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1.  Vaginal deployment and tenofovir delivery by microbicide gels 
Gels are one of the soft material platforms being evaluated to deliver topically acting anti-HIV drugs (microbicides) to the vaginal environment. For each drug, its loaded concentration, gel properties and applied volume, and frequency of dosing can be designed to optimize PK and, thence, PD. These factors also impact user sensory perceptions and acceptability. Deterministic compartmental modeling of vaginal deployment and drug delivery achieved by test gels can help delineate how multiple parameters characterizing drug, vehicle, vaginal environment, and dosing govern details of PK and PD and also gel leakage from the canal. Such microbicide delivery is a transport process combining convection, e.g., from gel spreading along the vaginal canal, with drug diffusion in multiple compartments, including gel, mucosal epithelium, and stroma. The present work builds upon prior models of gel coating flows and drug diffusion (without convection) in the vaginal environment. It combines and extends these initial approaches in several key ways, including: (1) linking convective drug transport due to gel spreading with drug diffusion and (2) accounting for natural variations in dimensions of the canal and the site of gel placement therein. Results are obtained for a leading microbicide drug, tenofovir, delivered by three prototype microbicide gels, with a range of rheological properties. The model includes phosphorylation of tenofovir to tenofovir diphosphate (which manifests reverse transcriptase activity in host cells), the stromal concentration distributions of which are related to reference prophylactic values against HIV. This yields a computed summary measure related to gel protection (“percent protected”). Analyses illustrate tradeoffs amongst gel properties, drug loading, volume and site of placement, and vaginal dimensions, in the time and space history of gel distribution and tenofovir transport to sites of its anti-HIV action and concentrations and potential prophylactic actions of tenofovir diphosphate therein.
Electronic supplementary material
The online version of this article (doi:10.1007/s13346-015-0227-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4420798  PMID: 25874971
Microbicide; Compartmental model; Pharmacokinetics; Pharmacodynamics; Gel; Vagina; Tenofovir
2.  Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384 
Translational Psychiatry  2013;3(8):e295-.
ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-2H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1–50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ⩾2 mg daily maintained peripheral HSD-1 inhibition ⩾88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ⩾81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ⩾2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.
PMCID: PMC3756293  PMID: 23982627
central nervous system; cerebrospinal fluid; deuterium label; enzyme inhibition; hydroxysteroid dehydrogenase; target engagement
3.  Hepatic vascular shunts: embryology and imaging appearances 
The British Journal of Radiology  2011;84(1008):1142-1152.
The purpose of this pictorial review is to understand the embryological basis of the development of congenital hepatic vascular shunts and to review the multimodality imaging appearances of congenital and acquired hepatic vascular shunts. Hepatic vascular shunts are commonly seen in imaging. Familiarity with their characteristic appearances is important in order to accurately characterise these shunts and diagnose the underlying disorders.
PMCID: PMC3473823  PMID: 22101582
4.  New design of a cementless glenoid component in unconstrained shoulder arthroplasty: a prospective medium-term analysis of 143 cases 
The uncemented glenoid implants in total anatomical shoulder arthroplasty are likely to be accused of problems like dissociations, secondary rotator cuff tear, and wear of polyethylene (PE). This work is a clinical and radiological prospective review of 143 cases of anatomical total shoulder arthroplasty using a new metal back uncemented glenoid implant (MB) in order to see if this new implant induces those complications. A total of 143 cases were operated between 2003 and 2011. In a first part, the whole series of 143 cases was radiologically studied in order to quantify the lateralisation induced by the MB implant. In a second study, 37 cases had a mean follow-up of 38 months (24–75, mean 32) and served for the clinical and radiological final study. Pre- and postoperative clinical evaluation was done using the Constant–Murley score and the simple shoulder test from Matsen. The final X-rays served to detect an eventual secondary narrowing of the joint space and to analyse the frequency of radio lucent lines (RLL) and loosenings. Despite a small radiological lateralisation in comparison with the normal contralateral side (0.36 cm, p = 0.02), the clinical results after 2 years were similar to the published cemented glenoid implants series but without any RLL, glenoid loosening or joint narrowing. Some dissociations occured in the beginning and definitely eliminated by a design modification of the PE tray. The discussion tried to show that, despite a still short follow-up, this series is encouraging to continue to use this new MB implant. Different applications of the concept of universality and conversion are discussed, this tray been also the support of a glenosphere in reverse arthroplasty.
PMCID: PMC3535408  PMID: 23293576
Glenoid; Osteoarthritis; Shoulder; Total shoulder arthroplasty; Uncemented metal back
5.  Enterolith ileus: liberated large jejunal diverticulum enterolith causing small bowel obstruction in the setting of jejunal diverticulitis 
The British Journal of Radiology  2011;84(1004):e154-e157.
We present an 80-year-old man with multiple medical problems, and acute abdominal pain with feculent emesis. An unenhanced CT examination of the abdomen and pelvis demonstrated jejunal diverticulitis and findings of high-grade small bowel obstruction caused by a large enterolith. Enterolith ileus has rarely been reported in the radiology literature. This phenomenon has occasionally been reported in the surgical and gastroenterology literature. We highlight the CT findings associated with enterolith ileus in the setting of jejunal diverticulitis, to alert radiologists to this unusual diagnosis.
PMCID: PMC3473425  PMID: 21750131
7.  Outpatient parenteral antibiotic therapy with daptomycin: insights from a patient registry 
To compare and contrast the characteristics and clinical outcomes of patients who have received daptomycin as outpatients and inpatients.
The Cubicin Outcomes Registry and Experience (CORE) is a retrospective chart review of patients who have received daptomycin in participating institutions. Patients treated in 2005 were included in this analysis. Demographic characteristics and clinical outcomes (success = cured + improved) were compared among patients who received outpatient parenteral antibiotic therapy (OPAT) and patients who had received inpatient parenteral antibiotic therapy (IPAT).
Of 1172 patients reported by 52 CORE 2005 participating institutions/investigators, 949 (81.0%) patients were evaluable: 539 (56.8%) received OPAT (OPAT patients), and 410 (43.2%) received only IPAT (IPAT patients). Of the 539 OPAT patients, 273 (50.6%) also received some IPAT, usually preceding OPAT therapy. Successful outcomes [no. of successes/(no. of successes + no. of failures)] for OPAT patients vs. IPAT patients were 94.6% and 86.3% respectively (chi-square test, p < 0.001). OPAT patients were younger, had fewer underlying diseases, were clinically stable, and had fewer adverse events than IPAT patients.
Outpatient parenteral antibiotic therapy use was common (539/949 or 56.8%) among patients in CORE 2005. Clinical outcomes among OPAT patients appeared at least as good as or better than IPAT patients. Better outcomes among OPAT patients were most likely because of patient selection for OPAT. Additional studies should focus on clinical characteristics of patients who would be ideal candidates for daptomycin OPAT.
PMCID: PMC2658009  PMID: 18705821
8.  Acetylcholinesterase inhibition with pyridostigmine improves heart rate recovery after maximal exercise in patients with chronic heart failure 
Heart  2003;89(8):854-858.
Objective: To characterise the effects of acetylcholinesterase inhibition with pyridostigmine on parasympathetic tone in patients with chronic heart failure (CHF).
Design: Prospective randomised, double blind crossover trial.
Setting: University hospital outpatient heart failure clinic.
Patients: 20 ambulatory subjects with stable CHF (mean age 55 years, mean ejection fraction 24%).
Interventions: Oral administration of a single dose of pyridostigmine 30 mg and matching placebo on separate days.
Main outcome measures: Heart rate recovery at one minute and three minutes after completion of maximal exercise.
Results: Heart rate recovery at one minute after exercise was significantly greater after administration of pyridostigmine than after administration of placebo (mean (SEM) 27.4 (3.2) beats/min v 22.4 (2.4) beats/min, p < 0.01). Heart rate recovery at three minutes after exercise did not differ after administration of pyridostigmine and placebo (mean (SEM) 44.4 (3.9) beats/min v 41.8 (3.6) beats/min, NS). Peak heart rate, peak oxygen uptake, peak respiratory exchange ratio, plasma noradrenaline (norepinephrine) concentrations, and plasma brain natriuretic peptide concentrations did not differ after administration of pyridostigmine and placebo.
Conclusions: Acetylcholinesterase inhibition with pyridostigmine increased heart rate recovery at one minute but not at three minutes after exercise. A specific effect of pyridostigmine on heart rate one minute after exercise suggests that pyridostigmine augments parasympathetic tone in patients with CHF.
PMCID: PMC1767776  PMID: 12860856
autonomic nervous system; parasympathetic nervous system; autonomic agents; exercise physiology
10.  Collaborative research and action to control the geographic placement of outdoor advertising of alcohol and tobacco products in Chicago. 
Public Health Reports  2001;116(6):558-567.
Community activists in Chicago believed their neighborhoods were being targeted by alcohol and tobacco outdoor advertisers, despite the Outdoor Advertising Association of America's voluntary code of principles, which claims to restrict the placement of ads for age-restricted products and prevent billboard saturation of urban neighborhoods. A research and action plan resulted from a 10-year collaborative partnership among Loyola University Chicago, the American Lung Association of Metropolitan Chicago (ALAMC), and community activists from a predominately African American church, St. Sabina Parish. In 1997 Loyola University and ALAMC researchers conducted a cross-sectional prevalence survey of alcohol and tobacco outdoor advertising. Computer mapping was used to locate all 4,247 licensed billboards in Chicago that were within 500- and 1,000-foot radiuses of schools, parks, and playlots. A 50% sample of billboards was visually surveyed and coded for advertising content. The percentage of alcohol and tobacco billboards within the 500- and 1,000-foot zones ranged from 0% to 54%. African American and Hispanic neighborhoods were disproportionately targeted for outdoor advertising of alcohol and tobacco. Data were used to convince the Chicago City Council to pass one of the nation's toughest anti-alcohol and tobacco billboard ordinances, based on zoning rather than advertising content. The ordinance was challenged in court by advertisers. Recent Supreme Court rulings made enactment of local billboard ordinances problematic. Nevertheless, the research, which resulted in specific legislative action, demonstrated the importance of linkages among academic, practice, and grassroots community groups in working together to diminish one of the social causes of health disparities.
PMCID: PMC1497388  PMID: 12196615
11.  Clinical diagnosis of malaria on the Thai-Myanmar border. 
BACKGROUND: To evaluate the prevailing practice of presumptively diagnosing malaria in all cases of febrile illness in a clinic serving a refugee population on the Thai-Myanmar border METHODS: A retrospective review of 3,506 patient charts from December 1993 through June 1994 at the MaeSot medical clinic to compare clinical signs of malaria to blood smear findings. Patients presenting without fever were assumed not to have malaria; the remaining 2,111 patients presenting with fever had blood smears examined for malaria infection. RESULTS: Fever alone sufferedfrom poorpositive predictive value (54.7 percent) and specificity (59.3 percent). When fever was combined with hepatosplenomegaly and anemia, the positive predictive value and specificity improved (84.5 percent and 98.5 percent, respectively). However, this combination also resulted in an unacceptably poor sensitivity (16.5 percent) and false negative error rate (835/1,000). CONCLUSIONS. In this nonimmune refugee population, severe complications of falciparum malaria occur quickly and commonly; aggressive chemotherapy is necessary to reduce morbidity and mortality. Until laboratory facilities are made available, all cases offever should continue to be treated presumptively as malaria.
PMCID: PMC2588739  PMID: 11769335
12.  Usability issues in developing a Web-based consumer health site. is a Web-based system intended for a diverse audience, including patients, family members and other members of the public. Throughout the system design and development process, our decisions have been driven by usability concerns. We first describe the overall design of the site, including the home page, which provides a site overview and rapid access to the information contained within it. Next we discuss the data presentation format which has been standardized in spite of data coming to us from many different sources. We provide a detailed description of the search and browse features that are intended to simplify the complexities of medical terminology and support information discovery. We conclude with a review of our evaluation activities and future plans.
PMCID: PMC2244083  PMID: 11079945
13.  Differential effects of cisplatin in proximal and distal renal tubule epithelial cell lines 
British Journal of Cancer  1999;79(2):293-299.
Pathological studies suggest that cisplatin injures different portions of the nephron to different extents. To investigate this issue further, we examined the cytotoxicity and uptake of cisplatin in cell lines derived from S1 and S3 proximal tubule and distal convoluted tubule segments isolated from a mouse carrying the SV40 large T-antigen transgene. S1 cells displayed the highest sensitivity to cisplatin cytotoxicity, followed by S3 and distal convuluted tubule (DCT) cells. These differences in cytotoxicity did not correlate with differences in cisplatin uptake. Cytotoxic concentrations of cisplatin triggered apoptosis in all three cell lines. Although BAX and BCL-2 expression was similar among the three cell lines, the expression of the anti-apoptotic protein, BCL-XL, was significantly lower in S1 cells than in S3 and DCT cells, and this may have contributed to the heightened sensitivity of S1 cells. Cisplatin transport characteristics demonstrated a saturable component of cisplatin uptake and differences in apparent KM and Vmax values among the three cell lines. The three cell lines were 43- to 176-fold more sensitive to cisplatin than to carboplatin. This distinction between the two drugs could not be fully explained by differences in the uptake rates of carboplatin and cisplatin. We conclude that cells from different portions of the nephron display different sensitivities to cisplatin, different transport characteristics for cisplatin and different levels of expression of BCL-XL. In addition, the relative resistance of renal cells to carboplatin vs cisplatin is mostly due to the differential effects that follow internalization. © 1999 Cancer Research Campaign
PMCID: PMC2362192  PMID: 9888471
renal tubule epithelial cell lines; cisplatin; carboplatin; nephrotoxicity; transport; apoptosis
14.  Barriers between guidelines and improved patient care: an analysis of AHCPR's Unstable Angina Clinical Practice Guideline. Agency for Health Care Policy and Research. 
Health Services Research  1999;34(1 Pt 2):377-389.
OBJECTIVES: To describe common barriers that limit the effect of guidelines on patient care, with emphasis on recommendations for triage in the Agency for Health Care Policy and Research (AHCPR) Unstable Angina Clinical Practice Guideline. DATA SOURCES: Previously reported results from a prospective clinical study of 10,785 patients presenting to the emergency department (ED) with symptoms suggestive of acute cardiac ischemia. STUDY DESIGN: Design is an analysis of the AHCPR guideline with regard to recognized barriers in guideline implementation. Presentation of hypothetical scenarios to ED physicians was used to determine interrater reliability in applying the guideline to assess risk and to make triage decisions. PRINCIPAL FINDINGS: The AHCPR guideline's triage recommendations demonstrate (1) poor interobserver reliability in interpretation by ED physicians; (2) limited applicability of recommendations for outpatient management (applies to 6 percent of patients presenting to the ED with unstable angina); (3) incomplete specifications of exceptions that may require deviation from guideline recommendations; (4) unexpected effects on medical care by significantly increasing the demand for limited intensive care beds; and (5) unknown effects on patient outcomes. In addition, analysis of the guideline highlights the need to address organizational barriers, such as administrative policies that conflict with guideline recommendations and the need to adapt the guideline to conform to local systems of care. CONCLUSIONS: Careful analysis of guideline attributes, projected effect on medical care, and organizational factors reveal several barriers to successful guideline implementation that should be addressed in the design of future guideline-based interventions.
PMCID: PMC1089008  PMID: 10199682
15.  Cyclosporiasis associated with imported raspberries, Florida, 1996. 
Public Health Reports  1999;114(5):427-438.
OBJECTIVES: Until 1995, infection with Cyclospora cayetanenis, a parasite that causes gastroenteritis, was diagnosed in the US primarily in overseas travelers; its modes of transmission were largely unknown. In 1995, 45 cases of cyclosporiasis were diagnosed in Florida residents who had no history of recent foreign travel, but an investigation could not pinpoint a source for the parasite. In 1996, a North American outbreak of cyclosporiasis resulted in more than 1400 cases, 180 of them in Florida. The authors investigated the 1996 Florida outbreak to identify the vehicle of transmission. METHODS: The authors conducted a matched case-control study in which each of 86 laboratory-confirmed sporadic cases was matched with up to four controls. They also investigated nine clusters of cases associated with common meals and attempted to trace implicated foods to their countries of origin. RESULTS: In the case control study, eating raspberries was strongly associated with cyclosporiasis (matched odds ratio = 31.9; 95% confidence interval [CI] 7.4, 138.2). In the cluster investigation, raspberries were the only food common to all nine clusters of cases; a summary analysis showed a strong association between consumption of raspberries and confirmed or probable cyclosporiasis (risk ratio = 17.6; 95% CI 1.9, 188.8). Guatemala was the sole country of origin for raspberries served at six of nine events. CONCLUSIONS: Guatemalan raspberries were the vehicle for the 1996 Florida cyclosporiasis outbreak. Cyclospora is a foodborne pathogen that may play a growing role in the etiology of enteric disease in this country as food markets become increasingly international.
PMCID: PMC1308515  PMID: 10590765
16.  Pulmonary veno-occlusive disease presenting with thrombosis of pulmonary arteries. 
Thorax  1995;50(6):699-700.
Pulmonary veno-occlusive disease is a rare cause of pulmonary hypertension. An unusual case presenting with thrombosis of the right pulmonary artery and serological evidence of autoimmunity is reported.
PMCID: PMC1021281  PMID: 7638821
17.  Two 21-kilodalton components of the Epstein-Barr virus capsid antigen complex and their relationship to ZEBRA-associated protein p21 (ZAP21). 
Journal of Virology  1996;70(11):8047-8054.
The viral capsid antigen complex of Epstein-Barr virus (EBV), an important serodiagnostic marker of infection with the virus, consists of at least four components, with molecular masses of 150, 110, 40, and 21 kDa. Here we show that the 21-kDa component of the viral capsid antigen consists of products of two EBV genes, BFRF3 and BLRF2. Both products were expressed from late transcripts, were recognized by human antisera, and were present in virions. The BFRF3 product, but not that of BLRF2, fulfilled the definition of ZEBRA-associated protein p21 (ZAP21). In cells in which EBV was lytically replicating, BFRF3 protein was coimmunoprecipitated together with ZEBRA by a rabbit antiserum directed against amino acids 197 to 245 of BZLF1. In EBV-negative cells cotransfected with BZLF1 and BFRF3 expression vectors, BFRF3 was also coimmunoprecipitated with this antiserum. Although this antiserum could not detect BFRF3 on an immunoblot, it was able to immunoprecipitate BFRF3 in the absence of ZEBRA expression. The rabbit antiserum to amino acids 197 to 245 of BZLF1 was found to detect the same epitope at the carboxy end of BFRF3 as was recognized by rabbit antiserum to BFRF3 itself. Thus, coimmunoprecipitation of BFRF3 p21 with ZEBRA appeared to be due to cross-reactivity of the immunoprecipitating antiserum rather than to direct association of ZEBRA and BFRF3 p21.
PMCID: PMC190878  PMID: 8892929
18.  Comparison of positron emission tomography, cognition, and brain volume in Alzheimer's disease with and without severe abnormalities of white matter. 
OBJECTIVES--To examine cerebral metabolism, cognitive performance, and brain volumes in healthy controls and two groups of patients with probable Alzheimer's disease, one group with severe abnormalities of white matter (DAT+) and the other group with none, or minimal abnormalities (DAT-). METHODS--Neuropsychological tests, CT, MRI, quantitative MRI, and PET studies were carried out to allow comparison between the DAT+ and DAT- groups and the healthy controls. RESULTS--Compared with the healthy controls, both demented groups had significantly reduced global and regional cerebral metabolism, significant brain atrophy, and significantly lower scores on neuropsychological testing. The DAT- patient group showed a pattern of parietal-temporal cerebral metabolic reductions and neuropsychological performance deficits typical of Alzheimer's disease. In addition, metabolism in the association neocortex (AD ratio) and measures of neuropsychological task performance were significantly correlated in the DAT- patient group. Comparison of DAT+ with DAT- patients showed a significantly higher ratio of parietal to whole brain glucose utilisation for the DAT+ group. Moreover, when comparing group z score differences from the healthy controls, the DAT+ group had, on average, smaller differences from controls in the frontal, parietal, and temporal regions than did the DAT- group. Discriminant analysis using metabolic ratios of the frontal, parietal, and temporal regions showed cerebral metabolic patterns to be significantly different among the DAT+, the DAT-, and the healthy controls. These differences were due primarily to relatively higher frontal, parietal, and temporal metabolic ratios in the DAT+ group which resulted in discriminant scores for the DAT+ group between the healthy controls and the DAT- group. Group mean scores on tests of neuropsychological performance were not significantly different between the DAT- and DAT+ patients. By contrast with the DAT- group, however, no significant correlations between the AD ratio and any neuropsychological task were seen in the DAT+ group. Multiple regression analysis showed significant between group differences in the relation between the AD ratio and neuropsychological scores on three tasks. The slopes of the relations between the AD ratio and memory scores (memory and freedom from distractability deviation quotient of the Wechsler adult intelligence scale (WMDQ)) also were significantly different for the two groups. CONCLUSIONS--Although multiple causes for abnormalities of white matter exist in patients with Alzheimer's disease, these data suggest that the presence of severe abnormalities of white matter indicate a second pathological process in the DAT+ patients. The DAT- patients showed the parietal-temporal metabolic deficits and correlations between association neocortical metabolism and neuropsychological task performance typical of patients with Alzheimer's disease. By contrast, the DAT+ group had a pattern of cerebral metabolism significantly different from healthy controls and DAT+ patients, as well as no significant correlations between metabolism in the association neocortex and neuropsychological performance. These differences probably reflect the superimposed pathology of the abnormalities of white matter which may exert their affect through disruption of long corticocortical pathways.
PMCID: PMC1073796  PMID: 8708645
19.  Functional regulation of thyroid hormone receptor variant TR alpha 2 by phosphorylation. 
Molecular and Cellular Biology  1995;15(5):2341-2348.
The thyroid hormone (T3) receptor (TR) variant TR alpha 2 is abundant in brain but does not bind T3 because of its unique C terminus. The only known function of TR alpha 2, inhibition of TR-dependent transactivation, involves competition for T3 response elements. Paradoxically, in vitro-translated TR alpha 2 bound poorly to these sites. We report here that dephosphorylation of TR alpha 2 restored its DNA binding. Mutation of C-terminal serine residues to alanine (TR alpha 2-SA) was equally effective. The C terminus of TR alpha 2 was phosphorylated in a human cell line, whereas that of TR alpha 2-SA was not. Conversely, TR alpha 2-SA was a much better inhibitor of T3 action than was wild-type TR alpha 2. The dominant negative activity of TR alpha 2-SA was less than stoichiometric with TR concentration, possibly because it was unable to heterodimerize with retinoid X receptor, which enhances the binding of other TRs. Purified casein kinase II as well as a reticulocyte casein kinase II-like activity phosphorylated TR alpha 2 on serines 474 and 475. Mutation of these two residues to alanine was sufficient to restore DNA binding. Thus, DNA binding by TR alpha 2 is regulated by phosphorylation at a site distant from the DNA-binding domain. The increased dominant negative activity of a nonphosphorylatable form of TR alpha 2 suggests that phosphorylation may provide a rapid, T3-independent mechanism for cell-specific modulation of the expression of T3-responsive genes.
PMCID: PMC230462  PMID: 7739517
20.  A comparison between cytology and histology to detect anal intraepithelial neoplasia. 
Genitourinary Medicine  1994;70(1):22-25.
INTRODUCTION--Anal intraepithelial neoplasia (AIN), which may be a precursor of anal carcinoma, has been identified on histology following minor anal surgical procedures, in particular the removal of perianal condylomata, in increasing numbers of homosexual and bisexual men. Anal cytology has recently been proposed as a useful method of identifying AIN lesions. OBJECTIVE--To compare anal cytology with histology as a method of detecting AIN. METHODS--215 homosexual and bisexual men attending a central London sexually transmitted diseases clinic had an anal cytological smear performed under standard conditions. The perianal area and anal canal were then examined using a colposcope, and areas macroscopically suggestive of intraepithelial neoplasia were biopsied. RESULTS--176 of the 215 patients were biopsied of whom 76 had AIN on histology. 154 of the 215 patients had an adequate anal smear of whom 46 and 85 had cytological features of both HPV and AIN, or HPV alone respectively. Including features of HPV alone as an abnormal smear, anal cytology, when compared with anoscopy and histology as the gold standard for diagnosing AIN, resulted in a sensitivity of 87.5%, a specificity of 16.3%, a positive predictive value of 37.4% and a negative predictive value of 69.6%. Restricting abnormal smears to those with features of both HPV and AIN resulted in a sensitivity of 33.9%, a specificity of 72.5%, a positive predictive value of 41.3% and a negative predictive value of 65.7%. CONCLUSION--Anal cytology is a sensitive but nonspecific method of identifying patients with biopsy proven AIN if cytological features of HPV alone are included as abnormal smears. Specificity is improved by restricting abnormal smears to those with features of both HPV and AIN but this markedly lowers the sensitivity of the test. At present, anoscopy and histology are required in addition to anal cytology to differentiate between patients who simply have anal condylomata and those who also have AIN.
PMCID: PMC1195174  PMID: 8300094
22.  Intermittent hypercalcaemia and vitamin D sensitivity in Hodgkin's disease. 
Postgraduate Medical Journal  1990;66(779):757-760.
A patient with Hodgkin's disease spontaneously developed steroid-responsive hypercalcaemia during two consecutive summers. Administration of 3000 U/day of vitamin D, while he was normocalcaemic, caused a sharp increase in serum 1,25(OH)2D3 (from 59 pg/ml to 142 pg/ml) and subsequently hypercalcaemia while serum 25(OH)D3 rose moderately within the normal range (from 2.8 ng/ml to 10 ng/ml). During a spontaneous episode of hypercalcaemia which was accompanied by increased circulating 1,25(OH)2D3 concentrations, administration of hydrocortisone decreased serum 1,25(OH)2D3 rapidly (from 115 pg/ml to 62 pg/ml) and eventually led to normocalcaemia while serum 25(OH)D3 remained unchanged. Thus the disturbances of mineral metabolism found in this patient with Hodgkin's disease are very similar to those previously described in sarcoidosis.
PMCID: PMC2426864  PMID: 2235811
23.  Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. 
British Heart Journal  1993;69(5):377-381.
OBJECTIVE--To assess the size of the lipid pool and the number of smooth muscle cells and monocyte/macrophages in human aortic plaques that were intact and to compare the results with those in aortic plaques undergoing ulceration and thrombosis. DESIGN--The lipid pool was measured as a percentage of the total cross sectional area of the plaque. Immunohistochemistry was used to identify cell types (monocytes/macrophages (M phi) by EBM11 and HAM56, smooth muscle cells by alpha actin). The area of the tissue occupied by each cell type was measured by quantitative microscopy in the peripheral (shoulder) area of the plaque and the plaque cap. Absolute counts of each cell type were expressed as the ratio of SMC:M phi. MATERIAL--Aortas were obtained at necropsy from men aged less than 69 years who died suddenly (within 6 hours of the onset of symptoms) of ischaemic heart disease. 155 plaques from 13 aortas were studied. Four aortas showed intact plaques only (group A, n = 31). Nine aortas showed both intact plaques (group B, n = 79) and plaques that were undergoing thrombosis (group C, n = 45). RESULTS--In 41 (91.1%) of the 45 plaques undergoing thrombosis (group C) lipid pools occupied more than 40% of the cross sectional area of the plaque. Only 12 (10.9%) of the 110 intact plaques (groups A + B) had lipid pools of this size. The mean size of the lipid pool in plaques of groups A, B, and C was 12.7%, 27.3% and 56.7% respectively. Compared with intact plaques those undergoing thrombosis contained a smaller volume of smooth muscle cells (2.8% v 11.8%) and a larger volume of monocyte/macrophages (13.7% v 2.9%) in the plaque cap. The ratio of the number of smooth muscle cells to monocytes/macrophages was 7.8 in group A plaques, 4.1 in group B plaques, and 1.0 in group C plaques. This gradient was the result of an absolute increase in monocyte/macrophages and an absolute decrease in smooth muscle cells. CONCLUSIONS--In the aorta ulceration and thrombosis were characteristic of plaques with a high proportion of their volume occupied by extracellular lipid, and in which there was a shift toward a preponderance of monocyte/macrophages compared with smooth muscle cells in the cap.
PMCID: PMC1025095  PMID: 8518056
24.  Transcriptional synergy by the Epstein-Barr virus transactivator ZEBRA. 
Journal of Virology  1992;66(8):4803-4813.
ZEBRA is an Epstein-Barr virus (EBV) transcriptional activator that mediates a genetic switch between the latent and lytic states of the virus by binding to the promoters of genes involved in lytic DNA replication and activating their transcription. A computer survey revealed that 9 of 23 potential or known ZEBRA-responsive EBV genes contained two or more upstream binding sites; this suggested that ZEBRA can stimulate transcription synergistically. By using a series of synthetic promoters bearing one, two, three, five, and seven upstream recognition sites, we showed that ZEBRA activates transcription synergistically when templates bearing multiple sites were compared with a template bearing a single site. This phenomenon was observed in both uninfected and EBV-infected B-lymphoid cells and in vitro in a HeLa cell nuclear extract. DNase I footprinting was used to show that the synergy was not due to cooperative DNA binding mediated by direct contact between ZEBRA dimers. The in vitro experiments revealed two manifestations of synergy. One was seen when the levels of transcription observed with the same amounts of ZEBRA added to templates bearing different numbers of sites were compared. The other was observed when the two lowest concentrations of ZEBRA that stimulated measurable transcription from any given template were compared. On the basis of both the number of sites and the calculated Kd of ZEBRA for a single site, we estimated that the critical concentration of ZEBRA needed to elicit transcriptional synergy corresponds to a site occupancy of two or three bound ZEBRA dimers. Our results have biologic implications for both the EBV lytic cycle and other processes in which the concentration of an activator changes either temporally or spatially.
PMCID: PMC241308  PMID: 1321270
25.  Divergent envelope E2 alphavirus sequences spanning amino acids 297 to 352 induce in mice virus-specific protective immunity and antibodies with complement-mediated cytolytic activity. 
Journal of Virology  1992;66(2):1084-1090.
We have proposed a general algorithm for identification of potential immunoprotective domains (cassettes) on the envelope E2 polypeptide of alphaviruses (H. Grosfeld, B. Velan, M. Leitner, S. Cohen, S. Lustig, B.E. Lachmi, and A. Shafferman, J. Virol. 63:3416-3422, 1989). To assess the generality of our approach, we compared analogous E2 cassettes from Sindbis virus (SIN) and Semliki Forest virus (SFV), two alphaviruses which are philogenetically very remote. The antigenically distinct SFV E2 and SIN E2 cassettes exhibit comparable immunological characteristics. Most significantly, the SIN E2 LMN cassette cluster (E2 amino acids 297 to 352 fused to beta-galactosidase), like the analogous SFV E2 LMN cassettes, elicited high titers of antivirus antibodies in mice and proved to be highly effective in protection against lethal challenge. Mice immunized with SIN E2 LMN were completely protected against intracerebral challenge of 10 to 100 50% lethal doses of different neurovirulent SIN strains. Anti-SIN LMN antibodies, like anti-SFV LMN antibodies, lacked in vitro neutralizing activity, yet both exerted protection against homologous challenge upon transfer to mice. The two antibody preparations exhibited virus-specific complement-mediated cytolysis of cells infected with the homologous but not heterologous virus. These results suggest a possible mechanism for virus-specific E2 LMN-induced protection and demonstrate the generality of our methodology for deciphering immunogenic and protective domains in alphavirus systems. Results suggest also that the E2 LMN sequence of any given alphavirus should be considered as a component of a synthetic vaccine against that specific virus.
PMCID: PMC240812  PMID: 1309890

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