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3,5-bis(4-amidinophenyl)isoxazole (3)-an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in which the central furan ring is replaced by isoxazole-and 42 novel analogues were prepared by two general synthetic pathways. The 43 isoxazole derivatives were assayed against Trypanosoma brucei rhodesiense (T. brucei rhodesiense) STIB900, Plasmodium falciparum (P. falciparum) K1, and rat myoblast L6 cells (for cytotoxicity) in vitro. Eleven compounds (3, 13, 16-18, 22, 26, 29, 31, 37, and 41) exhibited antitrypanosomal IC50 values less than 10 nM, five of which displayed cytotoxic indices (ratios of cytotoxic IC50 to antiprotozoal IC50 values) at least 10 times higher than that of furamidine. Eighteen compounds (4-8, 12, 14, 18-22, 25, 26, 28, 29, 32, and 43) were more active against P. falciparum than furamidine, with IC50 values less than 15 nM. Fourteen of these compounds had cytotoxic indices ranging between 10 and 120 times higher than that of furamidine, and five analogues exhibited high selectivity for P. falciparum over T. brucei rhodesiense.

The Donald W. Reynolds Institute on Aging at the University of Arkansas for Medical Sciences in Little Rock is addressing one of the most pressing policy issues facing the United States: how to care for the burgeoning number of older adults. In 2001, the Institute created the Arkansas Aging Initiative, which established seven satellite centers on aging across the state using $1.3 to $2 million dollars annually from the state's portion of the Master Tobacco Settlement. These centers on aging assist the state's population of older adults, many of whom reside in rural areas, live in poverty, and suffer from poor health. The centers provide multiple avenues of education for the community, health care providers, families, and caregivers. The Arkansas Aging Initiative, in partnership with local hospitals, also makes geriatric primary and specialty care more accessible through senior health clinics established across rural Arkansas. In 2005, older adults made more than 36,000 visits to these clinics. All sites have attracted at least one physician who holds a Certificate of Added Qualifications in geriatrics and one advanced practice nurse. Other team members include geriatric medical social workers, pharmacists, nutritionists, and neuropsychologists. This initiative also addresses other policy issues, including engaging communities in building partnerships and programs crucial to maximizing their limited resources and identifying opportunities to change reimbursement mechanisms for care provided to the growing number of older adults. We believe this type of program has the potential to create a novel paradigm for nationwide implementation.

Objectives: Identify endocrine differences between human immunodeficiency virus- (HIV) infected versus uninfected children and evaluate associations of growth and body composition with endocrine measures., Study Design: Nested case-control study in 21 HIV-infected and 46 age- and sex-matched uninfected children in the Women and Infant Transmission Study. Plasma specimens from children between 2.5 to 7.0 years of age, taken during 3-4 visits, were tested for insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, dehydroepiandrosterone (DHEA), growth hormone and thyroid studies. Longitudinal mixed and generalized estimating equation models compared group means and examined effects of endocrine measures on growth and body composition, respectively., Results: HIV-infected children had lower IGFBP-3 than uninfected children (1.96 +/- 0.09 mg/L versus 2.34 +/- 0.06 mg/L, P < 0.001). In infected but not in uninfected children, IGFBP-3 values and DHEA:cortisol ratios were associated with weight- and body mass index-for-age z scores ([WAZ] P = 0.019, <.001 respectively, and [BMZ] P = 0.029, 0.038). DHEA concentration was associated with height-for-age z score (P = 0.049)., Conclusions: In these HIV-infected children compared with their uninfected counterparts, IGFBP-3 concentration was different between groups. Infected children had multiple endocrine associations with growth and body composition not found in their uninfected peers. We hypothesize that in HIV-infected children, growth hormone resistance and shunting of precursors from adrenal androgen to cortisol production contributes to altered body composition and stunting.

Background: The ability of patients to adhere to a medication regimen is imperative for achieving optimal outcomes. Elderly patients, especially those with memory loss, should be evaluated for their ability to manage medications to prevent significant drug-related problems. Assessment tools to determine the ability to manage medication therapy have not been tested in elderly patients with cognitive impairment., Objectives: This study compared the Medication Management Ability Assessment (M1V1AA) and the Drug Regimen Unassisted Grading Scale (DRUGS) as standardized tools to assess medication management skills in elderly patients with a range of cognitive function and evaluated the association between the results obtained from these scales and self-reported drug-related problems., Methods: This was a cross-sectional study of older individuals living in the community. At a scheduled study visit, the research assistant (RA) questioned participants with a structured interview to document demographic information, medical history, prescription use, over-the-counter drug and dietary supplement use, health care resource use, medication management practices, and adverse drug events. Cognitive status was assessed with the Mini-Mental State Examination (MMSE) and functional status with the instrumental activities of daily living rating scale. The MMAA, which uses a fictitious medication regimen with labeled prescription bottles, and the DRUGS, which uses the patient's own prescription bottles, were administered. Three months after the visit, the RA telephoned participants to determine recent changes in living situation and drug-related problems., Results: The study group comprised 52 people with a mean (SD) MMSE score of 28.3 (2.5). The participants had a mean (SD) age of 75.8 (6.2) years; 69% (36/52) were women, and 96% (50/52) were white. Participants reported an average of 4.1 medical conditions, and 88% (46/52) reported good to excellent health. Skipping doses or cutting them in half was reported by 25% (13/52) of participants who adjusted doses themselves. Almost half (44%) reported medication problems and/or medication ineffectiveness during the past 3 months at both the study visit and the 3-month follow-up (23/52 for both). The 49 participants who took the MMAA had a mean (SD) score of 19.4 (6.1), with a range of 0 to 25. Of the 49 participants with scores, 34 took less than the correct number of tablets and 13 took more. The 46 participants who took the DRUGS had a mean (SD) score of 91.6 (24.7), with a range of 0 to 100. Forty of 46 participants attempting the test attained the maximum score. Higher scores for both tests indicate better accuracy. Analysis revealed that the MMAA and the DRUGS correlated with one another (P = 0.000). We found no significant associations between these medication management assessment tools and selfreported adherence or drug-related events., Conclusions: The MMAA and DRUGS tools correlated positively with cognitive function in this population of community-living elderly persons but need further evaluation of their ability to predict who is at greatest risk for drug related problems due to nonadherence to medication regimens.

Ferromagnetic embolization hyperthermia (FEH) is a novel treatment for liver cancer. Magnetic microspheres are injected into the hepatic artery and cluster in the periphery of tumours and are heated with externally applied magnetic fields. In order to more accurately simulate FEH, we modelled a three-dimensional heterogeneous distribution of heat sources. We constructed a fractal model of the vasculature in the periphery of a tumour. We used this model to compute the spatial distribution of the microspheres that lodge in capillaries. We used the distribution model as input to a finite-element heat transfer model of the FEH treatment. The overall appearance of the vascular tree is subjectively similar to that of the disorganized vascular network which encapsulates tumours. The microspheres are distributed in the tumour periphery in similar patterns to experimental observations. We expect the vasculature and microsphere deposition models to also be of interest to researchers of any targeted cancer therapies such as localized intra-arterial chemotherapy and selective internal radiotherapy. Our results show that heterogeneous microsphere distributions give significantly different results to those for a homogeneous model and thus are preferable when accurate results are required.

Colorectal cancer is a major cause of death for men and women in the Western world. When the cancer is detected through an awareness of the symptoms by a patient, typically it is at an advanced stage. It is possible to detect cancer at an early stage through screening and the marked differences in survival for early and late stages provide the incentive for the primary prevention or early detection of colorectal cancer. This paper considers mathematical models for colorectal cancer screening together with models for the treatment of patients. Illustrative results demonstrate that detailed attention to the processes involved in diseases, interventions and treatment enable us to combine data and expert knowledge from various sources. Thus a detailed operational model is a very useful tool in helping to make decisions about screening at national and local levels.

Ankyrins-R, -B, and -G are a family of membrane-associated adaptors required for localization of structurally diverse proteins to specialized membrane domains, including axon initial segments, cardiomyocyte T-tubules, and epithelial cell lateral membranes. Ankyrins are often co-expressed in the same cells and, although structurally similar, have non-overlapping functions. We previously determined that the regulatory domain of ankyrin-B defines specificity between ankyrins B and G in cardiomyocytes. Here, we identify key residues on the surface of an amphipathic alpha-helix unique to the regulatory domain of ankyrin-B that are essential for the function of ankyrin-B in cardiomyocytes. Using circular dichroism, we determined that a peptide representing the predicted helix folds as a helix in solution. Alanine-scanning mutagenesis revealed that residues 1773, 1777, 1780, 1784, and 1788 located in a patch on one surface the helix are critical for ankyrin-B function in cardiomyocytes. In a parallel set of experiments we determined that the molecular co-chaperone human DnaJ homologue 1 (Hdj1)/Hsp40 interacts with the ankyrin-B regulatory domain. Moreover, interaction of Hdj1/Hsp40 with the regulatory domain was mapped by random mutagenesis to same surface of the alpha-helix that is required for ankyrin-B function. These results provide new insight into the molecular basis for specificity between ankyrin-based pathways by defining a key alpha-helix structure in the divergent regulatory domain of ankyrin-B as well as interaction of the helix with Hdj1/Hsp40, the first downstream target for ankyrin-B-specific function.

This study investigated the efficacy of surgeon-directed focused assessment with sonography for trauma (FAST) in conjunction with physical exam (PEx) as a predictor of intra-abdominal injury in children. Injured children (ages < or = 17) presenting to a level I trauma center with abdominal trauma were evaluated in the emergency department (ED) by the trauma team of surgical attendings and residents. PEx and FAST were performed immediately upon arrival to the ED and results compared to CT, the standard exam for presence of intra-abdominal injury. Data was collected prospectively from July 1, 2000, until April 30, 2002. One hundred and twenty injured children underwent evaluation of abdominal trauma with PEx, FAST, and abdominal CT. Two patients had false-negative CT scans. Bayesian analysis was applied to the results of the remaining 118 patients. FAST compared with CT findings revealed sensitivity 70 per cent, specificity 100 per cent, positive predictive value 100 per cent, and negative predictive value 92 per cent. FAST results were combined with PEx findings such that either suggestive of intra-abdominal injury was regarded as a "positive exam." Sensitivity was 100 per cent, specificity 74 per cent, positive predictive value 53 per cent, and negative predictive value 100 per cent. Surgeon-directed FAST with consideration of PEx is a predictor of intra-abdominal injury in children.

Objective: This study was undertaken to determine the effect of pregnancy on progression of human immunodeficiency virus (HIV) disease., Study Design: We compared the immunologic, clinical, and virologic courses of 953 women who had no additional pregnancy after their index pregnancy, with the courses of 329 women who had a second pregnancy subsequent to their index pregnancy. Baseline variables included use of antiretroviral therapy, and CD4 and HIV RNA values. A linear spline growth curve model was used to describe trajectories of variables. The Cox proportional hazards model was used to assess selected covariates on the time to development of clinical class C events or death., Results: Women with repeat pregnancies were less likely to be on antiretroviral therapy at baseline and had a higher CD4% count immediately after their first delivery. The average trajectory of CD4 values in the one-pregnancy group was almost identical to the average trajectory in the repeat pregnancy group. RNA levels in the single-pregnancy group started higher but ended lower than in the second-pregnancy group, although slope differences were modest. There were no significant differences in time to class C events, although women in the repeat-pregnancy group tended to survive longer., Conclusion: Repeat pregnancies do not have significant effects on the course of HIV disease.

Rabbit liver was loaded with ferrimagnetic particles of gamma -Fe2 O3 (designed for magnetic hyperthermia treatment of liver tumors) by injecting various doses of a suspension of the particles into the hepatic artery in vivo. Proton transverse relaxation rate (R(2)) images of the livers in vivo, excised, and dissected were generated from a series of single spin-echo images. Mean R(2) values for samples of ferrimagnetic-particle-loaded liver dissected into approximate 1 cm cubes were found to linearly correlate with tissue iron concentration over the range from approximately 0.1 to at least 2.7 mg Fe/g dry tissue when measured at room temperature. Changing the temperature of ferrimagnetic-particle-loaded samples of liver from 1 degrees C to 37 degrees C had no observable effect on tissue R(2) values. However, a small but significant decrease in R(2) was found for control samples containing no ferrimagnetic material on raising the temperature from 1 degrees C to 37 degrees C. Both chemically measured iron concentrations and mean R(2) values for rabbit livers with implanted tumors tended to be higher than those measured for tumor-free liver. This study indicates that tissue R(2) measurement and imaging by nuclear magnetic resonance may have a useful role in magnetic hyperthermia therapy protocols for the treatment of liver cancer.

Nonsynchronized segmented heterochromia in black scalp hair is a rarely reported entity, the only previous report being described in association with iron deficiency anaemia. A 14-year-old girl presented with a 2-year history of nonsynchronized segmented heterochromia. She was otherwise well and her serum iron, copper, zinc and protein levels were all within the normal range. She had no clinical evidence of vitiligo or alopecia areata. This patient is believed to represent the first reported case of nonsynchronized segmented heterochromia in black scalp hair as a presentation of premature greying of the hair.

Neuromuscular blocking agents (NMBA) are increasingly being used in the management of critically ill patients. These medications are used to facilitate mechanical ventilation. Strange and colleagues estimated that only 4% of intensive care units utilize train-of-four (TOF) monitoring on a regular basis and that 70% never use this type of monitoring. The ease of use and low cost of the equipment lends itself to the increasingly frequent recommendations for this type of monitoring. Although unwilling to go so far as to establish this as a standard of care, the American College of Critical Care Medicine of the Society of Critical Care Medicine released an executive summary recommending train-of-four monitoring for patients receiving continuous or sustained NMBAs. This protocol and algorithm was developed to facilitate the objective monitoring of patients receiving continuous NMBAs.

Symptoms associated with Dientamoeba fragilis include diarrhoea, abdominal pain, nausea, vomiting, epigastric pain and weight loss. A possible link between D. fragilis and irritable bowel syndrome (IBS)-like symptoms has been reported, and therefore the presence of this parasite should be excluded before making a diagnosis of IBS. Over a six-month period, 976 faecal samples were submitted to NPHS Microbiology Aberystwyth for routine microbiological analysis. All samples were also cultured for parasites using Robinson's xenic medium. Trichrome staining was undertaken whenever practicable, but many stools had insufficient material. D. fragilis was isolated from 25 (2.6%) patients, whereas Cryptosporidium spp. was detected in 16 (1.6%) patients. D. fragilis was only detected in nine (1.3%) out of 685 specimens stained with trichrome, although four of the 25 culture-positive stools had insufficient sample for staining. Parasite culture proved to be less laborious than trichrome staining and dramatically increased D. fragilis detection rate.

Objective: Arterial embolization hyperthermia (AEH) consists of arterially embolizing tumours with ferromagnetic particles that generate hysteretic heating on exposure to an alternating magnetic field. It was the objective of this study to determine if such particles are cleared from the liver., Method: A lobe of normal liver in three pigs was arterially embolized with 300 mg of gamma-Fe2O3 particles (150 nm) suspended in lipiodol. The same liver lobe of three other pigs was embolized with 300 mg of ferromagnetic polymer matrix-encapsulated microspheres (32 microm) suspended in 1% tween-water. Samples of liver and blood were obtained before infusion, and at 60 min and 28 days after arterial infusion. At 28 days, samples of lung and other abdominal viscera were also obtained. The tissue samples were chemically analysed for iron content, and submitted to histopathological examination., Results: There was no significant reduction in the hepatic iron concentration in either treatment group 28 days after infusion. Both types of particles illicited an immunogenic response and were extensively phagocytosed in the liver. The particle/lipiodol suspension caused extensive necrosis of liver, while the microsphere/tween-water suspension was well tolerated. Small amounts of both types of ferromagnetic particles embolized in the lungs, but there was no evidence of embolization into other organs. There were no haematological or biochemical changes and all subjects experienced uneventful 28-day survivals., Conclusion: This study has shown that, although arterially infused ferromagnetic particles were extensively phagocytosed, there was no significant hepatic clearance 28 days after infusion. It also determined that the suspension of 150 nm ferromagnetic particles in lipiodol was too vaso-occlusive for use in hepatic tissue. However, the suspension of 32 microm microspheres containing ferromagnetic particles in tween-water was safe and well tolerated.

A 34-year-old woman with systemic lupus erythematosus and high titres of antiphospholipid antibodies was admitted to hospital suffering a viral illness but developed haemorrhagic and necrotic areas on the neck and anterior chest 7 days following cessation of warfarin. Anticoagulation had been initiated following a retinal vein thrombosis, but was ceased on day 4 of admission when she was found to be excessively anticoagulated (international normalized ratio (INR) > 10). However, at the time of developing the cutaneous lesions, the INR was sub-therapeutic. Histology of a skin biopsy from the neck revealed thrombosis of upper dermal blood vessels without vasculitis, consistent with antiphospholipid antibody-related skin necrosis. This case illustrates one of the cutaneous features that can occur in patients with elevated titres of antiphospholipid antibodies and the importance of closely monitoring anticoagulation in such patients.

The use of hyperthermia in the treatment of cancers is appealing because, as a physical therapy, hyperthermia would have far fewer restrictive side effects than chemotherapy and radiotherapy, and it could be used in combination with these therapies. However, the currently available modalities of hyperthermia are often limited by their inability to selectively target tumour tissue and, hence, they carry a high risk of collateral organ damage or they deposit heat in a very localized manner which can result in under-treatment of a tumour. Magnetically mediated hyperthermia (MMH) has the potential to address these shortcomings. MMH consists of the localization of magnetic particles or seeds within tumour tissue followed by exposure to an externally applied alternating magnetic field to cause them to heat. Since this concept was introduced (over 40 years ago), MMH has evolved into four general sub-classes: arterial embolization hyperthermia (AEH), direct injection hyperthermia (DIH), intracellular hyperthermia (IH) and interstitial implant hyperthermia (IIH). It is the purpose of this article to review these four sub-classes in terms of experimental or clinical results, advantages, limitations and current status.

Background and Objectives: It is possible to arterially embolize or directly inject liver tumors in small animal models with ferromagnetic particles that generate hysteretic heating on exposure to an alternating magnetic field. The objective of this study was to compare the response of liver tumors to arterial embolization hyperthermia (AEH) and direct injection hyperthermia (DIH)., Methods: Ten rabbits containing experimental hepatic tumors were treated with AEH, and a second group of ten rabbits were treated with DIH. The tumors of both groups were heated to 43 degrees to 50 degrees C for 20 minutes. Tumor response, which was determined by measuring change in tumor volume and by comparison of tumor mass after treatment with the mass of untreated control tumors of the same age, was assessed 14 days after treatment., Results: All tumors treated with AEH decreased in volume by 50% to 94% (P = 0.005), and their average mass (median 1.73 gm) was significantly less than that of untreated control tumors (median 8.01 gm, n = 20; P < 0.001). Three of the treated tumors were completely necrotic, while the remainder were at least 80% necrotic. Nine of the ten tumors treated with DIH increased in volume by at least 143% (P = 0.01), and their average mass (median 5.68 gm) was not significantly different from that of the untreated control tumors (P = 0.56)., Conclusion: These results indicate that AEH is more effective than DIH at moderately elevated temperatures. This is probably because the more widespread particle distribution that can be achieved using arterial embolization results in more extensive and complete treatment of the tumor., (Copyright 2002 Wiley-Liss, Inc.)

Background: Arterial embolization hyperthermia (AEH) consists of arterially embolizing tumors with ferromagnetic particles that generate hysteretic heating on exposure to an alternating magnetic field. It was the objective of this study to evaluate AEH using the kidney of a large animal as a tumor model., Methods: Between 50 and 400 mg of ferromagnetic microspheres (32 microm in diameter) was arterially infused into the kidneys of three pigs. Temperature probes were inserted into renal tissue, skin, and subcutaneous fat. Each subject was then exposed to an alternating magnetic field for 5 min, while under a general anesthetic. A femoral artery catheter was used to monitor the cardiac pulse. Three days after treatment the renal tissue was chemically analyzed for iron content, which was then correlated with tissue heating rates., Results: There was a linear relationship between heating rate and iron concentration (N = 18, correlation = 0.72, P < 0.001) that suggested tissue iron concentrations in the range of 1.55 to 4.05 mg/g would yield tissue heating rates of 0.5 to 1.0 degrees C/min. No temperature increases were detected in control renal tissue (N = 6). The median increase in skin temperature after 5 min of heating was 0.8 degrees C (N = 6, min = 0.7 degrees C, max = 1.3 degrees C), and that in subcutaneous fat was 1.1 degrees C (N = 6, min = 0.8 degrees C, max = 1.2 degrees C). There was no detectable stimulation of cardiac or skeletal muscle or peripheral nerves during treatment. All subjects had uneventful 3-day posttreatment survivals., Conclusion: This study has shown that AEH can target deep-seated, vascularized tissue in a large animal with therapeutic temperatures (> 42 degrees C), and that the treatment is safe and well tolerated. Further assessment of treatment schedules should allow for a human trial in the near future.

Arterial embolization hyperthermia (AEH) consists of arterially embolizing liver tumours with ferromagnetic particles that generate hysteretic heating on exposure to an alternating magnetic field. A critical component of AEH is the concentration and distribution of ferromagnetic particles in the normal hepatic parenchyma (NHP), as well as in the tumour tissue. If the distribution of particles in NHP is heterogeneous, with areas of high concentration, then unwanted areas of necrosis may result during AEH. Using an in vivo rabbit liver tumour model, this study showed that hepatic arterial infusion of ferromagnetic particles does indeed result in a heterogeneous distribution of iron in NHP. The radiological technique of magnetic resonance imaging (MRI) was then evaluated as a potential tool for non-invasively and prospectively determining the concentration and distribution of particles within the hepatic tumour and NHP following hepatic arterial infusion. A preliminary in vitro experiment showed that although the concentration of iron within the tumour tissue (1.92-3.50 mg of iron per gram of tissue) was too great to measure, MRI was able to accurately determine the lower iron concentration (0.10-0.53 mg of iron per gram of tissue) in NHP. Further work is needed to evaluate MRI under in vivo conditions. If successful, MRI could become an important component of an emerging novel treatment for advanced hepatic malignancies.

Objective: Ferromagnetic Embolization Hyperthermia (FEH) consists of arterially embolizing tumours with ferromagnetic particles to cause hysteretic heating upon subsequent exposure to an alternating magnetic field. The objective was to determine the effect of tumour size during FEH using a rabbit liver tumour model., Method: Thirty-three rabbits containing implanted hepatic VX2 carcinomas received a hepatic arterial infusion of ferromagnetic particles suspended in lipiodol. Following hysteretic heating, tumour and normal hepatic tissues were chemically analysed for iron content. Tumours were classed as small if their mass was less than the median mass for the whole group of subjects (2.1 g), and as large if their mass was greater than or equal to the median. To control for variability in tumour iron concentration, 13 small tumours were matched to 13 large tumours by iron concentration, and their heating characteristics compared., Results: The heating rate in large tumours (median = 5.0 degrees C/min) was significantly greater than that in the matched small tumours (median = 2.8 degrees C/min), p = 0.006. Regression analysis determined that the slope of the heating rate vs iron concentration curve for large tumours was 1.5 times greater than that for the matched small tumours, p < 0.001. After cessation of heating in large tumours, there was continued heat dissipation into surrounding tissues, which led to anomalous temperature increases. There was an inverse linear relationship between tumour size and tumour iron concentration for a given dose of particles., Conclusion: For a given tumour iron concentration, larger tumours heat at a greater rate than small tumours, due to the poorer tissue cooling and better heat conduction in the necrotic regions of large tumours. This warrants further investigation as this finding could confer a significant advantage on FEH over other hyperthermic modalities in the treatment of hepatic malignancies.

Experimental rabbit liver tumours were preferentially heated to therapeutic temperatures without compromising the surrounding normal hepatic parenchyma. This was achieved by the use of hepatic arterially infused ferromagnetic microspheres that heat as a result of magnetic hysteresis loss when exposed to an alternating magnetic field. Treatment sessions involving a single 20-min exposure to the alternating field resulted in total suppression of tumour growth at 14 days compared to controls, in which tumour sizes increased dramatically over the same period. Histopathological examination of treated tumour sections showed total tumour destruction in some cases. Separate animal groups used to control for the effects of the embolized microspheres alone and for the effect of the applied magnetic field yielded similar tumour growth responses to a control group with no intervention whatsoever. The achievement of positive temperature differentials between tumour and normal liver and the consequent therapeutic responses encourages further development of this technology for the treatment of liver cancer in humans.

A 45-year-old premenopausal woman presented with an 18-month history of a band-like area of fibrosing alopecia affecting the frontoparietal scalp. She also had marked thinning of the eyebrows. The histopathology was consistent with frontal fibrosing alopecia (FFA). Several months later she developed multiple pruritic papules on the wrists and feet. The clinical presentation and histopathology were consistent with cutaneous lichen planus. Although FFA has been reported to occur with mucosal lichen planus this is the first reported case of FFA associated with cutaneous lichen planus. This provides further evidence that FFA is a variant of lichen planopilaris.

Over a one-year period, 1390 faecal samples were submitted to Aberystwyth Public Health Laboratory for routine microbiological examination. All were stained using a commercial trichrome method. Blastocystis hominis was detected in 96 (6.9%), making it the most common parasite found in the study. Of the B. hominis-positive specimens, 73% were missed on direct microscopy. Molecular typing of B. hominis has revealed extensive genetic diversity in morphologically identical strains and thus detection by microscopy alone may not be sufficient to confirm the role of this organism in human disease.

Background and Objectives: Ferromagnetic embolization hyperthermia (FEH) consists of arterially embolizing liver tumors with ferromagnetic particles, and then applying an external alternating magnetic field to generate hysteretic heating within the embolized particles. The objective of this study was to assess the ability of FEH to selectively target liver tumors with hyperthermia., Methods: Twenty rabbits containing hepatic VX2 carcinomas were arterially infused with ferromagnetic particles suspended in lipiodol, and then exposed to an external alternating magnetic field. Temperatures in the tumor, normal hepatic parenchyma (NHP), and rectum were recorded. Tumour and NHP were chemically analyzed for iron content, which was then correlated with the observed heating rates., Results: The mean tumor-to-NHP iron concentration ratio was 5.3:1 (P < 0.001, N = 20). The mean tumor heating rates were 3.0-11.5 times greater than those in the NHP (P < 0.001, N = 20). After 5 min of heating, the greatest increase in mean tumor temperature was 11.0 degrees C and the greatest increase in mean NHP temperature was 1.3 degrees C. There was a positive relationship between tumor iron concentration and heating rate (correlation coefficient = 0.82, P < 0.001, N = 20). A tumor iron concentration of 2-3 mg/g resulted in tumor heating rates of 0.5-1.0 degrees C/min., Conclusions: Hepatic arterial infusion of lipiodol containing ferromagnetic particles can result in excellent targeting of liver tumors with hyperthermia on the subsequent application of an external alternating magnetic field. The promising results of this study warrant further investigation of FEH as a potential treatment for advanced liver cancer., (Copyright 2001 Wiley-Liss, Inc.)

The vast majority of patients with malignant liver tumors have inoperable disease. These patients must rely on chemotherapy, radiotherapy, and various locoregional treatments. Although these treatments have demonstrated encouraging response rates, symptom palliation and occasional down staging of tumors, their impact on survival is minor. As a result there has been renewed interest in hyperthermia as a treatment option. This study reviews the current modalities of hyperthermia in terms of clinical results, side effects, limitations, and therapeutic standing., (Copyright 2001 Wiley-Liss, Inc.)

It is known that significant heating can be generated by magnetic hysteresis effects in small ferromagnetic particles exposed to a rapidly alternating magnetic field. If such particles can be made to infiltrate the vascular bed surrounding a tumour by intravascular infusion then it may be possible to generate sufficient heating to destroy the tumour by hyperthermia. One of the constraints on such a technique is the limited amount of magnetic material that can be delivered to a tumour via the intravascular route and the consequent heating that can be induced by this material. Here, we report on a series of experiments in which doses of microspheres containing different amounts of ferromagnetic material were infused into rabbit kidneys via the renal artery with the aim of testing whether adequate tissue heating could be achieved using realistic concentrations of the embolised material. Heating rates were measured for each infused quantity under similar conditions with the animal alive and dead to examine the role of blood flow in the heating process. The results show that tissue temperatures above the therapeutic threshold of 42 degrees C can be readily achieved using this method with clinically relevant concentrations of microspheres in living tissue.

Aromatic dicationic drugs have a broad spectrum of activity against protozoal and fungal pathogens including Pneumocystis carinii, Leishmania mexicana amazonensis, Cryptosporidium parvum and Cryptococcus neoformans. Pentamidine serves as the exemplar for an extensive collection of newly synthesized related compounds, which have reduced toxicity and a wider range of target organisms. Assays of pentamidine and related compounds have depended on HPLC-tandem mass spectrometry (HPLC-TMS) for the quantitation and identification of drug and metabolites. Immunoassays for pentamidine would have many advantages over the HPLC methods including relative simplicity of assay format and required equipment, convenience in sample preparation and reduction in time and cost of assays. In this report we describe a simple ELISA based immunoassay for pentamidine and pentamidine-like drugs with requisite sensitivity and specificity for use as a clinical assay (EC50 value of about 50 nanomolar). Immunogen was synthesized by coupling the hapten aminopentamidine to ovalbumin (chemically modified to provide an optimal number of -SH groups) using sulfo-MBS. Maleic-anhydride activated ELISA plates were covalently sensitized using the aminopentamidine hapten and used in an inhibitory ELISA assay format whereby the ability of analyte to suppress antibody binding to sensitized plate was measured. The assay detects primarily the phenolic amidine of pentamidine when in a para position and hence can also detect structurally related derivatives of pentamidine of potential interest as new therapeutic agents., (Copyright 2000 Wiley-Liss, Inc.)

Chloroquine and hydroxychloroquine (4-aminoquinolones) are used by dermatologists for the treatment of a wide range of disorders. It is widely recognized that their use may lead to ocular complications, but policies for ophthalmological screening and follow-up vary widely. In this article, the current literature on the ocular complications of antimalarials is reviewed, together with the results of a recent survey of dermatological practice on screening. New recommendations for ophthalmological screening recently produced by the Royal College of Ophthalmologists, the British Association of Dermatologists and the British Association of Rheumatologists are presented. It is recommended that baseline screening should include an assessment of renal and liver function, an enquiry about visual impairment and the recording of near visual acuity. Follow-up should comprise an enquiry about visual problems at each clinic visit and assessment of visual acuity once yearly. The multidisciplinary nature of the committee producing the new guidelines will hopefully mean that they will be acceptable to and usable by all those who routinely prescribe antimalarial drugs.

Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 microg/ml, and it was the most potent compound against C. neoformans (MIC,

Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

The binding of the antagonists N-(8-aminooctyl)-5-iodonaphthalene-1-sulfonamide (J-8) and trifluoperazine (TFP) to intact calcium-saturated bovine calmodulin (CaM) and also of J-8 to the C-terminal domain (tr2c) has been investigated. Using a combination of NMR methods, including NOESY data, mobility measurements, and chemical shift and line-shape analysis, we show that the primary interaction between J-8 and tr2c is between the naphthalene ring of the antagonist and the hydrophobic pocket of the protein, similar to the binding of the hydrophobic side-chain residues of calmodulin target peptides. Comparison of the mobility of the drug, the intensity and pattern of intermolecular NOESY cross-peaks, and chemical shift changes shows that there is no significant change in the binding mode in J-8. CaM compared to J-8.tr2c, with one molecule binding to each domain. In particular, we find that the mobility of the aliphatic amino "tail" of J-8 remains highly mobile in both systems. This contrasts with the notion that the tail may bridge between the two domains to give a "globular" form of CaM. We also show that TFP induces very similar shift changes to J-8 and that the stoichiometry of the major binding event in all three cases is one drug molecule per domain. It also appears that secondary binding sites for the drug molecules are present in all three systems.

Seven dicationic 2,5-diarylfurans have been synthesized, and their interactions with poly(dA-dT) and the duplex oligomer d(CGCCAATTCGCG)2 were evaluated by Tm measurements. The inhibition of topoisomerase II isolated from Giardia lamblia, the inhibition of growth of G. lamblia in cell culture by these furans, and the effectiveness of these compounds against Pneumocystis carinii in the immunosuppressed rat model have been assessed. Strong binding affinities to poly(dA-dT) and to the oligomer were observed for the dicationic furans, and the interaction strength is directly correlated to the biological activity of the compounds. An X-ray structure for the complex of the dicationic amidine derivative, 2,5-bis(4-guanylphenyl)furan (1), with the oligomer demonstrates the snug fit of these compounds with the AATT minor-groove binding site and hydrogen bonds to AT base pairs at the floor of the minor groove. The stronger DNA binding molecules are the most effective inhibitors of topoisomerase II and G. lamblia in cell culture, and there is a correlation for both DNA interaction and topoisomerase II inhibition with the biological activity of these compounds against G. lamblia. Compound 1 is the most effective against P. carinii, it is more active and less toxic than pentamidine on intravenous administration and it is also effective by oral dosage. The results presented here suggest a model for the biological action of these compounds in which the dication first binds in the minor groove of DNA and forms a complex that results in the inhibition of the microbial topoisomerase II enzyme.

We have synthesized cis and trans geometric isomers 1-8 as semirigid congeners of pentamidine. Compounds 1-4 were more potent than pentamidine in treating Pneumocystis carinii pneumonia in immunosuppressed rats. These compounds also demonstrated no clinical toxicity or histopathologic abnormalities. Introduction of methoxy substituents meta to the amidine or imidazoline groups of the phenyl rings as in compounds 5-8 generally resulted in compounds with decreased anti-P. carinii activity and increased toxicity to the host. Compounds 1-4 were evaluated as DNA binders. These compounds showed greater affinity for poly(dA).poly(dT) than for calf thymus DNA. The cis isomers, 1 and 2, demonstrated greater affinity for DNA than their trans counterparts 3 and 4. This difference in DNA binding affinity, however, did not reflect in a corresponding difference in the anti-P. carinii activity of these compounds.

1. Iowa farmers die from work related injuries at a rate of two to three times the rate of manufacturing workers. Farming ranks second highest in occupational fatalities in Iowa. 2. While all deaths involved multiple causal factors, the tractor was the most frequent agent of injury causing death. 3. In Iowa, 89% of agriculture related deaths occur in males. 4. Iowa was the first state to require statewide reporting of agriculture related injuries for the purpose of planning interventions.

On the basis of a previously observed correlation between the antimicrobial activity and DNA binding strength of dicationic molecules, a series of 10 dicationically substituted bis-benzimidazoles were tested for activity in the rat model of Pneumocystis carinii pneumonia. One of the compounds, 1,4-bis[5-(2-imidazolinyl)-2-benzimidazolyl]butane, was found to be more potent and less toxic than pentamidine.

Groups of chicks were infected with a virulent strain of Mycoplasma gallisepticum (MG) and treated with either danofloxacin or tylosin while one infected group was left untreated and a further group was uninfected and untreated. Control of clinical signs and mortality was better with danofloxacin than tylosin and there was significantly (P < 0.05) greater weight gain with danofloxacin at 21 days after infection. However at necropsy the prevalence of lesions of the airsac walls was similar in both groups. MG was recovered from fewer live chicks for the first week following treatment with danofloxacin, but at 2 weeks and at necropsy, at the termination of the experiment, it was recovered from a similar proportion of birds in both treated groups. This was reflected also in the serological results at the end of the trial.

Butamidine analogues possessing unsaturation in the ether bridge between the bisamidinophenyl or bisimidazolinophenyl functionalities have been synthesized as semirigid congeners of pentamidine. These compounds demonstrated good anti-P. carinii pueumonia activity in a rat model of the disease.

The utility of microspheres as targeted drug delivery agents is addressed with reference to using heat during formulation and to administration in combination with hyperthermia. It was demonstrated that rate of loading of the drug doxorubicin onto resin microspheres is enhanced under conditions of elevated temperature but this was shown to increase the incidence of microsphere aggregation. Total amount of drug loaded was related to time rather than temperature such that low temperature loading for up to 24 h produced optimum quality injectates. However, release of doxorubicin from microspheres was significantly increased during elevations of temperature to 43 degrees C. Thus, during hyperthermia doxorubicin release can be increased to provide periods of high drug availability targeted to tumour tissue for concomitant thermochemotherapy with microspheres. The therapeutic benefit derived from this combined therapy was assessed in 20 rabbits with VX2 carcinoma implanted in the liver. Hyperthermia was delivered by 2450 MHz microwave applicator to the exteriorized liver at 43 degrees C for 30 min, while chemotherapy was administered by intratumoural injection of doxorubicin microspheres (2.3 mg) into each tumour. Both hyperthermia and chemotherapy alone significantly reduced the size of tumours 10 days following treatment (p less than 0.01). However, in animals treated with both modalities, the size of tumours was significantly less than either treatment alone (p less than 0.05). These results provide a strong rationale for combining hyperthermia with targeted chemotherapy using microspheres.

Ultraviolet B light (UVB) has previously been shown to induce the expression of the extractable nuclear antigens (e.g. Ro/SSA) on the surfaces of human keratinocytes in vitro. This study assessed whether injurious, metabolic, inflammatory, immunological or hormonal stimuli would also induce this expression or modulate that produced by UVB. No stimulus initiated expression alone, but 17-beta oestradiol doubled that found in response to UVB. These findings confirm the potential role of UVB in the initiation and potentiation of cutaneous lupus lesions and may help to explain the female preponderance of the disease.

Antinuclear antibodies are useful markers of connective tissue disease. In this study, UVB but not UVA induced the expression of Ro/SSA antigen on keratinocyte surfaces in vitro. This expression was also found with the extractable nuclear antigens RnP and Sm, but not with single or double-stranded DNA. The expression was prevented by blocking protein synthesis, suggesting that it was an active process. The results suggest that UVB exposure may result in the expression of Ro/SSA antigen on the surfaces of basal keratinocytes in vivo. This antigen could then bind circulating antibody leading to the cutaneous lesions in neonatal and subacute cutaneous lupus erythematosus.

In an attempt to produce a persistent infection with M. iowae (Mi) three separate trials were conducted using strain B 11/80, a virulent strain, strain M 012-118, a recent isolate of unknown virulence, and strain Iowae 695 (I 695), the type strain. In each trial groups of 2-day-old poults were infected via the oesophagus, trachea, cloaca and directly into the lungs. Isolation during life was attempted from the oropharynx and the cloaca, and at necropsy at the end of the experiment (21 days after infection) from the trachea, lungs and airsacs, and the brain. The highest proportion of isolations were made at necropsy from the lungs and air sacs, and trachea, from birds infected with B 11/80 or M 012-118 via the lungs or B 11/80 given via the trachea. During life the proportion of isolations was lower than at necropsy but highest, overall, with B 11/80 given via the lungs or trachea and isolated from the oropharynx, or administered via the cloaca and isolated form this site. Strain I 695 was rarely isolated whatever the route of infection. There were few recoveries following infection via the oesophagus with any strain and no mycoplasmas were isolated from the brain. For the production of MI infection suitable for monitoring antimicrobials in young poults we would recommend infection with a pathogenic strain of the organism directly into the lungs.

An analogue of pentamidine, 1,3-di(4-imidazolino-2-methoxyphenoxy)propane (DMP) lactate, was tested against rat Pneumocystis carinii pneumonia (PCP). The drug was found to be highly active in the treatment of rat PCP at a dose of 1.75 mg/kg (parent molecule) when administered by intravenous (i.v.) injection (daily for 2 wk). The compound was also active against PCP when given orally, however, significantly higher doses of DMP were necessary when compared to the i.v. dosing regimen. Prophylactic doses (i.v.) of the drug also proved highly effective in preventing PCP.

Comparison was made of the protection afforded by Baytril, Tylosin and Tiamulin for turkey poults infected with Mycoplasma iowae (MI) by injection of the organism into the lungs. Poults were infected at 2 days of age and treatment commenced 3 days later by including the appropriate drug in the drinking water. Following treatment with Baytril at 50 mug/ml for 5 days, MI was not isolated at 7, 14 and 19 days after infection from the oropharynx or cloaca, during life, but was recovered from five of 23 poults at necropsy. With the same concentration of Baytril, but for only 3 days, isolations of MI were made at 19 days post infection from the oropharynx and cloaca, from 2 of 23 live birds, but at necropsy at this time from 19/23 birds. From poults given Tylosin or Tiamulin (at 500 and 250 mug/ml respectively for 5 days) MI was isolated from a proportion of birds on all occasions during life, after infection, and from 19/21 and 18/21, respectively, at necropsy.