Measuring the cost of care in benign prostatic hyperplasia using time-driven activity-based costing (TDABC).

BACKGROUND: Determining '"value'" in health care, defined as outcomes per unit cost, depends on accurately measuring cost. We used time-driven activity-based costing (TDABC) to determine the cost of care in men with benign prostatic hyperplasia (BPH) - a common urologic condition. METHODS: We implemented TDABC across the entire care pathway for BPH including primary and specialist care in both inpatient and outpatient settings. A team of expert stakeholders created detailed process maps, determined space and product costs, and calculated personnel capacity cost rates. A model pathway was derived from practice guidelines and calculated costs were applied. RESULTS: Although listed as 'optional' in practice guidelines, invasive diagnostic testing can increase costs by 150% compared with the standalone urology clinic visit. Of five different surgical options, a 400% cost discrepancy exists between the most and least expensive treatments. CONCLUSIONS: TDABC can be used to measure cost across an entire care pathway in a large academic medical center. Sizable cost variation exists between diagnostic and surgical modalities for men with BPH. IMPLICATIONS: As financial risk is shifted toward providers, understanding the cost of care will be vital. Future work is needed to determine outcome discrepancy between the diagnostic and surgical modalities in BPH.

Diagnostic value of hepatocyte paraffin 1 antibody to discriminate hepatocellular carcinoma from metastatic carcinoma in fine-needle aspiration biopsies of the liver.

BACKGROUND: Diagnosing liver tumors by fine-needle aspiration biopsy is safe and accurate. However, there are cases that prove diagnostically difficult. Traditionally, immunostains for alpha-fetoprotein and polyclonal carcinoembryonic antigen have been used to distinguish adenocarcinomas from hepatocellular carcinomas (HCCs). In poorly differentiated tumors, these immunostains have limitations in both sensitivity and specificity. An hepatocyte-specific immunostain has been described in the surgical pathology literature. To the authors' knowledge, this hepatocyte antibody has not been studied in liver fine-needle aspiration biopsies. The authors examined the Hepatocyte Paraffin 1 (HP1) antibody for its diagnostic utility in this cytologic setting. METHODS: Cell-block material from 40 cases of HCC and 53 cases of metastatic adenocarcinoma were studied. Slides were stained for HP1 by the avidin-biotin complex method following antigen retrieval. The percentage of malignant cells that exhibited coarse granular staining in the cytoplasm was estimated for all cases of HCC, poorly differentiated HCC, and metastatic adenocarcinoma. RESULTS: HP1 was expressed in 83% of all HCCs but in only 56% of poorly differentiated HCCs. Only 2 of 53 (4%) of metastatic tumors expressed HP1. The overall sensitivity of HP1 was 79% and its specificity was 96%. CONCLUSION: HP1 was found to be a specific immunostain that may prove helpful in diagnosing all but the most undifferentiated liver tumors biopsied by fine-needle aspiration.

Subjective swelling: a new sign for carpal tunnel syndrome.

This single-blinded, randomized cohort study of 186 patients was conducted to determine whether the subjective complaint of swelling of the hand or wrist is associated with the diagnosis and/or prognosis of carpal tunnel syndrome. All patients were referred for splinting with a presenting clinical diagnosis of carpal tunnel syndrome from outpatient specialty clinics, including orthopedics, rheumatology, and neurology. Patients were assessed before splinting for the complaint of subjective swelling and underwent a clinical examination including Phalen testing and carpal compression testing. In addition, 211 of the 290 joints underwent electrodiagnostic testing by the end of this study. Among the 211 joints for which electrodiagnosis was used, a chi2 analysis was performed to determine the correlation among subjective swelling, the Phalen and carpal compression tests, and the electrodiagnostically verified carpal tunnel syndrome. Two weeks after splinting, an assessment was made of the subjective response to splinting. Chi2 analysis was then performed to assess the correlation among the Phalen test, carpal compression test, and nerve conduction study results and the symptom of subjective swelling at presentation with that of response to splinting. Subjective swelling of the hand showed a trend toward association with electrodiagnostic results (although this finding was not statistically significant) and proved to be significantly correlated with a poor clinical response to splinting. Positive electrodiagnostic findings were significantly, though positively, correlated with pain relief from splinting. This study, therefore, introduces the complaint of subjective swelling of the affected hand as an important diagnostic and prognostic symptom for the assessment and treatment of carpal tunnel syndrome.

Population biology, evolution, and immunology of vaccination and vaccination programs.

The purpose of prophylactic vaccination is to reduce morbidity and mortality in a population. Many questions related to the design of vaccines and vaccination programs require a population standpoint for their sharp formulation and laboratory and field studies to understand their immunologic background. Practical suggestions of the workshop included increased studies of age-specific immunity, better immunoepidemiologic surveillance, better design of efficacy studies, and more systematic sampling of parasite strains to study the evolutionary pressure exerted by vaccines. Theoretical immunology has much to contribute. One of the realizations of the workshop was the value of a strong interdisciplinary approach in vaccine development, utilizing relevant contributions from immunology, population biology, mathematical modeling, epidemiology, molecular biology, and virology.

Lipid in renal clear cell carcinoma: detection on opposed-phase gradient-echo MR images.

PURPOSE: To determine if comparison of in-phase and opposed-phase gradient-echo magnetic resonance (MR) images enables detection of lipid in renal clear cell carcinoma. MATERIALS AND METHODS: A retrospective search of MR and pathologic records identified 43 patients with biopsy-proved renal masses who underwent in-phase and opposed-phase MR imaging. Thirty-three patients had renal cell carcinoma (27 with clear cell carcinoma), and 10 patients had other renal tumors. With MR images, a region-of-interest measurement of signal intensity of the renal mass was divided by that of reference tissue. In each patient, a ratio of these region-of-interest measurements on the opposed-phase images to those on the in-phase images was calculated and termed the opposed-phase/in-phase signal intensity ratio (OIR). RESULTS: The mean OIR of clear cell carcinomas was significantly different from that of other renal masses (P < .0002); in 16 (59%) of 27 patients with clear cell carcinoma, the OIR was less than 2 standard deviations below the mean OIR of other masses. In cases of clear cell carcinoma, focal signal intensity on opposed-phase images was less than that on in-phase images. CONCLUSION: On opposed-phase images, some clear cell carcinomas show relative focal and diffuse loss of signal intensity. In renal masses, this signal intensity loss-which is consistent with lipid-does not necessarily indicate angiomyolipoma.

Reliability of Spanish translations of select urological quality of life instruments.

PURPOSE: Many patients with urological disease do not speak English. In medical studies restricting patients to those who speak only English undermines efforts to understand disease because restrictions decrease efficiency of patient recruitment, and because language and culture are associated with variable outcomes. In Spanish speaking locations, such as South Florida, studies would suffer severe selection bias if patients were required to speak English. To allow grouping in future studies of English and Spanish speaking patients we examined the English-Spanish reliability of select instruments that measure health related quality of life in patients with urological disease. MATERIALS AND METHODS: We assembled available Spanish versions and translated English versions of questions regarding satisfaction, the American Urological Association symptom index, the University of California, Los Angeles Prostate Cancer Index and a pain inventory. We then examined English-Spanish reliability by asking bilingual men 50 years old or older to complete English and Spanish versions at the same sitting. A convenience sample was recruited from outpatients and volunteers at the Miami Veterans Affairs Medical Center and population based subjects living in largely Hispanic Hialeah, Florida. Reliability estimates were calculated with kappa coefficients for categorical data and intraclass correlation coefficients for quantitative data. RESULTS: A total of 100 subjects a median of 59 years old completed the questionnaire, including 55 born in Puerto Rico or Cuba, while the remainder were born at various sites throughout the Americas and Spain. Reliability estimates showed that kappa = > 0.81 for almost all items. For 2 items relating to health and social interactions reliability was poor, and stratification showed that poor reliability was primarily a feature of subjects in good health who are theoretically socially active. CONCLUSIONS: Almost all items tested have excellent English-Spanish reliability in a mixed sample of bilingual men. Nonreliability of 2 items relating to health and social interactions probably originates from the effect of language on perception, and invalidates English and Spanish grouping of these items. Because the sample represents many dialects of Spanish, the translations tested may be transported to other cities. In studies that use these instruments investigators can reasonably group answers from English and Spanish speaking study subjects or study the effects of acculturation on quality of life.

Modeling the proliferative response of T cells to IL-2 and IL-4.

Interleukin (IL) -2 and IL-4 are growth factors for both T and B cells. When both cytokines are present, synergy is observed in some cases and antagonism in others. The studies presented here describe the use of a detailed mathematical model for the proliferative response of the T cell line, HT-2. This cell line responds to IL-2 and to IL-4 and shows a synergistic response when both cytokines are present. This model incorporates the observed synergy between these two cytokines while at the same time incorporating the known down-regulatory effect of IL-4 on the number of IL-2 receptors (IL-2R) at the cell surface, and it is able to reproduce a variety of experimental data. The major results from these studies include the following: the observation that the binding of IL-4 to its receptor is 1/10 as effective in delivering a proliferative signal as IL-2 binding to its receptor, the determination of the threshold number of bindings required to signal proliferation stimulated by IL-2 and IL-4, the demonstration that many different sets of experimental data can be accurately modeled, and the use of simple parameter terms to model the synergy between IL-2 and IL-4.

Predictors of general quality of life in patients with benign prostate hyperplasia or prostate cancer.

PURPOSE: Studies in disease specific populations have emphasized disease specific quality of life with little study of general quality of life. Furthermore, studies of general quality of life in disease specific populations have mostly examined the importance of disease specific variables, and have generally yielded poor correlations of such variables and general quality of life. We attempted to model the emotional component of general quality of life in patients with prostate disease. MATERIALS AND METHODS: We integrated prospectively collected disease specific and nonspecific clinical and self-reported patient data. We also applied neural network and more conventional statistical tools to examine the relative use of various available analytical methodologies in modeling general quality of life. RESULTS: Neural networks created reasonably good models of the emotional component of general quality of life. Logistic regression analysis also created reasonably good models and, given current computational schemes, allowed for identification of significant inputs in the models more readily than did the feed-forward, back propagation neural networks. All models of general quality of life relied primarily on disease nonspecific inputs, including social support, activities of daily living and coping. CONCLUSIONS: Our observations suggested that efforts to optimize general quality of life in patients with prostate disease must integrate disease nonspecific variables.

Median nerve hamartoma: MR imaging using chemical shift techniques.

Magnetic resonance imaging findings of median nerve hamartoma are presented in three patients with palpable wrist masses and median neuropathy. Fat-suppressed T1-weighted images demonstrated adipose tissue separating the neural and fibrous tissue bundles in two of three patients, which results in the distinctive appearance of these tumors on magnetic resonance imaging. Fibrous tissue appeared as enhancing longitudinal bundles within the tumor on gadolinium enhanced fat-suppressed T1-weighted images.

Marriage and mortality in prostate cancer.

PURPOSE: We evaluated the association of marital status and survival in patients with prostate cancer. MATERIALS AND METHODS: Using the 146,979 prostate cancer patients of the 1973 to 1990 public use tape of the Surveillance, Epidemiology and End Results program we performed survival analysis and multivariate proportional hazards modeling to estimate the relative risk of mortality. RESULTS: Married patients had significantly longer median survival than those who were divorced, single, separated or widowed. In models that controlled for age, stage, race and treatment, married patients had a significantly lower risk of mortality than those who were divorced, single, separated or widowed. CONCLUSIONS: Several hypothetical models can explain the association of marital status and mortality in men with prostate cancer. The most attractive model relies on the putative salutary effects of being married on social support and/or mood. A social support and depressed mood model of mortality raises the possibility that in prostate cancer quality of life determines quantity of life. Understanding the relationships among marital status, social support, mood and mortality could open the way to rational strategies for postponing death in men with prostate cancer.

Functional fetal nigral grafts in a patient with Parkinson's disease: chemoanatomic, ultrastructural, and metabolic studies.

A patient with Parkinson's disease received bilateral fetal human nigral implants from six donors aged 6.5 to 9 weeks post-conception. Eighteen months following a post-operative clinical course characterized by marked improvement in clinical function, this patient died from events unrelated to the grafting procedure. Post-mortem histological analyses revealed the presence of viable grafts in all 12 implant sites, each containing a heterogeneous population of neurons and glia. Approximately 210,146 implanted tyrosine hydroxylase-immunoreactive (TH-ir) neurons were found. A greater number of TH-ir grafted neurons were observed in the right (128,162) than the left (81,905) putamen. Grafted TH-ir neurons were organized in an organotypic fashion. These cells provided extensive TH-ir and dopamine transporter-ir innervation to the host striatum which occurred in a patch-matrix fashion. Quantitative evaluations revealed that fetal nigral grafts reinnervated 53% and 28% of the post-commissural putamen on the right and left side, respectively. Grafts on the left side innervated a lesser area of the striatum, but optical density measurements were similar on both sides. There was no evidence that the implants induced sprouting of host TH-ir systems. Electron microscopic analyses revealed axo-dendritic and occasional axo-axonic synapses between graft and host. In contrast, axo-somatic synapses were not observed. In situ hybridization for TH mRNA revealed intensely hybridized grafted neurons which far exceeded TH mRNA expression within residual host nigral cells. In addition, gamma-amino butyric acid (GABA)-ergic neurons were observed within the graft that formed a dense local neuropil which was confined to the implant site. Serotonergic neurons were not observed within the graft. Cytochrome oxidase activity was increased bilaterally within the grafted post-commissural putamen, suggesting increased metabolic activity. In this regard, a doubling of cytochrome oxidase activity was observed within the grafted post-commissural putamen bilaterally relative to the non-grafted anterior putamen. The grafts were hypovascular relative to the surrounding striatum and host substantia nigra. Blood vessels within the graft stained intensely for GLUT-1, suggesting that this marker of blood--brain barrier function is present within human nigral allografts. Taken together, these data indicate that fetal nigral neurons can survive transplantation, functionally reinnervate the host putamen, establish synaptic contacts with host neurons, and sustain many of the morphological and functional characteristics of normal nigral neurons following grafting into a patient with PD.

Making sense of the combined effect of interleukin-2 and interleukin-4 on lymphocytes using a mathematical model.

The cytokines are the information superhighway of the immune system. They are an important component of the integrated behavior of the system. In order to be able to have a good understanding of the immune system, we must be able to model the effect of cytokines and their combined effect. This work is a step in that direction. We study the combined effect of two cytokines: interleukin-2 (IL-2) and interleukin-4 (IL-4) on some cells of the immune system. Interleukin-2 and interleukin-4 are important growth and differentiation factors for B and T cells. Interleukin-4 antagonizes the effect of interleukin-2 on B cells and some T cells while it synergizes with interleukin-2 on other T cells. We build a mathematical model of the interaction of both cytokines on T and B cells as a building block toward a model of the Th1/Th2 cross-regulation. The response of a given cell to the combination of interleukin-2 and interleukin-4 is shown to involve competing dynamical effects which can lead to either antagonistic or synergistic combined effect.

Not all patients pursue prostate biopsy after abnormal prostate specific antigen results.

In prostate cancer, digital rectal examination (DRE) and serum prostate specific antigen (PSA) are used to evaluate the risk of prostate cancer. However, in published community-based screening samples, not all patients with abnormal test results pursue biopsy. To test the existence of and quantify diagnostic dropout in clinic-based early detection samples, we conducted a prospective patterns-of-care study designed to identify variables associated with pursuit of diagnostic steps. Of 76 patients with abnormal PSA and/or DRE, only 43 (57%) pursued prostate biopsy. Prostate specific antigen, but not age or chart-based comorbidities, was predictive of further diagnostic and therapeutic steps. Among patients with abnormal test results, age and abnormal PSA and DRE, but not chart-based comorbidities, strongly correlated with physician intention to diagnose prostate cancer. The factors that cause diagnostic dropout are unknown, but based on experience with other cancers, they may relate to psychological variables in tested patients. That pursuit of diagnosis and treatment appears to occur with no association with chart-based comorbidities is worrisome given the power of comorbidities to predict mortality in prostate cancer patients. Finally, from a public health perspective, a reproducible dropout phenomenon implies that the positive predictive value of DRE and PSA testing may be seriously underestimated.

Loss of developing cholinergic basal forebrain neurons following excitotoxic lesions of the hippocampus: rescue by neurotrophins.

Previous studies have demonstrated that the viability of developing cholinergic basal forebrain neurons is dependent upon the integrity of neurotrophin-secreting target cells. In the present study, we examined whether infusions of nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) could prevent the loss of cholinergic septal/diagonal band neurons following excitotoxic lesions of their target neurons within the hippocampus. Postnatal Day 10 rat pups received unilateral intrahippocampal injections of ibotenic acid. Rats then received intracerebroventricular (icv) injections of nerve growth factor (30 micrograms/injection), brain-derived neurotrophic factor (60 micrograms/injection), or saline immediately following the lesion and continuing every third day for 27 days. Both saline- and BNDF-treated rats displayed a significant loss of septal/diagonal band neurons expressing the protein and mRNA for choline acetyltransferase (ChAT) and p75 low-affinity nerve growth factor receptor ipsilateral to the lesion. The magnitude of this loss was significantly attenuated in BNDF-treated rats. Many remaining neurons were atrophic with stunted dendritic processes. In contrast, NGF treatment completely rescued these cells and prevented the shrinkage of remaining cholinergic septal neurons. In addition, both NGF and BDNF induced a sprouting of cholinergic processes within the residual hippocampal remnant ipsilateral to the infusions. The present study demonstrates that icv injections of NGF, and to a lesser extent BDNF, prevent the loss of developing basal forebrain neurons which occurs following removal of normal target cells. Diffusion studies revealed relatively poor penetration of BDNF into brain parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrastriatal infusions of brain-derived neurotrophic factor: retrograde transport and colocalization with dopamine containing substantia nigra neurons in rat.

The pattern of retrogradely transported BDNF, a member of the nerve growth family of neurotrophins, following intrastriatal infusion was immunohistochemically visualized within the rodent central nervous system. Human recombinant BDNF was infused at a rate of 3 micrograms/h for 7 days with an Alzet 2002 minipump prior to sacrifice. Tissue immunohistochemically processed using a turkey anti-BDNF antibody revealed retrogradely transported BNDF within neurons located mainly within the ipsilateral frontoparietal cortex (predominantly layer V), parafascicular and posterior thalamic nuclei, and substantia nigra, pars compacta. Sections dual immunoreacted for BNNF and tyrosine hydroxylase revealed a subpopulation of dopaminergic neurons (approximately 28%) within the pars compacta which contained retrogradely transported BDNF. Experiments in which a mixture of BDNF and the retrograde tracer fluorogold were simultaneously infused for 7 days into the striatum revealed BDNF and fluorogold single-labeled neurons as well as BDNF and fluorogold dual-labeled cells within the substantia nigra, pars compacta. These observations indicate that only a subpopulation of neurons within the substantia nigra retrogradely transport BDNF following intrastriatal infusion and thus only a subpopulation of cells may be responsive to the trophic influences of BDNF. The retrograde transport of trophins, such as BDNF, represents a unique neuroanatomical tool to selectivity map the location of specific neurotrophin-responsive systems. Unraveling the trophic anatomy of BDNF will aid in understanding its role in development, degeneration, and experimental animal models of regeneration providing essential data for its use in clinical neurodegenerative disorders including Parkinson's disease.

Age-related vulnerability of developing cholinergic basal forebrain neurons following excitotoxic lesions of the hippocampus.

Previous studies have demonstrated that depleting the hippocampus of endogenous neurotrophins via excitotoxic lesions fails to alter the viability of adult cholinergic septal/diagonal band neurons. Since cholinergic basal forebrain neurons may be more vulnerable during development, we investigated whether excitotoxic lesions produced in neonatal animals alter the viability of these cells. Postnatal Day 7, 10, 14, and 28 rats pups received unilateral intrahippocampal injections of ibotenic acid and were sacrificed 4 weeks later. At 7, 10, and 14 days of age, significant reductions in the number of choline acetyltransferase (ChAT)- and p75 nerve growth factor receptor (NGFr)-immunoreactive neurons were observed within the medial septum ipsilateral to the hippocampal lesion. In contrast, rats receiving similar lesions on Day 28 failed to display a significant reduction in ChAT-immunoreactive medial septal neurons. The magnitude of ChAT-immunoreactive neuronal loss within the medial septum and the age at which the lesion was made were inversely correlated (r2 = 0.887), indicating that cholinergic septal neurons become less vulnerable to target removal as the cells develop. Similar results were observed in the vertical limb of the diagonal band although a small but significant loss of ChAT-immunoreactive neurons was seen in this structure ipsilateral to the hippocampal lesion when lesions were performed on Postnatal Day 28. At all age groups, many remaining cholinergic septal/diagonal band neurons appeared dystrophic with stunted fiber outgrowth. The present study demonstrates that unlike adult rats, removal of hippocampal target neurons during development alters the viability and morphology of cholinergic neurons of the medial septum and diagonal band. This suggests that target neurons which synthesize endogenous neurotrophins are needed for normal development of cholinergic basal forebrain neurons, but may not be required for the normal maintenance of the adult cell.

A pilot study of a structured interview addressing sexual function in men with schizophrenia.

Twenty physically healthy men with schizophrenia responded to a 15-item questionnaire inquiring about their usual and their present (on medications) sexual functioning. Two summary measures of present impairment (the average of items 7-13 that detail the patients' specific complaints of impairment, and item 15, the interviewer's global judgment of impairment) were significantly correlated with each other and with the differences between usual and present reported frequencies of erection and masturbation. More severe impairment on these summary measures was significantly associated with greater biological evidence of dopamine blockade (more severe extrapyramidal side effects and higher serum prolactin levels).