[Influence of personal attitude of the manager on antibiotic use in pig production]. / Einfluss der persönlichen Einstellung des Betriebsleiters auf den Antibiotika-Verbrauch in der Schweineproduktion.

The attitude as well as the expertise of a person affect the behavior and actions in daily life. To investigate the influence of attitude and knowledge of pig producers on the use of antibiotics in farms, 220 Swiss pig producers were questioned on health awareness, attitude towards sustainable production, risk behavior, intrinsic motivation and knowledge about antibiotics and resistance development. In addition, the strategy of antibiotic use (therapeutic or prophylactic) and the business practice (single or group therapy) for the amount of antibiotics on one hand and for the risk of antibiotic resistance development on the other hand, were determined in a personal interview. Farmers using antibiotics only therapeutically had a better business practice. A direct link between the personal attitude and the antibiotic use or a higher risk of development of antibiotic resistance was not found in this investigation.

Clinical value of the Taylor Spatial Frame: a comparison with the Ilizarov and Orthofix fixators.

PURPOSE: Evaluation of the advantages and limitations of the Taylor Spatial Frame (TSF) with regard to the healing index (HI), distraction-consolidation time (DCT), accuracy of correction complications, and cost of the device. METHODS: Comparison of results with the traditional Ilizarov apparatus and a unilateral Orthofix fixator in a consecutive patient series with 135 bony deformity corrections. RESULTS: The HI did not differ significantly between all three fixators and was 57 days/cm for all patients. The DCT was significantly shorter for the TSF (148 days) compared to the Ilizarov fixator (204 days) and the Orthofix device (213 days). The accuracy of deformity correction was higher for the TSF than the other devices. The mean values of the measured angles after correction did not differ, but the variance of the results was the lowest. Also, the total rate of complications was considerably lower for the TSF. The Orthofix device showed a high rate of angular deformity during treatment, whereas both ring fixators had a relatively higher number of pin-related problems. CONCLUSIONS: The findings in our patient series suggest the use of the Orthofix apparatus for simple lengthening over short to median distances and the Ilizarov device for the correction of simple bony deformities and pure lengthening over long distances. The TSF allows multiplanar corrections and lengthenings without complex modifications of the device. But, due to the remarkably higher costs, it has not yet been established as our routine device. LEVEL OF EVIDENCE: Level IV-case series. Therapeutic Study-Investigating the Results of Treatment.

Effect of antiretroviral therapy on apoptosis markers and morphology in peripheral lymph nodes of HIV-infected individuals.

BACKGROUND: CD4+ T cell depletion and destruction and the involution of the lymphoid tissue are hallmarks of HIV infection. Although the underlying mechanisms are still unclear, apoptosis appears to play a central role. The objective of this study was to investigate the effect of antiretroviral therapy on the lymph node tissue, particularly with respect to morphology and apoptosis. PATIENTS AND METHODS: Between 1997 and 1999, two inguinal lymph nodes were excised from 31 previously untreated individuals who were in an early stage of HIV infection, the first one prior to treatment and the second after 16 to 20 months of treatment. Paraffin sections were investigated for lymph node architecture, distribution of cellular and viral markers, apoptosis, and expression of apoptotic key molecules which indirectly reflect apoptotic processes. RESULTS: After 16-20 months of antiretroviral therapy, a significant decrease in highly activated HIV-driven immune response was observed in the lymph node tissue as a marked reduction in follicular hyperplasia, a normalization of the follicular dendritic cell network, a significant increase in the number of CD4+ T cells, and a significant decrease in the number of CD8+ T cells. The expression of several proapoptotic (Fas, TRAIL, and active caspase 3) and antiapoptotic (Bcl-2 and IL-7Ralpha) molecules that were reconstituted in the tissues during therapy resembled their expression in lymph nodes of HIV-negative individuals. Limitations of the study are (a) the lack of untreated patients in the late stages, (b) for ethical reasons, the lack of a control group with untreated patients, and (c) for methodological reasons, the restriction of sequential measurements of apotpotic markers to one-third of the patients. CONCLUSION: Antiretroviral therapy initiated in the early stages in HIV infection may halt the irreversible destruction of the lymph node tissue and may partially normalize apoptotic processes.

CD4+ CCR5+ T-cell dynamics during simian immunodeficiency virus infection of Chinese rhesus macaques.

Simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) provides a reliable model to study the relationship between lentivirus replication, cellular immune responses, and CD4+ T-cell dynamics. Here we investigated, using SIVmac251-infected RMs of a Chinese genetic background (which experience a slower disease progression than Indian RMs), the dynamics of CD4+ CCR5+ T cells, as this subset of memory/activated CD4+ T cells is both a preferential target of virus replication and a marker of immune activation. As expected, we observed that the number of circulating CD4+ CCR5+ T cells decreases transiently at the time of peak viremia. However, at 60 days postinfection, i.e., when set-point viremia is established, the level of CD4+ CCR5+ T cells was increased compared to the baseline level. Interestingly, this increase correlated with faster disease progression, higher plasma viremia, and early loss of CD4+ T-cell function, as measured by CD4+ T-cell count, the fraction of memory CD4+ T cells, and the recall response to purified protein derivative. Taken together, these data show a key difference between the dynamics of the CD4+ CCR5+ T-cell pool (and its relationship with disease progression) in Chinese RMs and those described in previous reports for Indian SIVmac251-infected RMs. As the SIV-associated changes in the CD4+ CCR5+ T-cell pool reflect the opposing forces of SIV replication (which reduces this cellular pool) and immune activation (which increases it), our data suggest that in SIV-infected Chinese RMs the impact of immune activation is more prominent than that of virus replication in determining the size of the pool of CD4+ CCR5+ T cells in the periphery. As progression of HIV infection in humans also is associated with a relative expansion of the level of CD4+ CCR5+ T cells, we propose that SIV infection of Chinese RMs is a very valuable and important animal model for understanding the pathogenesis of human immunodeficiency virus infection.

[Salt, hypertension and cardiovascular risk]. / Salz, Hypertonie und kardiovaskuläres Risiko.

For more than a century salt and blood pressure have been linked. Prospective randomized clinical trials and meta-analyses provided evidence that a reduction of daily salt intake of 100 mmol will lower systolic blood pressure by 3-5 mm Hg, whereas diastolic blood pressure can be reduced by 1 mm Hg. The effect of salt restriction depends strongly on individual salt sensitivity. Whether a reduction of salt intake will ultimately result in a decline of cardiovascular morbidity and mortality remains to be determined in future studies.

[Unexpected formation of an estrone derivative from androsta-1,4-diene-3,17-dione]. / Unerwartete Bildung eines Estron-Derivates aus Androsta-1,4-dien-3,17-dion.

Reaction of androsta-1,4-diene-3,17-dione (1) with pyrrolidine and p-toluenesulfonic acid in toluene gives 3-pyrrolidino-estra-1,3,5(10)-triene-6,17-dione (7) in poor yield, whose structure is shown by X-ray analysis. Compared with 3H-estradiol, compound 7 shows only a weak receptor binding activity tested in an in vitro screening using rabbit uterus cytosol.

Novel deletion of HIV type 1 reverse transcriptase residue 69 conferring selective high-level resistance to nevirapine.

A novel deletion of residue 69 of the HIV-1 reverse transcriptase (RT) gene was detected in combination with mutations V75I/V and F77L/F in a patient with partial virological response to several antiretroviral drug regimens, including stavudine (D4T), didanosine (DDI), lamivudine (3TC), saquinavir (SQV), and nevirapine (NVP). Longitudinal analysis of samples revealed that this deletion emerged upon reinitiation DDI/D4T therapy following a toxicity-induced short discontinuation of all antiretrovirals. Analysis of the resistance phenotype showed a greater than 62-fold increase of the IC50 of NVP, but no significant change in sensitivity to other single nonnucleoside reverse transcriptase inhibitors (NNRTIs). The mutated virus showed only a moderately reduced sensitivity to DDI (6.7-fold) and D4T (4.8 fold). In a subsequent sample 3 months later additional RT mutations were found, including A62V, Y188L, and Q151M, conferring high-level cross-resistance to multiple nucleoside analogs. Our findings provide evidence that the deletion of RT residue 69 selectively confers high-level NVP resistance.

Replication protein A modulates its interface with the primed DNA template during RNA-DNA primer elongation in replicating SV40 chromosomes.

The eukaryal single-stranded DNA binding protein replication protein A (RPA) binds short oligonucleotides with high affinity but exhibits low cooperativity in binding longer templates, opposite to prokaryal counterparts. This discrepancy could reflect the smaller size of the replicative template portion availed to RPA. According to current models, this portion accommodates an RNA-DNA primer (RDP) of <40 nt (nested discontinuity) or a several-fold longer Okazaki fragment (initiation zone). Previous in situ UV-crosslinking revealed that RPA also interacts with nascent DNA, especially growing RDPs. Here we compare nascent SV40 DNA chains UV-crosslinked to the middle and large RPA subunits and use the data to re-examine the two models. The middle subunit interacted with the nascent chains after a few DNA residues were added to the RNA primer while the large subunit became accessible after extension by several more. Upon RDP maturation, the middle subunit disengaged while the large subunit remained accessible during further limited extension. A corresponding shift in preference in favor of the large subunit has been reported for purified RPA and synthetic gapped duplexes upon reduction of the gap from 19 to 9 nt. Combined, these facts support the proposal that the mature RDP faces downstream a correspondingly small gap, possibly created by removal of the RNA primer moiety from an adjacent, previously synthesized RDP (nested discontinuity) but insufficient for continuous elongation of the RDP into an Okazaki fragment (initiation zone).

Signal transduction pathways in directed migration of human monocytes induced by human growth hormone in vitro.

The human growth hormone (GH) was shown to modulate leukocyte functions such as stimulating directed migration of human monocytes in vitro. Dimerisation of GH-receptors leads to the activation of various signalling mechanisms. As transduction of GH signals to monocytes is unknown, we investigated GH signalling mechanisms in monocyte migration using a modified Boyden chamber chemotaxis assay. Inhibition of tyrosyl phosphorylation of GH receptor-associated tyrosine kinase by tyrphostin-23 or staurosporine blocked GH-stimulated monocyte migration down to random levels. Furthermore, pre-incubation with effective concentrations of 4B-phorbol-12-myristate-13-acetate (PMA), staurosporine and bisindolylmaleimide I, inhibitors of protein kinase C, significantly decreased GH-induced migration, suggesting that PKC is involved in the signalling cascade. Additionally, phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) activation seems to be required. This study revealed signalling pathways in monocyte movement toward GH in vitro.

Impact of HIV type 1 protease, reverse transcriptase, cleavage site, and p6 mutations on the virological response to quadruple therapy with saquinavir, ritonavir, and two nucleoside analogs.

Genotype alterations of HIV-1 protease, reverse transcriptase, cleavage sites p7/p1 and p1/p6, as well as p6(gag) and transframe protein p6* were studied in an observational cohort of 42 individuals who received antiretroviral therapy consisting of saquinavir, ritonavir, and two nucleoside analogs. In a multivariate logistic regression analysis, the prior protease inhibitor experience (odds ratio, 6.20; 95% CI, 1.22-31.38) and the presence of primary protease mutations (odds ratio, 9.99; 95% CI, 1.05-94.72) were independently associated with virological failure. Moreover, a trend was observed in that individuals with N-terminal amino acid insertions in the proline-rich motif of the p6(gag) protein were less likely to experience virological failure (OR, 0.17; 95% CI, 0.02-1.35; p = 0.09). In contrast, the presence of secondary protease, reverse transcriptase, or cleavage site mutations was not independently associated with treatment failure. However, mutations at cleavage site p7/p1 (p = 0.01) and C-terminal p6* mutations (p = 0.02) were both associated with primary protease mutations. In conclusion, the presence of primary protease mutations was the most important predictor of the subsequent virological response. Moreover, there is some evidence that insertions in the proline-rich area of the p6(gag) protein may affect the virological response. The relationship between mutations of cleavage sites or C-terminal p6* residues and protease mutations suggests that these alterations may serve a compensatory role, increasing viral fitness.

Cancer de mama: diagnostico asistido por computadoras / Breast cancer: computational assisted diagnosis

Las microcalcificaciones agrupadas en mamografias son un signo temprano de una lesion maligna en casi la mitad de los canceres de mama. La caracterizacion de las lesiones benignas y malignas representa un problema sumamente complejo aun para un radiologo con experiencia. Esto se refleja en el alto porcentaje de biopsias innecesarias que se llevan a cabo. La deteccion y clasificacion automatica pueden ayudar al radiologo en la evaluacion de las microcalcificaciones agrupadas. Desarrollamos un esquema de diagnostico asistido por computadora, utilizando hardware de PC, que automaticamente detecta, segmenta y clasifica las microcalcificaciones. El proceso de deteccion esta basado en una combinacion de filtros Gaussiano y morfologico. Dos clasificadores estadisticos fueron usados para la diferenciacion entre los casos malignos y los benignos, los cuales se basan en un conjunto seleccionado de caracteristicas cuantitativas. Para una tasa de falsos positivos del 10 por ciento, una tasa de verdaderos positivos del 87 por ciento fue alcanzada con el clasificador que utiliza el metodo de los K vecinos mas proximos

Cancer de mama: diagnostico asistido por computadoras / Breast cancer: computational assisted diagnosis

Las microcalcificaciones agrupadas en mamografias son un signo temprano de una lesion maligna en casi la mitad de los canceres de mama. La caracterizacion de las lesiones benignas y malignas representa un problema sumamente complejo aun para un radiologo con experiencia. Esto se refleja en el alto porcentaje de biopsias innecesarias que se llevan a cabo. La deteccion y clasificacion automatica pueden ayudar al radiologo en la evaluacion de las microcalcificaciones agrupadas. Desarrollamos un esquema de diagnostico asistido por computadora, utilizando hardware de PC, que automaticamente detecta, segmenta y clasifica las microcalcificaciones. El proceso de deteccion esta basado en una combinacion de filtros Gaussiano y morfologico. Dos clasificadores estadisticos fueron usados para la diferenciacion entre los casos malignos y los benignos, los cuales se basan en un conjunto seleccionado de caracteristicas cuantitativas. Para una tasa de falsos positivos del 10 por ciento, una tasa de verdaderos positivos del 87 por ciento fue alcanzada con el clasificador que utiliza el metodo de los K vecinos mas proximos (AU)

Relative significance of different pathways of immune reconstitution in HIV type 1 infection as estimated by mathematical modeling.

A major goal of antiretroviral HIV-1 therapy is the reversal of HIV-1-associated immunological dysfunction. However, the pathogenetic mechanisms involved and their significance are largely unknown. On the basis of the life cycle of naive, activated, and memory CD4(+) T cell subsets, a mathematical model of immune reconstitution was developed and applied to data for T cell subsets in individuals with acute or chronic HIV-1 infection receiving antiretroviral therapy. The final model that most accurately fitted the data, and resulted in realistic estimates for CD4(+) T cell turnover, considered three pathways of immune reconstitution for naive cells, including thymic production, peripheral expansion, and redistribution of naive cells from lymphoid tissue. The reconstitution of the memory compartment was fitted through differentiation and expansion of naive cells and peripheral expansion of memory cells as well as redistribution of memory cells trapped in the lymphoid tissue. Estimated median half-lives for naive and memory CD4(+) T cells were 114 and 21 days, while total production rates were 9.1 x 10(7) and 2.4 x 10(9) cells/day, respectively. Peripheral expansion and thymic production contributed equally to the regeneration of naive cells, but peripheral expansion of memory cells was larger than production of these cells by differentiation of naive cells. A comparison of immune reconstitution in acute and chronic HIV-1 infection revealed that, after adjustment for age, the main difference was the more rapid release of a larger number of naive cells in treated acute HIV-1 infection. Thymic function and peripheral expansion rates, however, were similar in both cohorts.

Influence of neuropeptides on neutrophil adhesion and transmigration through a lung fibroblast barrier in vitro.

The lung is richly supplied with peptidergic nerves that store and secrete substance P (SP), vasoactive intestinal peptide (VIP), and other neuropeptides known to potently modulate leukocyte function in vitro and airway inflammation in vivo. We examined the effect of SP, VIP and the novel sensory neuropeptide secretoneurin (SN), as well as of interleukin (IL)-8, IL-6, IL-1 beta, transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF), all associated with acute lung injury, on human neutrophil migration across a 5-mu pore polycarbonate filter system covered by human lung fibroblast monolayers. Additionally, we tested the ability of these neuropeptides to elicit neutrophil adhesion to fibroblast monolayers. SP, but not VIP and SN, may be important in directly influencing neutrophil adhesion to and subsequent migration across a subendothelial barrier of fibroblasts and extracellular matrix towards lung inflammatory sites. The effect was mainly mediated by neurokinin (NK)-1 receptors, as evaluated by a specific NK-1 antagonist, [[(S,S)Pro-Leu(spiro-y-lactam)]9,10, Trp11]substance P (1-11), whereas a specific NK-2 receptor antagonist, [Tyr5, D-Trp6,8,9, Lys10]neurokinin A (4-10), was ineffective. The SP analog septide and the NK-1 receptor agonist ([Sar9 Met(O2)11)SP were comparably effective. Furthermore, the SP effect was concentration and time dependent. However, the other tested neuropeptides might also affect neutrophil recruitment in inflammatory lung by modulating other lung cell functions. Additionally, all tested cytokines stimulated neutrophil transfibroblast migration in vitro, except IL-6. In conclusion, SP in concert with proinflammatory cytokines may regulate neutrophil interstitial accumulation and their traffic to the alveolar space in lung inflammation.

Increased turnover of CCR5+ and redistribution of CCR5- CD4 T lymphocytes during primary human immunodeficiency virus type 1 infection.

CCR5 is the major coreceptor for human immunodeficiency virus (HIV) type 1 during primary infection. CCR5+ CD4 T lymphocytes were studied in subjects with primary HIV-1 infection (PHI) or acute Epstein-Barr virus (EBV) infection and in HIV-uninfected controls. The early decline of CD4 T lymphocytes during PHI resulted from depletion of CCR5- CD4 T lymphocytes. After antiretroviral therapy, Ki-67- CCR5- CD4 T cell counts rapidly increased in the circulation, which suggests that the initial decrease was due to an alteration in trafficking and/or sequestration. In the CCR5+ subset of CD4 T cells, there was an elevation in the proliferative (Ki-67+) fraction during PHI, yet their total number remained in the normal range. In contrast, in acute EBV infection, proliferating CCR5+ CD4 T cells accumulated to very high levels, suggesting they have an important role in the early antiviral response, which may be impaired in HIV-1 infection.

Specific interaction between anticodon nuclease and the tRNA(Lys) wobble base.

The bacterial tRNA(Lys)-specific PrrC-anticodon nuclease cleaves its natural substrate 5' to the wobble base, yielding 2',3'-cyclic phosphate termini. Previous work has implicated the anticodon of tRNA(Lys) as a specificity element and a cluster of amino acid residues at the carboxy-proximal half of PrrC in its recognition. We further examined these assumptions by assaying unmodified and hypomodified derivatives of tRNA(Lys) as substrates of wild-type and mutant alleles of PrrC. The data show, first, that the anticodon sequence and wobble base modifications of tRNA(Lys) play major roles in the interaction with anticodon nuclease. Secondly, a specific contact between the substrate recognition site of PrrC and the tRNA(Lys) wobble base is revealed by PrrC missense mutations that suppress the inhibitory effects of wobble base modification mutations. Thirdly, the data distinguish between the anticodon recognition mechanisms of PrrC and lysyl-tRNA synthetase.

Vibration-induced phase errors in high-speed phase-shifting speckle-pattern interferometry.

We present results from numerical simulations of a dynamic phase-shifting speckle interferometer used in the presence of mechanical vibrations. The simulation is based on a detailed mathematical model of the system, which is used to predict the expected frequency response of the rms measurement error, in the time-varying phase difference maps, as a result of vibration. The performance of different phase-shifting algorithms is studied over a range of vibrational frequencies. Phase-difference evaluation is performed by means of temporal phase shifting and temporal phase unwrapping. It is demonstrated that longer sampling windows and higher framing rates are preferred in order to reduce the phase-change error that is due to vibration. A numerical criterion for an upper limit on the length of time window for the phase-shifting algorithm is also proposed. The numerical results are finally compared with experimental data, acquired with a phase-shifting speckle interferometer of 1000 frames/s.

Studies on modified estrogens: towards the synthesis of novel 14,15-cyclopropa[a]estra-1,3,5(10),8-tetraenes.

To improve the ratio of non-hormonal to hormonal activity, estrogens 3 and 4 were modified at various molecule positions. Isomerization of the 14 alpha,15 alpha-methylene bridge, controlled 3-methoxy group cleavage with respect to the 14 alpha,15 alpha-methylene bridge stereochemistry, reduction of the 8-double bond, and substitution of the oxyfunctionality at C-17 by a methylene and a difluoromethylene moiety were in the focus. As a result of in vivo and in vitro tests, compounds 27 and 29 were selected as potential follow-up candidates of lead 3.

Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection.

OBJECTIVE: To compare the effect of highly active antiretroviral therapy on immune reconstitution in subjects with acute and chronic HIV-1 infection. DESIGN: Prospective study including 58 treatment-naive subjects who commenced indinavir or nelfinavir and two nucleosides during primary (PHI; n = 28) or chronic HIV-1 infection (CHI; n = 30). METHODS: Naive (CD45RA+ 62L+), memory (CD45RA-) and activated (CD38+ HLA-DR+) T cell subsets were quantified at 1-2 monthly time intervals using 4-colour flow cytometry. RESULTS: At 1 year, HIV-1 RNA declined in both cohorts to undetectable levels (< 50 copies/ml), while median CD4 lymphocyte count increased from 470 to 758 x 10(6) cells/l in PHI and from 204 to 310 x 10(6) cells/l in CHI, reaching > 500 x 10(6) cells/l in 93% of PHI, but only in 37% of CHI subjects (P < 0.001). Naive CD4 lymphocytes increased from 106 to 176 x 10(6) cells/l in PHI and from 41 to 44 x 10(6) cells/l in CHI (PHI versus CHI at 12 months: P = 0.003), while memory cells rose from 368 to 573 x 10(6) cells/l in PHI and from 148 to 223 x 10(6) cells/l in CHI (P < 0.001). Early increases (< 3 months) of CD4 lymphocytes were larger in subjects with PHI, consisting of naive CD45RA+ CD62L+ as well as memory CD45RA- CD62L+ cells (P = 0.001). CD4 activation declined from 5 to 2% in PHI and from 13 to 6% in CHI (P = 0.001), while CD8 cell activation was reduced from 33 to 15% in PHI and from 42 to 19% in CHI (P = 0.02). CONCLUSION: Immune reconstitution was more complete, occurred earlier and comprised both naive and memory CD4 T lymphocytes in subjects who commenced antiretroviral therapy during primary HIV-1 infection.

Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.

Studies were conducted to assess progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) with respect to PR agonistic and antagonistic activities in vivo. These properties are not always adequately reflected in transactivation in vitro models. Studies were performed in pregnant rats, estrogen-primed rabbits (McPhail -Test), and cycling and pregnant guinea pigs. Tested compounds included mifepristone (RU486), onapristone, J867, J956, J1042, and ZK137316. J-compounds induced sub-maximum endometrial transformation and, paradoxically, inhibited effects of progesterone in rabbits. Mifepristone, onapristone, and ZK137316 behaved as 'pure' antagonists in this species. Inhibition of uterine PGF(2alpha) secretion and inhibition of luteolysis in cycling guinea pigs were more sensitive parameters of PR-agonistic and antagonistic properties. 'Pure' PAs inhibited uterine PGF(2alpha) secretion and luteal regression completely. The PR agonist R5020 reversed both effects which demonstrates a PR mediation. Agonistic PRMs (J-substances and mifepristone) showed no or blunted antiluteolytic effects compared to the 'pure' PR antagonist onapristone. When tested in pregnant guinea pigs for their labor-inducing potential, PR agonistic PRMs had much reduced or abolished abortifacient activity compared to mifepristone (mifepristone > J956 > J867/J912 > J1042). However, in cycling animals, superior antiovulatory and antiproliferative properties of the J-substances were seen. Antiovulatory effects of 'pure' and agonistic PRMs are probably due to different mechanisms. The relevance of rodent studies for antiovulatory and uterine antiproliferative effects for the human is still uncertain. The non-abortifacient PRM J1042 induced stromal compaction and inhibition of endometrial proliferation in monkeys, but this effect was not stronger than that of the 'purer' PAs. 'Pure' PAs are important pharmacological tools analogous to PRKO models to study the role of PR in the menstrual cycle and in pregnancy.