Glenoid screw position in the Encore Reverse Shoulder Prosthesis: an anatomic dissection study of screw relationship to surrounding structures.

BACKGROUND: Fixation of the baseplate to the glenoid for the Reverse Shoulder Prosthesis (DJO Surgical, Austin, TX, USA) requires secure screw purchase to avoid excessive micromotion and baseplate failure. The best screw length for fixation is unknown. In addition, excessively long screws or a plunge of the drill bit during baseplate insertion could injure surrounding structures. METHODS: Reverse Shoulder Prosthesis baseplates were inserted in 10 fresh-frozen shoulders by use of a 6.5-mm central screw and four 5.0-mm peripheral locking screws placed 90° to the baseplate. The top superior screw was placed into the base of the coracoid, corresponding to the 1-o'clock position in a right shoulder. The distances to surrounding vital structures were recorded, screws were removed, and screw hole lengths were measured to determine the most effective lengths in different parts of the glenoid scapula. RESULTS: The screw length was 30 mm for the superior screw holes, 28 mm for the inferior screw holes, 13 mm for the anterior screw holes, and 15 mm for the posterior screw holes. The central screw trajectory was through the anterior cortex. The anterior screw trajectory violated the subscapularis belly in all specimens. The posterior screw touched the suprascapular nerve or artery in 3 of 10 specimens. DISCUSSION: The superior and inferior screws have the longest bony fixation. Drill bit plunge during placement of the anterior screw poses a risk to the subscapularis muscle. Drilling for the posterior screw risks injury to the suprascapular nerve and artery at the spinoglenoid notch. CONCLUSIONS: The posterior screw should be placed with care to avoid neurovascular complications.

Human cystic fibrosis transmembrane conductance regulator directed to respiratory epithelial cells of transgenic mice.

Human cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in transgenic mice under the control of transcriptional elements derived from the human surfactant protein C (SP-C) gene. The hCFTR mRNA was expressed in lungs and testes: in the lung, we found hCFTR mRNA in bronchiolar and alveolar epithelial cells, and CFTR protein in respiratory epithelial cells. While the level of expression of hCFTR mRNA varied, hCFTR mRNA and protein were detected in pulmonary epithelial cells of several lines. Lung weight, morphology, somatic growth and reproductive capacity were not altered by expression hCFTR in lung and testes of the transgenics. Our findings suggest that hCFTR can be safely transferred to lung epithelial cells for CF therapy.

Management of deep infection after reverse total shoulder arthroplasty: a case series.

BACKGROUND: Reverse total shoulder arthroplasty (RSA) is being increasingly used in the treatment of disabling shoulder conditions. This study reports the management of deep infections after RSA. MATERIALS AND METHODS: Eight of 138 patients were treated for deep infection after the index procedure. A retrospective review was performed to identify risk factors, methods of management, and determine ultimate outcome. A minimum of 12-month follow-up was available in 7 of 8 patients. RESULTS: Six infections occurred in patients who had had previous shoulder surgery. The causative bacterial organism was identified in 6 patients. Deep infection occurred in 3 patients with diabetes mellitus. Antibiotic cement was used in all cases. Six patients were managed with irrigation and debridement and retention of components. Two patients with of Staphylococcus aureus infection ultimately required resection arthroplasty. Patients managed with irrigation and debridement, intravenous antibiotics, and retention of components demonstrated good pain relief and function, without evidence of radiographic loosening. Resection resulted in pain relief but poor functional outcomes. CONCLUSION: Limited literature is available regarding the management of deep infection in patients with RSA. Component removal after a RSA creates increased bone loss due to a cemented humeral component and glenoid baseplate with several large screws. Five of 7 patients with deep infection had undergone previous shoulder surgery. We recommend that patients should be managed with an initial irrigation and debridement, appropriate intravenous antibiotics, and component retention.

Changes in passive range of motion and development of glenohumeral internal rotation deficit (GIRD) in the professional pitching shoulder between spring training in two consecutive years.

BACKGROUND: Pitching causes increased mechanical stress to the arm and is thought to result in alterations in range of motion (ROM) as a result of osseous and soft tissue adaptations. Understanding the factors that contribute to alterations in ROM will allow for improved understanding of the pitching shoulder. This study examined humeral torsion (HT) and shoulder mobility over 2 consecutive years. METHODS: Bilateral shoulder mobility and HT were assessed in 33 asymptomatic professional pitchers over 2 spring trainings. A repeated-measures analysis of covariance was used to assess the change in motion of the dominant side/nondominant side across seasons while quantifying pre-existing HT. Prevalence of glenohumeral internal rotation deficit (GIRD) between seasons was compared with χ(2) analysis, and GIRD and non-GIRD pitchers were compared with the independent t test. RESULTS: The dominant shoulder displayed increased external rotation (11.5° ± 0.1°, P = .02) and decreased internal rotation (-8.4° ± 11.0°, P = .03) and horizontal adduction (-17.6° ± 13.8°, P = .01). The nondominant shoulder remained the same. Mean HT was significantly different (P = .001) in the dominant (10° ± 11°) arm than in the nondominant arm (23° ± 11°). A significant number of pitchers had with GIRD (P < .01) at each assessment. CONCLUSIONS: ROM was significantly altered between seasons of pitching. These changes likely resulted from soft tissue adaptations because we accounted for humeral retrotorsion. Pitchers who developed GIRD displayed a 7° increase in retrotorsion on the dominant shoulder. Changes in the pitching shoulder over time accounting for humeral retrotorsion may suggest pitching ROM is transient and should be monitored.

Imaging regional variation of cellular proliferation in gliomas using 3'-deoxy-3'-[18F]fluorothymidine positron-emission tomography: an image-guided biopsy study.

AIM: To compare regional variations in uptake of 3'-deoxy-3'- [(18)F]-fluorothymidine (FLT) images using positron-emission tomography (PET) with measures of cellular proliferation from biopsy specimens obtained by image-guided brain biopsies. MATERIALS AND METHODS: Fourteen patients with a supratentorial glioma that required an image-guided brain biopsy were imaged preoperatively with dynamic PET after the administration of FLT. Maps of FLT irreversible uptake rate (K(i)) and standardized uptake value (SUV) were calculated. These maps were co-registered to a gadolinium-enhanced T1-weighted spoiled gradient echo (SPGR) sequence that was used for biopsy guidance, and the mean and maximum K(i) and SUV determined for each biopsy site. These values were correlated with the MIB-1 labelling index (a tissue marker of proliferation) from these biopsy sites. RESULTS: A total of 57 biopsy sites were studied. Although all measures correlated with MIB-1 labelling index, K(i)(max) provided the best correlation (Pearson coefficient, r=0.68; p<0.001). In low-grade gliomas the K(i)(mean) (+/-SD) was significantly higher than in normal tissue (3.3+/-1.7x10(-3)ml(plasma)/min/ml(tissue) versus 1.2+/-0.7x10(-3)ml(plasma)/min/ml(tissue); p=0.001). High-grade gliomas showed heterogeneous uptake with a mean K(i) of 7.7+/-4x10(-3)ml(plasma)/min/ml(tissue). A threshold K(i)(mean) of 1.8x10(-3) differentiates between normal tissue and tumour (sensitivity 84%, specificity 88%); however, the latter threshold underestimated the extent of tumour in half the cases. SUV closely agreed with K(i) measurements. CONCLUSION: FLT PET is a useful marker of cellular proliferation that correlates with regional variation in cellular proliferation; however, it is unable to identify the margin of gliomas.

Current and future treatments of bone metastases.

Bone metastases contribute to a significant degree of morbidity in patients with common cancers through the development of skeletal related events (SRE) such as bone pain and pathological fracture. Traditional therapy has relied on surgical removal of lesions and, with the advent of adjuvant therapies, has been combined with radiotherapy, chemotherapy, and more recently osteoclast inhibiting agents like bisphosphonates. Although these therapeutic combinations can achieve a degree of local control, and rarely cure, across the vast majority of metastatic cancers they provide only palliation. Newer molecular agents currently under investigation, combined with innovations in surgery and radiation therapy offer a more targeted approach to bone metastasis. These utilise our understanding of key steps in the metastatic cascade including chemotactic attraction to bone, secretion of proteases, the cancer supporting microenvironment of bone matrix and the RANK-RANKL interaction for osteoclast activation. Direct inhibition of metastasis progression and osteolysis with less reliance on cytotoxic agents and invasive therapy should result in improved metastatic control, longer survival and less overall morbidity.

Selection of appropriate Chinese terms to represent intensity and types of physical activity terms for use in the Taiwan version of IPAQ.

In order to analyze the health risks of insufficient activity by international comparisons, the first author obtained the permission to translate and develop a Taiwan version of the International Physical Activity Questionnaire (IPAQ). The objective was to determine culturally sensitive Chinese translations for the terms "moderate", "vigorous" and "physical activity" as well as to identify representative types of physical activity for Taiwanese. This study used discussions by 12 expert focus groups, 6 expert audits, a scale survey, field study, Cognitive Aspect Survey Methodology (CASM), dual independent translation and back-translation to establish a consensus on physical activity-related concepts, terminologies and types that define the intensity of common activities of Taiwanese by integrating both local and foreign studies. The Chinese terms "fei li", "zhong deng fei li" and "shen ti huo dong", respectively, were identified as suitable and adequate translations for the English terms "vigorous", "moderate" and "physical activity". The common Taiwanese activities were accurately categorized and listed in questionnaires, forming culturally sensitive scales. Taiwan versions of IPAQ's self-administered long version (SL), self-administered short version (SS), and telephone interview short version (TS) were developed. Their content validity indices were .992, .994, and .980, as well as .994, .992, and .994 for language equivalence and meaning similarity between the English and Chinese versions of the IPAQ-LS, IPAQ-SS, and IPAQ-TS, respectively. Consistency values for the English and Chinese versions in terms of intraclass correlation coefficients were .945, .704, and .894, respectively. The IPAQ-Taiwan is not only a sensitive and precise tool, but also shows the effectiveness of the methodology (CASM) used in tool development. Subjects who did not regularly exercise and had an education less than a junior high school level underestimated the moderate-intensity physical activity.

Tumor necrosis factor-alpha inhibits expression of pulmonary surfactant protein.

Tumor necrosis factor-alpha (TNF-alpha) decreased the expression of pulmonary surfactant proteins SP-A and SP-B in human pulmonary adenocarcinoma cell lines. The effect of TNF alpha on SP-A content and mRNA in the pulmonary adenocarcinoma cell line, H441-4, was concentration and time dependent. TNF alpha decreased the cellular content of SP-A to less than 10% of control 48 h after addition. TNF alpha decreased de novo synthesis of SP-A and decreased the accumulation of SP-A in media. SP-A mRNA was decreased within 12 h of addition of TNF alpha, with nearly complete loss of SP-A mRNA observed after 24 h. Inhibitory effects of TNF alpha on SP-A mRNA were dose-related with nearly complete inhibition of SP-A mRNA caused by 25 ng/ml TNF alpha. The effects of TNF alpha on SP-A were distinct from the effects of interferon gamma which increased SP-A content approximately twofold in H441-4 cells. TNF alpha also decreased the content of SP-B mRNA. In contrast to the inhibitory effect of TNF alpha on SP-A and SP-B mRNA, TNF alpha increased mRNA encoding human manganese superoxide dismutase (Mn-SOD). TNF alpha did not inhibit growth, alter cell viability or beta-actin mRNA in either cell line. These in vitro studies demonstrate the marked pretranslational inhibitory effects of the cytokine, TNF alpha, on the expression of pulmonary surfactant proteins, SP-A and SP-B. The results support the concept that macrophage-derived cytokines may control surfactant protein expression.

Development of a combined microPET-MR system.

As evidenced by the success of PET-CT, there are many benefits from combining imaging modalities into a single scanner. The combination of PET and MR offers potential advantages over PET-CT, including improved soft tissue contrast, access to the multiplicity of contrast mechanisms available to MR, simultaneous imaging and fast MR sequences for motion correction. In addition, PET-MR is more suitable than PET-CT for cancer screening due to the elimination of the radiation dose from CT. A key issue associated with combining PET and MR is the fact that the performance of the photomultiplier tubes (PMTs) used in conventional PET detectors is degraded in the magnetic field required for MR. Two approaches have been adopted to circumvent that issue: retention of conventional, magnetic field-sensitive PMT-based PET detectors by modification of other features of the MR or PET system, or the use of new, magnetic field-insensitive devices in the PET detectors including avalanche photo-diodes (APDs) and silicon photomultipliers (SiPMs). Taking the former approach, we are assembling a modified microPET Focus 120 within a gap in a novel, 1T superconducting magnet. The PMTs are located in a low magnetic field (approximately 30mT) through a combination of magnet design and the use of fiber optic 'bundles'. Two main features of the modified PET system have been tested, namely the effect of using long fiber optic bundles in the PET detector, and the impact of magnetic field upon the performance of the position sensitive PMTs. The design of a modified microPET-MR system for small animal imaging is completed, and assembly and testing is underway.

Simian virus 40 large T antigen directed by transcriptional elements of the human surfactant protein C gene produces pulmonary adenocarcinomas in transgenic mice.

A model of pulmonary adenocarcinomas was produced in transgenic mice harboring a chimeric gene comprising the SV40 large T antigen under the control of a transcriptional region derived from the human surfactant protein C (SP-C) gene. Transgenic mice succumbed with pulmonary tumors within 4-5 months of age. By histology, the tumors were adenocarcinomas with lepidic, papillary, and solid growth patterns that were indistinguishable from adenocarcinomas occurring in humans. Immunocytochemistry demonstrated the lack of staining for neuroendocrine markers, consistent with the identification of the tumors as non-small cell rather than small cell carcinomas. The presence of SV40 large T mRNA in the lung and tumors was detected by in situ hybridization and Northern blot analysis. Exogenous SV40 large T mRNA and endogenous CC10 (a nonciliated respiratory epithelial cell marker) and SP-C (a Type II alveolar cell marker) mRNAs were expressed at variable levels in the lung tumors. SV40 large T mRNA and CC10 mRNA were detected in the majority of tumors, while SP-C mRNA was detected less frequently. The heterogeneity of bronchiolar and alveolar cell markers in the tumors from the transgenic mice supports the concept that tumorigenesis was initiated in distinct subsets of epithelial cells that produce characteristic adenocarcinomas of the lung.

Peripheral airway cell differentiation in human lung cancer cell lines.

Clara cells and type II pneumocytes are the progenitor cells of the bronchioles and alveoli, respectively. These peripheral airway cells (PAC) contain characteristic cytoplasmic structures and express surfactant associated proteins. PAC cell markers are expressed by many pulmonary adenocarcinomas having papillary and/or lepidic growth patterns, which are characteristics of the bronchioloalveolar and papillary subtypes. We investigated the expression of PAC markers in a panel of 41 lung cancer cell lines. Ultrastructural studies demonstrated the presence of cytoplasmic structures characteristic of Clara cells or of type II pneumocytes in 9 of 34 (26%) non-small cell lung cancer cell lines, including 7 of 17 (41%) adenocarcinomas, one squamous cell carcinoma, and one large cell carcinoma. Of interest, the cytoplasmic structures were present in 5 of 6 (83%) cell lines initiated from papillolepidic adenocarcinomas. In addition, we examined the lines for expression of the surfactant associated proteins SP-A, SP-B, and SP-C. Eight of the nine cell lines containing cytoplasmic inclusions characteristic of PAC cells also expressed protein and/or RNA of SP-A, the major surfactant associated protein. Five of these lines expressed SP-B RNA (either constitutively or after dexamethasone induction), while a single line expressed SP-C only after dexamethasone induction. None of six small cell lung cancer cell lines examined expressed any of the PAC markers. Thus, PAC markers are expressed frequently (but not exclusively) in pulmonary adenocarcinoma cell lines, especially in those initiated from tumors having papillolepidic growth patterns. The establishment and identification of multiple cell lines expressing PAC features provide an important new resource for biological and preclinical therapeutic studies.

Transforming growth factor-beta inhibits surfactant protein A expression in vitro.

Effects of members of the transforming growth factor-beta (TGF-beta) family on expression of surfactant protein A (SP-A) were determined in human pulmonary adenocarcinoma cells. TGF-beta decreased SP-A content in two distinct pulmonary adenocarcinoma cell lines with bronchiolar (NCI-H441-4) and alveolar (NCI-H820) cell characteristics. TGF-beta 1, beta 2 and beta 3 were equally effective in decreasing SP-A. Effects of the TGF-beta's on SP-A content were dose dependent, EC50 approximately 20-30 pg/ml for each form of TGF-beta. TGF-beta decreased cellular SP-A content in association with decreased levels of SP-A mRNA. Inhibitory effects of TGF-beta 1 on SP-A mRNA was time dependent, reaching maximal effects within 12-24 h, after which SP-A mRNA was approximately 10% of that present in untreated cells. Maximal inhibition of SP-A mRNA was observed at 250 pg/ml TGF-beta 1. TGF-beta-dependent inhibition of SP-A expression was not associated with altered cell morphology, growth, or viability. TGF-beta family members act directly on pulmonary adenocarcinoma cells to inhibit SP-A expression by mechanisms which are mediated, at least in part, at a pretranslational level.

Synthesis and processing of the precursor for human mangano-superoxide dismutase.

Superoxide dismutase comprises a family of metalloenzymes that catalyze the oxido-reduction of superoxide anion to H2O2. Manganese superoxide dismutase (Mn-SOD) is encoded by nuclear chromatin, synthesized in the cytosol, and imported posttranslationally into the mitochondrial matrix. We isolated and sequenced complementary DNA encoding human Mn-SOD. The Mn-SOD cDNA was 1001 base pairs long with a single open reading frame. It contained 95 base pairs of 5' untranslated sequence, and 216 base pairs of 3' untranslated sequence, followed by a short polyadenylation tract. The deduced amino acid sequence suggests a mature protein of 198 amino acids preceded by a 24 amino acid leader peptide. A major transcript of 1000 nucleotides was identified by hybridization of the cDNA with RNA isolated from human cells. Precursor Mn-SOD was produced by in vitro transcription of the human Mn-SOD cDNA followed by in vitro translation utilizing rabbit reticulocyte lysate. The primary translation product of the cDNA is a polypeptide of Mr 26,000 as determined by sodium dodecyl sulfate-polyacrylamide electrophoresis. When the Mr 26,000 propeptide was incubated with freshly isolated rat liver mitochondria, the peptide was proteolytically processed to a Mr 24,000 polypeptide. Proteolytic processing was accompanied by an energy-dependent import of the peptide into the isolated liver mitochondria. Mature 125I-labelled Mn-SOD, isolated from rabbit liver, was not imported in vitro into mitochondria, indicating that the energy-dependent uptake of Mn-SOD by liver mitochondria was specific for the Mn-SOD precursor.

Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography.

BACKGROUND: Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [18F]-fluorodeoxyglucose (18FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether 18FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques. METHODS AND RESULTS: Eight patients with symptomatic carotid atherosclerosis were imaged using 18FDG-PET and co-registered CT. Symptomatic carotid plaques were visible in 18FDG-PET images acquired 3 hours post-18FDG injection. The estimated net 18FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral asymptomatic lesions. There was no measurable 18FDG uptake into normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque. CONCLUSIONS: This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic, unstable plaques accumulate more 18FDG than asymptomatic lesions.

Imaging of cerebral blood flow and metabolism in brain injury in the ICU.

The heterogeneity of the initial insult and subsequent pathophysiology has made both the study of human head injury and design of randomised controlled trials exceptionally difficult. The combination of multimodality bedside monitoring and functional brain imaging positron emission tomography (PET) and magnetic resonance (MR), incorporated within a Neurosciences Critical Care Unit, provides the resource required to study critically ill patients after brain injury from initial ictus through recovery from coma and rehabilitation to final outcome. Methods to define cerebral ischemia in the context of altered cerebral oxidative metabolism have been developed, traditional therapies for intracranial hypertension re-evaluated and bedside monitors cross-validated. New modelling and analytical approaches have been developed.

Imprinting of hepatic estrogen-binding proteins by neonatal androgens.

Previous studies discovered a second class of estrogen-binding proteins distinct from estrogen receptor which exhibited higher capacity, lower affinity (HCLA) binding properties. HCLA sites underwent postpubertal sex differentiation, such that adult male levels were at least 10-fold higher than adult female levels. Neonatal castration of male rats prevented the subsequent sex differentiation of HCLA binding sites; adult male rats that were castrated neonatally exhibited typically female concentrations of these binding sites. If male rats were castrated at 19 days of age or later, postpubertal sex differentiation of HCLA binding sites proceeded as observed for intact males. Administration of testosterone propionate (TP) to castrated (neonatally) males during a critical period (days 6-13) imprinted for the subsequent sex differentiation of HCLA sites, whereas TP administration at other times did not. The expression of these imprinted sites was not manifested until puberty, as neonatal manipulation or TP treatment had no effect on HCLA sites in immature rats. The imprinted effect on HCLA binding sites appeared to be permanent and irreversible. Treatment of castrate males with diethylstilbestrol (DES) or zearalenol (P-1496) during the critical period was incapable of restoring development of normal male levels of HCLA sites. Competitive binding studies using several steroid hormones revealed similar data for intact males and castrate (neonatal) male rats that had received TP during the critical period. These studies demonstrate an early imprinting period during which androgen exposure programs for postpubertal development of sex differentiation of HCLA binding sites.

Measurement of cerebral blood flow using bolus inhalation of C15O2 and positron emission tomography: description of the method and its comparison with the C15O2 continuous inhalation method.

This article describes a rapid method for the regional measurement of cerebral blood flow using a single breath of C15O2 and positron emission tomography. The technique is based on the bolus distribution principle and utilises a reference table for the calculation of flow. Seven subjects were studied using both this method and the C15O2 continuous inhalation steady-state technique. The single-breath method gave flow values 20% higher than those obtained using the steady-state method. A simulation study was performed in an attempt to define the reasons for the difference between the two techniques. Estimations were made of identified sources of error in the measurement of regional cerebral blood flow using the single-breath technique and compared with results from a similar study previously described for the steady-state technique. However, further comparative studies will be necessary to satisfactorily explain the difference between both techniques.

Conditions for measuring DNA synthesis in PHA stimulated human lymphocytes in 20 microliters hanging drops with various cell concentrations and periods of culture.

We have studied conditions for measuring the uptake of [3H]thymidine ([3H]Tdr) by human lymphocytes in inverted microcultures, varying cell concentrations and periods in culture. Analysis of variance of the log values for [3H]Tdr uptake may be used to separate effects of variables and their interactions. A pulse time of 2 h, a total thymidine concentration of about 1 microgram/ml and a specific activity of [3H]Tdr of 2 Ci/mmole were optimal. Variables such as cell concentration, period of culture, type of serum and dose of PHA were shown to interact, suggesting that these variables should be examined together especially when comparing different samples of lymphocytes. Conditions for doing this simply in small volumes are now available for culturing, thymidine pulsing, harvesting and analysis of data.

Synthesis and structure-activity relationships in a series of antiinflammatory corticosteroid analogues, halomethyl androstane-17 beta-carbothioates and -17 beta-carboselenoates.

The preparation and topical antiinflammatory potencies of a series of halomethyl 17 alpha-(acyloxy)- 11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carbothioates, carrying combinations of 6 alpha-fluoro, 9 alpha-fluoro, 16-methyl, and 16-methylene substituents, are described. Key synthetic stages were the preparation of carbothioic acids and their reaction with dihalomethanes. The carbothioic acids were formed from 17 beta-carboxylic acids by initial reaction with dimethylthiocarbamoyl chloride followed by aminolysis of the resulting rearranged mixed anhydride with diethylamine, or by carboxyl activation with 1,1'-carbonyldiimidazole (CDI) or 2-fluoro-N-methylpyridinium tosylate (FMPT) and reaction with hydrogen sulfide, the choice of reagent being governed by the 17 alpha-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandrostane-17 beta-carboselenoate analogues. Anti-inflammatory potencies were measured in humans using the vasoconstriction assay and in rats and mice by a modification the Tonelli croton oil ear assay. Best activities were shown by fluoromethyl and chloromethyl carbothioates with a 17 alpha-propionyloxy group. S-Fluoromethyl 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-3-oxo-17 alpha- (propionyloxy)androsta-1,4-diene-17 beta-carbothioate (fluticasone propionate, FP) was selected for clinical study as it showed high topical antiinflammatory activity but caused little hypothalamic-pituitary-adrenal suppression after topical or oral administration to rodents.