only is reconstruction a reasonable goal at an experienced level-I trauma center, it results in lower lifetime costs. [ABSTRACT FROM AUTHOR]

Twenty-four adults with phantom limb pain (PLP) and/or residual limb pain (RLP) participated in a double-blind crossover trial. Participants were randomly assigned to receive gabapentin or placebo and later crossed over to the other treatment, with a 5-week washout interval in which they did not receive medication. Gabapentin was titrated from 300 mg to the maximum dose of 3,600 mg. Measures of pain intensity, pain interference, depression, life satisfaction, and functioning were collected throughout the study. Analyses revealed no significant group differences in pre- to posttreatment change scores on any of the outcome measures. More than half of the participants reported a meaningful decrease in pain during the gabapentin phase compared with about one-fifth who reported a meaningful decrease in pain during the placebo phase. In this trial, gabapentin did not substantially affect pain. More research on the efficacy of gabapentin to treat chronic PLP and RLP is needed. [ABSTRACT FROM AUTHOR]

Background: A recent study demonstrated that patients treated with amputation and those treated with reconstruction had comparable functional outcomes at two years following limb-threatening trauma. The present study was designed to determine whether those outcomes improved after two years, and whether differences according to the type of treatment emerged.Methods: Three hundred and ninety-seven patients who had undergone amputation or reconstruction of the lower extremity were interviewed by telephone at an average of eighty-four months after the injury. Functional outcomes were assessed with use of the physical and psychosocial subscores of the Sickness Impact Profile (SIP) and were compared with similar scores obtained at twenty-four months.Results: On the average, physical and psychosocial functioning deteriorated between twenty-four and eighty-four months after the injury. At eighty-four months, one-half of the patients had a physical SIP subscore of > or = 10 points, which is indicative of substantial disability, and only 34.5% had a score typical of a general population of similar age and gender. There were few significant differences in the outcomes according to the type of treatment, with two exceptions. Compared with patients treated with reconstruction for a tibial shaft fracture, those with only a severe soft-tissue injury of the leg were 3.1 times more likely to have a physical SIP subscore of 5 points (p < 0.05) and those treated with a through-the-knee amputation were 11.5 times more likely to have a physical subscore of 5 points (p < 0.05). There were no significant differences in the psychosocial outcomes according to treatment group. Patient characteristics that were significantly associated with poorer outcomes included older age, female gender, nonwhite race, lower education level, living in a poor household, current or previous smoking, low self-efficacy, poor self-reported health status before the injury, and involvement with the legal system in an effort to obtain disability payments. Except for age, predictors of poor outcome were similar at twenty-four and eighty-four months after the injury.Conclusions: The results confirm previous conclusions that reconstruction for the treatment of injuries below the distal part of the femur typically results in functional outcomes equivalent to those of amputation. Regardless of the treatment option, however, long-term functional outcomes are poor. Priority should be given to efforts to improve post-acute-care services that address secondary conditions that compromise optimal recovery. [ABSTRACT FROM AUTHOR]

PURPOSE: (1) To describe one aspect of social support, social integration, longitudinally for 2 years following lower limb amputation and (2) to explore the impact of social support on depression, pain interference, life satisfaction, mobility, and occupational functioning. METHOD: Eighty-nine adults recruited from consecutive admissions to an orthopaedic surgery service completed telephone interviews 1, 6, 12 and 24 months following amputation surgery. Dependent variables included the Social Integration (SI) sub-scale of the Craig Handicap Assessment and Reporting Technique (CHART) and the Multidimensional Scale of Perceived Social Support (MSPSS). RESULTS: There was a high level of SI among most persons following lower limb amputations that was relatively unchanged in the 2 years following surgery. However, mean levels of SI were lower in this group compared to a sample without disabilities. MSPSS scores were highly variable, ranging from almost no support to the maximum amount of support. MSPSS was an important concurrent predictor of pain interference, life satisfaction, and mobility, controlling for demographic and amputation-related factors. Baseline MSPSS predicted mobility and occupational functioning 6 months post-amputation, controlling for demographic and amputation-related factors. CONCLUSIONS: Findings suggest that interventions aimed at improving the quality of social relationships after amputation may facilitate participation in activities. [ABSTRACT FROM AUTHOR]

The measurement of physical activity, especially walking activity, is important for many outcome studies. In many investigations, the Physical Activity scale of the short-form-36 (SF-36) health assessment questionnaire is used in lieu of an actual physical measurement of walking. This study determined the relationship between the SF-36 questionnaire and the Step Activity Monitor (SAM), a real-world performance-based tool that counts the actual number of steps taken during daily activities. We studied the physical activity of 57 men with diabetes using step count monitoring and the SF-36 questionnaire. The subjects averaged 3,293 steps/day, but had a very wide range (111-11,654) and a large standard deviation (SD = 2,037). The correlations between total daily steps and the SF-36 Physical Component Summary score, and the Physical Function, the Bodily Pain, and the Vitality scales of the SF-36 were only fair (Pearson r = 0.376, 0.488, 0.332, 0.380, respectively). The corresponding coefficients of determination range from only 7.7% to 23.8%. Physical activity is a complex concept not completely represented by either the SF-36 or the step counts. The correlation between actual walking activity and the SF-36 is not as strong as many researchers believe. Caution should be used using the SF-36 to specifically measure walking activity. [ABSTRACT FROM AUTHOR]

Despite widespread availability of pain interventions in childbirth, for most women, childbirth is associated with labor pain that exceeds expectations. Although epidural is superior to other medical interventions, the choice to use epidural still remains a matter of patient and doctor preference. Whether racial or ethnic characteristics influence preference of physician use or interact with insurance coverage is still unknown. This study used a large national sample of women to measure significant determinants of epidural use in order to discuss disparities in pain management. The findings suggest the need for nurse leaders to foster health policies that are sensitive to diversity and economics. [ABSTRACT FROM AUTHOR]

Postamputation management is an important determinant of recovery from amputation. However, consensus on the most effective postoperative management strategies for individuals undergoing transtibial amputation (TTA) is lacking. Dressings can include simple soft gauze dressings, thigh-high rigid cast dressings, shorter removable rigid dressings, and prefabricated pneumatic dressings. Postoperative prosthetic attachments can be added to all but simple soft dressings. These dressings address the need to cleanly cover a fresh surgical wound, but not all postoperative dressings are designed to facilitate the strategic goals of preventing knee contractures, reducing edema, protecting from external trauma, or facilitating early weight bearing. The type of dressing and management strategy often overlap and are certainly interrelated. Current protocols and decisions are based on local practice, skill, and intuition. The current available literature is challenging, and difficulties include variations in healing potential, in comorbidity, in surgical-level selection, in techniques and skill, in experience with postoperative strategies, and with poorly defined outcome criteria. This paper reviews the published literature and compares measures of safety, efficacy, and clinical outcomes of the various techniques. Analysis of 10 controlled studies supported only 4 of the 14 claims cited in uncontrolled, descriptive studies. [ABSTRACT FROM AUTHOR]

Objective. To describe footwear preferences of people with diabetes and a history of foot ulcer from two large western Washington State healthcare organizations. Methods. As part of a clinical trial of footwear, self-reported information on footwear preferences, use, and cost were obtained from persons with diabetes and a prior healed foot ulcer for the year before their study enrollment. All participants' shoes were allocated into optimal, adequate, and dangerous categories based on design, structural and safety features, and materials. Results. The 309 males and 91 females in this study averaged 62 years of age. At baseline, men owned an average of 6 (+3) pairs of shoes, with an average purchase price of $56, while women owned an average of 8 (+5) pairs, with an average purchase price of $42. Women spent an average of 51% of their time in shoes in dangerous shoes compared to men who spent 27% of their time. Men and women spent nearly 30% of their time while out of bed in slippers, stockings, and barefoot. Conclusions. People with a history of diabetes and foot ulcers needed several styles of safe and attractive shoes for regular activities. Healthcare professionals can provide patients with information on good footwear choices to help them select adequate shoes while avoiding dangerous shoes. This approach is more realistic than trying to move all people with prior foot risk factors or ulcers into uniformly optimal footwear, since recent evidence does not support this practice. [ABSTRACT FROM AUTHOR]

This report examines the current clinical uses of CAD/CAM in prosthetics and orthotics. We conducted interviews to contrast patterns of CAD/CAM use in different private practice settings, at two different teaching institutions, and within two large Prosthetic and Orthotic delivery systems. Investigation into these patterns of use has revealed several lessons. First, there currently exist several very different models of use in clinical practice and these different models will most likely continue. The clinical models range from all traditional techniques with no use of CAD/CAM, to full in-house suites of CAD/CAM equipment with extensive utilization, to a simplified office with minimal in-house equipment and minimal fabrication and a near total dependency on central fabrication. Second, a growing number of prosthetic and orthotic devices are successfully being fabricated and fit with CAD/CAM technology after starting the process with simple measurements instead of casted, scanned, or digitized exact anatomic data. Starting the CAD process with 'by-the-numbers approach' has revealed the reality that for some devices, the 'input' needed to define the shape of the residual limb or torso, may not need to be as accurate as originally thought. Third, the fabrication techniques that are currently being used with CAD/CAM systems are still rather traditional techniques. Most devices are still laminated or formed over computer carved models. Although research continues into advanced fabrication techniques, the prosthetics and orthotics industry has not yet taken advantage of the possibilities in the computer-assisted manufacturing side of the equation. Finally, the business of manufacturing and selling up-to-date CAD/CAM equipment and software has a tremendous impact on how this technology is used in prosthetics and orthotics. The size of the prosthetics and orthotics industry and the potential number of customers for major equipment are relatively small. Being in the business of providing the advanced CAD/CAM systems of tomorrow is an expensive and difficult proposition. Current users of full in-house CAD systems have expressed concern that upgrading equipment and software might not be economical with today's decreasing revenues. For all of these reasons, many believe that the number of practitioners who use a central fabrication model will grow more rapidly than the number of practitioners who own and operate a full in-house system. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare patients with diabetes and new onset foot ulcers treated in Veterans Health Administration (VHA) and non-VHA settings. METHODS: The treatment of patients with new onset diabetic foot ulcers was prospectively monitored in three VHA and three non-VHA hospitals and outpatient settings until ulcer healing, amputation, or death. RESULTS: Of the 302 individuals enrolled in this study, 47% were veterans receiving VHA care. There were no significant differences between veterans and nonveterans in baseline wound classification, diabetes severity, or comorbid conditions. Veterans received significantly fewer sharp debridements, total contact casts, and custom inserts than their nonveteran counterparts, and they had significantly more x-rays, local saline irrigations, IV antibiotics, and prescriptions for bed rest. The percentage of amputations was higher in veterans but did not achieve statistical significance. CONCLUSIONS: Many commonly held stereotypes of veteran men were not found. Veterans and nonveterans with foot ulcers were similar in terms of health and foot history, diabetes severity, and comorbid conditions. There was considerable variation in treatment of diabetic foot ulcers between VHA and non-VHA care. Yet this variation did not result in statistically significant differences in ulcer outcomes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Little prospective research exists on risk factors for diabetic foot ulcer that considers the independent effects of multiple potential etiologic agents. We prospectively studied the effects of diabetes characteristics, foot deformity, behavioral factors, and neurovascular function on foot ulcer risk among 749 diabetic veterans with 1,483 lower limbs. RESEARCH DESIGN AND METHODS: Eligible subjects included all diabetic enrollees of a general internal medicine clinic without foot ulcer, of whom 83% agreed to participate. Baseline assessment included history and lower-limb physical examination, tests for sensory and autonomic neuropathy, and measurements of macro- and microvascular perfusion in the foot. Subjects were followed for the occurrence of a full thickness skin defect on the foot that took > 14 days to heal, with a mean follow-up of 3.7 years. RESULTS: Using stepwise Cox regression analysis, the following factors were independently related to foot ulcer risk: foot insensitivity to the 5.07 monofilament (relative risk [95% CI]) 2.2 (1.5-3.1), past history of amputation 2.8 (1.8-4.3) or foot ulcer 1.6 (1.2-2.3), insulin use 1.6 (1.1-2.2), Charcot deformity 3.5 (1.2-9.9), 15 mmHg higher dorsal foot transcutaneous PO2 0.8 (0.7-0.9), 20 kg higher body weight 1.2 (1.1-1.4), 0.3 higher ankle-arm index 0.8 (0.7-1.0), poor vision 1.9 (1.4-2.6), and 13 mmHg orthostatic blood pressure fall 1.2 (1.1-1.5). Higher ulcer risk was associated with hammer/claw toe deformity and history of laser photocoagulation in certain subgroups. Unrelated to foot ulcer risk in multivariate models were diabetes duration and type, race, smoking status, diabetes education, joint mobility, hallux blood pressure, and other foot deformities. CONCLUSIONS: Certain foot deformities, reduced skin oxygenation and foot perfusion, poor vision, greater body mass, and both sensory and autonomic neuropathy independently influence foot ulcer risk, thereby providing support for a multifactorial etiology for diabetic foot ulceration. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To identify risk factors for lower-extremity amputation (LEA) in individuals with diabetes and to estimate the incidence of LEA. RESEARCH DESIGN AND METHODS: This is a prospective study of 776 U.S. veterans in a general medicine clinic in Seattle, Washington. The outcome was first LEA during follow-up. Potential risk factors evaluated in proportional hazards models included, among others, peripheral vascular disease (PVD), sensory neuropathy, former LEA, foot deformities and ulcers, diabetes duration and treatment, and hyperglycemia. RESULTS: Associated with an increased risk for LEA were PVD defined as transcutaneous oxygen < or = 50 mmHg (relative risk [RR] = 3.0, 95% CI 1.3-7.1), insensitivity to monofilament testing (RR = 2.9, odds ratio = 1.1-7.8), lower-extremity ulcers (RR = 2.5, CI 1.1-5.4), former LEA, and treatment with insulin when controlling for duration of diabetes and other factors in the model. PVD defined as absent or diminished lower-extremity pulses or an ankle arm index < or = 0.8 was also associated with a significantly higher risk of LEA in separate models. Foot ulcers were associated with an increased ipsilateral risk of amputation. The age-adjusted incidence among men only for LEA standardized to the 1991 U.S. male diabetic population was 11.3/1,000 patient-years. CONCLUSIONS: This prospective study shows that peripheral sensory neuropathy, PVD, foot ulcers (particularly if they appear on the same side as the eventual LEA), former amputation, and treatment with insulin are independent risk factors for LEA in patients with diabetes. [ABSTRACT FROM AUTHOR]

In many areas of research and medicine, objective data describing an individual's ambulatory function are sought as useful indicators of that person's condition. Normally, detailed measurements are taken over short periods of time within a controlled laboratory setting. To complement this approach, Prosthetics Research Study has developed a small, unobtrusive instrument that continuously records a simple measure--step counts per unit time--as an individual goes about normal daily life. The Step Activity Monitor (SAM) is approximately the size and weight of a pager and is worn at the ankle. It can detect steps with better than 99% accuracy across a wide range of gait styles for adults, children, and large animals. During monitoring, step counts are recorded at consecutive, adjustable time intervals over weeks to months at a time. Recording at 1-min intervals for a minimum of 2 weeks is recommended. Once monitoring is completed, the data are transferred to a computer, and the levels and patterns of activity can be analyzed. This article provides a detailed description of the SAM, guidelines for use, results of accuracy and reliability testing, case study descriptions demonstrating the ability to measure differences that result from medical interventions or changes in health status, and a discussion of considerations pertinent to long-term monitoring of activity. [ABSTRACT FROM AUTHOR]

Clinical epidemiology studies suggest the majority of lower limb amputations were preceded by a minor traumatic event, often footwear-related, and lower limb ulcers. To reduce foot trauma and ulcers, the diabetic patient with foot insensitivity has unique footwear needs. To address these needs for patients not requiring custom shoes, the DVA/Seattle Footwear System was developed. The six components of this system include: 1) a specially designed shoe last based on the geometry of the diabetic foot and research findings on foot regions at highest risk of ulceration, 2) a depth-inlay shoe, 'Custom Stride by PRS,' designed to be paired with either a custom-fabricated cork insole or a preformed polyurethane insole, 3) a laser digitizing system that captures 3-D plantar foot contours, 4) DVA/Seattle ShapeMaker software adaptation for modifying plantar surface contours and applying free-form and template modifications to increase or relieve loading, 5) software that translates files into code used by a milling machine to define the cutting path and carve cork blockers into custom insoles, and 6) a preformed polyurethane insole thicker than a typical insole to accommodate the extra volume and the interior dimensions of the shoe. A 6-month pilot cross-over trial of 24 diabetic male veterans without prior foot ulcers was conducted to determine the feasibility of producing, and the safety of wearing, these depth-inlay shoes and both types of insoles. During the first 4 weeks, patients were assigned to the study shoes and one type of insole. During the next 4 weeks, they wore the other type of insole, and during the final 4 months, they chose which pair of insoles to wear with the study shoes. Over 150 person-months of footwear observation revealed no breaks in the cutaneous barrier with use of either cork or polyurethane insoles and the study shoes. Patient compliance with the footwear was 88%. Patients were highly satisfied with the appearance, stability, and comfort of the shoes and the comfort of both types of insole. However, 75% of the patients noted that the study shoes felt heavier than their customary shoes. Further research is needed to determine the long-term effectiveness of footwear in prevention of foot ulcers in the population at highest risk for diabetic reulceration and amputation. [ABSTRACT FROM AUTHOR]

1. We have studied the disposition of stable strontium after the intravenous administration of strontium gluconate to eight healthy male volunteers both in control conditions and while they were taking the calcium antagonist nifedipine 10 mg three times daily. 2. Nifedipine, presumably by its action in blocking voltage-operated calcium channels, altered the in vivo disposition of strontium, causing large reductions in the half-life and the apparent volume of distribution of strontium. Total and renal clearances of strontium were unaltered by nifedipine. 3. These results support our previous suggestion that the delineation of strontium disposition can be used as a means of studying calcium disposition in vivo in man, and of studying the effects of drugs and diseases on that disposition. [ABSTRACT FROM AUTHOR]

1. We have studied the pharmacokinetics of stable strontium in 10 healthy male volunteers. We gave each volunteer 5 mmol strontium gluconate by intravenous infusion over 1 h and measured strontium concentrations in plasma and urine samples for 20 days. The plasma strontium concentration vs time data for each volunteer were fitted by a triexponential function using NONLIN. Compartmental model-dependent and model-independent pharmacokinetic variables were then calculated. 2. The mean half-life we report (5.4 days) is longer than that previously reported (about 2 days), since we continued sampling for 20 days. However, the rates of clearance (CL 9.4 ml min-1. CLR 5.4 ml min- 1, and CLNR 4.0 ml min-1) are similar to those previously reported, and the apparent volume of distribution at steady state (64 l) is similar to the values previously reported for the size of the exchangeable pool of both strontium and calcium. 3. The similarities in the pharmacokinetic behavior of strontium and calcium suggest that the in vivo disposition of strontium may be used as a marker of calcium disposition and for studying the effects of drugs such as the calcium antagonists. [ABSTRACT FROM AUTHOR]

1. We have measured the effect of oral salbutamol on cation transport in vivo by studying the disposition of an oral load of rubidium chloride in healthy treated volunteers and in untreated matched controls. 2. During the administration of salbutamol there was a significantly lower plasma rubidium concentration 5 h after the administration of the oral load of rubidium chloride, reflecting an increase in the net clearance of rubidium from the plasma into at least some tissues in vivo. 3. There was no difference in either intraerythrocytic rubidium concentrations or the pseudo-rate constant for erythrocyte rubidium uptake in vivo after salbutamol. 4. Ex vivo incubation of whole blood preloaded in vivo with rubidium showed that the clearance of rubidium from the plasma was inhibited by 95% in the presence of the Na+,K(+)-ATPase inhibitor digoxin. 5. These data suggest that salbutamol stimulates cation transport via Na+,K(+)-ATPase in vivo into some tissues but not into the erythrocyte. 6. This pattern of change in rubidium disposition after salbutamol is completely different from the patterns of change we have seen in patients with essential hypertension or acute manic illness. We therefore suggest that the changes in erythrocyte rubidium uptake which we have previously described in vivo in patients with essential hypertension or acute manic illness do not result from beta 2-adrenoceptor-mediated catecholamine stimulation of Na+,K(+)-ATPase. [ABSTRACT FROM AUTHOR]

1. We have given an oral load of lithium carbonate to healthy volunteers in order to investigate the transport of lithium across the erythrocyte membrane in vivo and the effects of known inhibitors of that transport. 2. Using this technique we have shown that pretreatment with either digoxin, an inhibitor of the sodium/potassium pump, or dipyridamole, an inhibitor of the anion transporter, does not alter the plasma or erythrocyte lithium concentration profiles, nor any of the pharmacokinetic variables derived from these data, and we conclude that these two transport pathways do not contribute significantly to the in vivo handling of lithium by erythrocytes. 3. We have also shown that erythrocyte lithium concentrations measured directly differ significantly from the predicted concentrations calculated using the two-compartment pharmacokinetic model which has been used in some earlier comparisons of in vitro and in vivo lithium handling. 4. We suggest that the in vivo administration of lithium carbonate may permit a specific measure of the in vivo activity of the sodium/sodium countertransport pathway. [ABSTRACT FROM AUTHOR]

The effects of aspirin on the metabolism of phosphoinositides in human platelets were studied in vitro and in vivo. Eight volunteers received, at two-weekly intervals, a single dose of 10, 30, 100 or 600 mg aspirin. Before the first dose platelets were taken and incubated in vitro with a range of concentrations (10 nM-100 microM) of aspirin. Formation of inositol phosphates (IP) was measured in [3H]-inositol labelled platelets after incubation with collagen and thrombin for 30 min, a time at which a maximal increase in [3H]-IP was observed. The in vitro IC50 for inhibition of the response to collagen by aspirin was approximately 1 microM; the in vivo ID50 was 40-50 mg. Aspirin did not fully inhibit the collagen stimulated IP formation either in vitro or in vivo, and the response to thrombin was unaffected. The ID50 and IC50 of aspirin is thus in accord with the doses of aspirin associated with inhibition of platelet aggregation and thromboxane production in other studies. The possible relevance of these data to the clinical uses of aspirin is discussed. [ABSTRACT FROM AUTHOR]

We have quantified specific [3H]-ouabain binding sites in normal human lymphocytes, and have measured the changes in the numbers of those sites which occur in response to various stimuli. We have confirmed previous findings that incubation for 72 h in the presence of fetal calf serum causes an increase in [3H]-ouabain binding, and that this does not occur if the cells are incubated in fetal calf serum which has first been dialysed. During incubation of the lymphocytes for 3 days in the presence of dialysed fetal calf serum each of the following stimuli caused an increase in specific [3H]-ouabain binding: addition of ethacrynic acid (1 mumol l-1), addition of lithium (1 mmol l-1), and reduction of the external potassium concentration (to 0.75 mmol l-1). By analogy with the similar results in HeLa cells reported by others, we suggest that the increase in [3H]-ouabain binding may, in the case of ethacrynic acid and the reduction of the external potassium concentration, be initiated by an increase in the intracellular sodium concentration. The mechanisms whereby fetal calf serum and lithium cause an increase in [3H]-ouabain binding are not clear. [ABSTRACT FROM AUTHOR]

We have studied the effects of digoxin on cation transport in vivo by measuring the changes in plasma and red cell rubidium concentrations following an oral load of rubidium chloride. In eight patients who had been taking digoxin for 7 to 10 days (mean plasma digoxin concentration 1.3 ng ml-1) the rise in plasma rubidium concentrations was enhanced and the rise in red cell rubidium concentrations was attenuated following the oral load of rubidium chloride, by comparison with the changes in well-matched controls. In contrast, the disposition of rubidium was not altered in 12 patients who had been taking digoxin for more than 3 months (mean plasma digoxin concentration 1.1 ng ml-1). These results suggest that the inhibitory effects of digoxin on cation transport are detectable in vivo during short-term therapy, but not during long-term therapy, and confirm our previous in vitro findings. [ABSTRACT FROM AUTHOR]

Plasma melatonin was used to determine overall beta-adrenergic transmission through pineal neuro-effector junctions during desmethylimipramine (DMI) treatment in 10 normal subjects. Changes in plasma melatonin indicated that an initial increase in noradrenaline (NA) transmission produced by DMI was counteracted by adaptive changes which restored transmission to normal by the third week of treatment. A 'rebound' increase in NA transmission was seen on DMI withdrawal. The results suggest that the adaptive changes which occur in NA synapses during DMI treatment do not, as has been proposed, decrease NA transmission below normal levels, but instead restore homeostasis in the presence of the drug. [ABSTRACT FROM AUTHOR]

Using a [3H]-lysergic acid diethylamide [(3H]-LSD) binding technique, platelet 5-hydroxytryptamine (5-HT) receptor number and affinity were compared in schizophrenics treated with depot thioxanthenes and phenothiazines and controls. There was an approximately 30% increase in platelet receptor number (Bmax) in the patient group. There was a decrease in affinity (increase in Kd) of about 30% in the patient group. This was probably due to the persistence of the neuroleptic in the platelet membrane preparation. There was a weak positive correlation between receptor number and total neuroleptic dosage. The increased number of 5-HT receptors is consistent with the previously reported enhancement of 5-HT-induced platelet aggregation in patients treated with long-term phenothiazines and thioxanthenes. Our findings are compatible with 5-HT up-regulation in human platelets produced by depot neuroleptic therapy. It is not known whether parallel changes may be occurring in brain 5-HT receptors. [ABSTRACT FROM AUTHOR]

We have studied the specific binding of [3H]-ouabain to intact mononuclear leucocytes (82% lymphocytes) and polymorphonuclear leucocytes. In both types of cells [3H]-ouabain binding was saturable, confined to a single site of high affinity, slow to reach equilibrium, slow to reverse, temperature-dependent, competitively antagonized by potassium, and facilitated by the presence of divalent cations. The equilibrium dissociation constants were 2.4 +/- 0.7 nmol/l (polymorphs) and 2.4 +/- 0.4 nmol/l (mononuclear cells) (NS). The values of maximal specific ouabain binding, measured by Scatchard analysis of concentration vs binding curves (Bmax), were 33.9 +/- 6.0 fmol/10(6) cells (polymorphs) and 59.3 +/- 11.6 fmol/10(6) cells (mononuclear cells) (P less than 0.02). The corresponding numbers of sites per cell were 20415 +/- 3616 and 35712 +/- 6986 respectively (P less than 0.02). When the numbers of binding sites were expressed per square micron of cell surface area the difference between the two cell types was proportionately greater (83 and 186 sites per micron 2 respectively). We conclude that the [3H]-ouabain binding sites on mononuclear and polymorphonuclear leucocytes are similar in nature, but different in both number and density on the cell surface. Measurements of Bmax in mixed cell populations should therefore take account of cell type as well as cell size and number. [ABSTRACT FROM AUTHOR]

1 The effects of treatment with a range of neuroleptic drugs on 5- hydroxytryptamine (5-HT) induced platelet aggregation in vivo were examined in a group of recently admitted psychiatric patients and in a larger group of chronic schizophrenic patients. 2 Five of seven recently admitted patients treated with chlorpromazine showed enhanced aggregation. Four of seven patients treated with fluphenazine, flupenthixol, trifluoperazine and haloperidol showed enhancement. 3 Enhanced aggregation responses were observed in only 20% of chronic schizophrenic patients being treated with a neuroleptic drug. 4 The relationship between changes in platelet aggregation and clinical changes in recently admitted patients was variable and platelet aggregation responses were not predictive of response to treatment. 5 Chronic schizophrenic patients with enhanced aggregation showed significant week to week variation in platelet aggregation response. Variability of responses was not related to the drug used or to the dose administered. There was some evidence that higher plasma concentrations of neuroleptic drugs were associated with enhanced platelet aggregation responses. 6 Treatment with neuroleptic drugs leads to enhancement of platelet aggregation responses induced by 5-HT. The frequency and reliability with which such responses can be elicited is unpredictable and the value of platelet aggregation responses as an empirical guide to treatment with neuroleptic drugs is therefore open to question. [ABSTRACT FROM AUTHOR]

1 The aggregation response of platelets induced by 5-HT was greatly increased in psychiatric patients receiving chlorpromazine therapy when compared with normal volunteers and psychiatric patients not receiving chlorpromazine. 2 Platelet aggregation responses to ADP were normal during chlorpromazine therapy, but 5-HT induced aggregation was increased in rate and the typical transient reversible response was converted to an irreversible response in all subjects. This was usually indistinguishable from the ADP response. 3 When chlorpromazine therapy was stopped, plasma concentrations of chlorpromazine, monodesmethylchlorpromazine and chlorpromazine sulphoxide fell rapidly within one week, whereas 5-HT induced platelet aggregation responses became normal after three weeks. The enhanced responses returned when chlorpromazine therapy was re-instituted. 4 It is possible that platelet aggregation responses to 5-HT in vitro could prove to be a useful index of the pharmacological effect of chlorpromazine in vivo. [ABSTRACT FROM AUTHOR]