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Objectives Therapeutic drug monitoring (TDM) plays a crucial role in personalized medicine. It helps clinicians to tailor drug dosage for optimized therapy through understanding the underlying complex pharmacokinetics and pharmacodynamics. Conventional, non-continuous TDM fails to provide real-time information, which is particularly important for the initial phase of immunosuppressant therapy, e.g., with cyclosporine (CsA) and mycophenolic acid (MPA). Methods We analyzed the time course over 8 h of total and free of immunosuppressive drug (CsA and MPA) concentrations measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 16 kidney transplant patients. Besides repeated blood sampling, intravenous microdialysis was used for continuous sampling. Free drug concentrations were determined from ultracentrifuged EDTA-plasma (UC) and compared with the drug concentrations in the respective microdialysate (µD). µDs were additionally analyzed for free CsA using a novel immunosensor chip integrated into a fluorescence detection platform. The potential of microdialysis coupled with an optical immunosensor for the TDM of immunosuppressants was assessed. Results Using LC-MS/MS, the free concentrations of CsA (fCsA) and MPA (fMPA) were detectable and the time courses of total and free CsA comparable. fCsA and fMPA and area-under-the-curves (AUCs) in µDs correlated well with those determined in UCs (r≥0.79 and r≥0.88, respectively). Moreover, fCsA in µDs measured with the immunosensor correlated clearly with those determined by LC-MS/MS (r=0.82). Conclusions The new microdialysis-supported immunosensor allows real-time analysis of immunosuppressants and tailor-made dosing according to the AUC concept. It readily lends itself to future applications as minimally invasive and continuous near-patient TDM.

A novel therapeutic drug monitoring point of care testing (POCT) optical device for the detection of immunosuppressants in transplanted patients was designed and tested, with the body interface constituted by an intravascular microdialysis catheter (MicroEye®) which provides the dialysate as clinical sample. An optical biochip with 10 microchannels, based on total internal reflection fluorescence (TIRF), enables the frequent measurement of immunosuppressants. Heterogeneous competitive immunoassays for the detection of mycophenolic acid, tacrolimus and cyclosporine A are implemented on the different microchannels, with the derivative of the immunosuppressants immobilised on the bottom part of the micro-channels.

Purpose Despite increasing frequency, little evidence guides cholesterol screening in less traditional health care settings, such as rural health fairs. Methods The Miller School of Medicine Department of Community Service (DOCS) is a student-run organization providing free basic health care to underserved South Florida communities. We retrospectively reviewed all new patients seen at 2007 DOCS rural fairs to describe their low-density lipoprotein (LDL) and high-density lipoprotein (HDL) values. In addition, we assessed if patient characteristics were associated with cholesterol abnormalities and whether patients with abnormalities who returned to a subsequent fair in 2008 or 2009 improved their cholesterol. Findings Of 252 patients, 145 (58%) had an LDL cholesterol over 129 mg/dL and 61 (24%) had an HDL cholesterol below 40 mg/dL or 50 mg/dL for males and females, respectively. Baseline LDL cholesterol was not associated with body-mass index (BMI), age over 60 years, gender, healthy lifestyle habits, or insurance status. Of 36 patients with elevated LDL cholesterol and a follow-up screening, 24 (67%) reduced their LDL cholesterol by at least 16 mg/dL though reductions were not associated with BMI reduction, and 22 (61%) increased their HDL cholesterol by at least 5 mg/dL, trending with BMI reduction. Conclusions Cholesterol screening at rural fairs can identify a high proportion of patients with abnormal cholesterol, including those who might not be considered at high risk. Although this may catalyze favorable cholesterol changes, the lack of an association with weight loss suggests patients seek additional medical care, which should be considered before offering cholesterol screening at fairs.

Only half of eligible patients in the United States undergo colorectal cancer (CRC) screening as recommended. Hypothesizing that the medical philanthropy platform may be effective in improving access to CRC screening, we aimed to demonstrate the feasibility of a flexible sigmoidoscopy (FS)-based CRC screening "health fair" for uninsured patients.Uninsured patients older than 50 years who had not undergone CRC screening in the preceding 10 years were recruited through local free clinics and health fairs. A standard medical clinic was transformed into a fully functional endoscopy unit. Medicolegal protection for volunteers was obtained through the Florida Department of Health's Volunteer Health Care Provider Program. Unsedated FS with polypectomy was performed. Those with high-risk endoscopic features were given instructions on obtaining a full colonoscopy.Fifty-two patients without access to any form of CRC screening underwent FS. Ninety-four percent had an adequate bowel preparation, although 40% required on-site enema. Eighteen patients had a total of 22 polyps, 4 of which were adenomatous. There were no complications. The total cost of the fair, excluding donated resources such as endoscopes and processors, was $6,531.47, amounting to $126 per patient screened.Health fair-style CRC screening for uninsured patients is feasible. With improved efficiency, widespread application of CRC screening using the medical philanthropy platform may represent a viable approach to reducing the underuse of CRC screening among the uninsured.

Medical school faculty members are charged with the critical responsibility of preparing the future physician and medical scientist workforce. Recent reports suggest that medical school curricula have not kept pace with societal needs and that medical schools are graduating students who lack the knowledge and skills needed to practice effectively in the 21st century. The majority of faculty members want to be effective teachers and graduate well-prepared medical students, but multiple and complex factors-curricular, cultural, environmental, and financial-impede their efforts. Curricular impediments to effective teaching include unclear definitions of and disagreement on learning needs, misunderstood or unstated goals and objectives, and curriculum sequencing challenges. Student and faculty attitudes, too few faculty development opportunities, and the lack of an award system for teaching all are major culture-based barriers. Environmental barriers, such as time limitations, the setting, and the physical space in which medical education takes place, and financial barriers, such as limited education budgets, also pose serious challenges to even the most committed teachers. This article delineates the barriers to effective teaching as noted in the literature and recommends action items, some of which are incremental whereas others represent major change. Physicians-in-training, medical faculty, and society are depending on medical education leaders to address these barriers to effect the changes needed to enhance teaching and learning.

To determine the dose-response efficacy of once-daily administration of placebo or a new long-acting calcium channel blocker amlodipine in patients with mild to moderate hypertension, a randomized, multicenter, placebo-controlled, double-blind trial was conducted. The study included 210 patients with diastolic hypertension (blood pressure 95 to 114 mm Hg) without major hematologic, renal, hepatic, cardiac, or endocrine abnormalities. After a 4-week single-blind placebo run-in period, patients were given placebo or amlodipine (1.25, 2.5, 5, or 10 mg) daily for 4 weeks. To assess the antihypertensive effect of amlodipine over a 24-hour period, blood pressure and pulse rate at weeks 0 and 4 were recorded for 12 hours after the dose and then again at 24 hours. At the end of the study patients treated with all doses of amlodipine greater than 1.25 mg daily had significantly reduced diastolic blood pressure in both supine and standing than 1.25 mg daily had significantly reduced diastolic blood pressure in both supine and standing positions. Amlodipine, 1.25 mg daily, was also associated with a decrease in standing diastolic blood pressure. Response to treatment was greater in all amlodipine-treated patients than in those receiving placebo. Pulse rate in both the supine and standing positions was not significantly affected by amlodipine. At doses of 2.5, 5.0, or 10.0 mg daily, amlodipine maintained blood pressure below values obtained with placebo throughout the 24-hour period. Treatment with amlodipine was well tolerated and the incidence of side effects was low.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of daily pretreatments with the prototypical 5-HT1A receptor agonist 8-hydroxy-(di-n-propylamino) tetralin (8-OH-DPAT) (1.0 mg/kg s.c.) on behavioural responses to challenge by 8-OH-DPAT (0.5 mg/kg s.c.) due to activation of 5-HT1A receptors were determined. The responses had strikingly different susceptibilities to pretreatment. These were not explicable by different effects on pre- and postsynaptic responses. Thus, two components of the 5-HT syndrome due to action at postsynaptic sites (i.e. flat body posture and reciprocal forepaw treading) were substantially attenuated 1 day after a single pretreatment with 8-OH-DPAT, but the tail-flick response, though due to action at postsynaptic 5-HT1A sites, was completely unimpaired by 14 pretreatments while the hypothermic response which also probably involves postsynaptic sites showed progressively increased attenuation on 14 pretreatments. 8-OH-DPAT-induced hyperphagia which depends on activation of presynaptic sites was unimpaired by the pretreatment schedule. The results are discussed in relation to receptor reserve, second messenger changes and effects at NMDA receptors. They imply a need for caution in the use of chronic effects of 5-HTergic drugs on specific 5-HT1A receptor-dependent responses as indices of mechanisms for the therapeutic actions of the drugs.

Venography is the current standard for the diagnosis of deep vein thrombosis (DVT). Noninvasive tests have differing sensitivity and specificity, are technically demanding, and may be subject to variability in interpretation. Light reflection rheography (LRR) is a noninvasive method utilizing light-emitting diodes and a sensor to measure light reflected from the skin surface. The intensity of reflected light establishes a graphic pattern that indirectly quantifies parameters of venous function by measuring changes in the microcirculation. Seventy-two patients who underwent contrast venography at our institution were also evaluated with LRR. Twenty-four patients were found to have DVT as demonstrated by venography. Of these, 23 also had DVT detected by LRR. No evidence of thrombus was seen in 45 patients studied by venography; in this group, 35 had normal venous emptying indicated by LRR. Using LRR, a sensitivity of 96% was achieved in the evaluation of clinically suspected DVT. This sensitivity is comparable with other noninvasive tests. In addition, LRR is easy to operate, portable, inexpensive, and not technically demanding. Further investigation is needed to confirm these data and further define the role of LRR in the evaluation of clinically suspected DVT.

Risk factors for vibratory perception threshold abnormalities were studied in 200 diabetic patients between the ages of 21 and 70 years and 62 control subjects of similar age. Vibratory perception (measured with the Biothesiometer) was absent over one or both halluces in 18 percent of the patients. In a stepwise multiple logistic regression analysis, height was the variable most strongly associated with absent vibratory perception (coefficient +/- SE, 0.501 +/- 0.097/inch; p less than 0.0001). Duration of diabetes (p less than 0.001), age (p less than 0.05), and ethanol use (p less than 0.05) were also associated. The prevalence of absent vibratory perception in the lower, middle, and upper thirds of the height distribution was 0.05, 0.08, and 0.40, respectively. Among the control subjects, there was no association of vibratory perception with either height or ethanol use. These data strongly suggest that body stature is a major risk factor for diabetic sensory neuropathy.

Plasma fibronectin levels in 66 medical ICU (MICU) patients were measured daily. Mean values of initial levels were significantly higher in survivors (266 +/- 14 mg/L) than nonsurvivors (179 +/- 13 mg/L; p less than .0003). There was extensive overlap between survivors and nonsurvivors. The clinical categories of sepsis, disseminated intravascular coagulation (DIC), adult respiratory distress syndrome (ARDS), and hepatic failure with GI bleeding were associated with low fibronectin levels. Within all diagnostic categories the mean initial fibronectin level of the survivors was higher than that of nonsurvivors. This difference was significant only in the septic group (p less than .02). Patients with minimum fibronectin levels less than 195 mg/L had a 65% mortality rate; patients with minimum levels greater than or equal to 195 mg/L had a 17% mortality rate. Fibronectin, via its role in reticuloendothelial system (RES) function, may have a pathophysiologic role in a variety of medical illnesses.

Characteristic pathological alterations of the liver in chimpanzees inoculated with non-A, non-B hepatitis sera have been described, but no corresponding findings have been reported in humans. Electron microscopic studies of the liver biopsy specimens of two homosexual patients with acquired immune deficiency syndrome, one without hepatitis (Patient 1) and one with chronic active hepatitis in remission (Patient 2), revealed the cytoplasmic tubular structures which are characteristic of chimpanzee non-A, non-B hepatitis. A cluster of 23 nm double-shelled particles was also seen in the cytoplasm of a hepatocyte in patient 1 who had received a blood transfusion 8 days before the biopsy. These particles were smaller than the Dane particles, Epstein-Barr virus, cytomegalovirus or herpes simplex virus, and different from hepatitis A virus particles; the antibodies to all of which are found in high concentration in acquired immune deficiency syndrome patients. These observations may reflect the morphologic findings for non-A, non-B hepatitis infection in humans.

Over a 12-month period, we observed adult patients with suspected pulmonary embolism referred for lung scanning to determine variability in the diagnostic process. Among 269 studies, 157 lung scans were judged necessary by predetermined criteria. Ninety-three of these 157 patients had inconclusive results (low probability, intermediate probability, or indeterminate). Of these 93 patients, 42 had pulmonary angiograms, ten of which were positive. Of the 51 patients with necessary but inconclusive scans, five were poor candidates for angiography, 15 had other indications for anticoagulation, seven refused the study, and 24 had physicians who considered further studies unwarranted. Patients with and without pulmonary angiography were demographically and clinically similar. Although confirmatory testing such as pulmonary angiography was used frequently (45%) after an inconclusive lung scan, the question of pulmonary embolism was often left unanswered (55%). Methods for linking clinical judgment to lung scan results are necessary to select proper patients for invasive confirmatory testing.

Twenty Haitian patients, hospitalized from 1 April 1980 to 20 June 1982, had Pneumocystis carinii pneumonia, central nervous system toxoplasmosis, esophageal candidiasis, cryptococcosis, disseminated cytomegalovirus, progressive herpes simplex virus, chronic enteric coccidiosis, or invasive Kaposi's sarcoma. Ten patients died. Opportunistic infections were frequently multiple and were recurrent in three patients. In seven patients disseminated tuberculosis preceded the other infections by 2 to 15 months. There was no evidence of an underlying immunosuppressive disease, and no history of homosexuality or intravenous drug abuse. At least three patients probably acquired the syndrome in Haiti. Lymphadenopathy was common. Seventeen patients tested had anergy, and 18 had lymphopenia. Monoclonal antibody analysis of peripheral-blood T-cell subsets done on 11 patients showed a marked decrease in T-helper cells and an inversion of the normal ratio of T-helper cells to T-suppressor cells. This syndrome among heterosexual Haitians is strikingly similar to the syndrome of immunodeficiency described recently among American homosexuals.

• Necrotizing vasculitis is not usually considered in the differential diagnosis of hypertensive crisis. Three cases are presented in which hypertensive crisis with encephalopathy was the principal initially seen manifestation of systemic necrotizing vasculitis. The correct diagnosis was suspected because of the patients' young age, elevated ESRs, and evidence of previous exposure to hepatitis B virus and was confirmed by renal angiography. All three patients had metabolic alkalosis, and two of the three patients had hyponatremia and hypokalemia. The literature presents a picture of hypertension in necrotizing vasculitis as insidious, relentless, and progressive. Our cases illustrate that it can be a dramatic, life-threatening initial manifestation. A renal angiogram can be justified in similar patients, since effective therapy for necrotizing vasculitis exists. In these patients control of BP ultimately depends on successful treatment of the underlying vasculitis. (Arch Intern Med1985;145:265-267)