Successful treatment of PASH syndrome with infliximab, cyclosporine and dapsone.

BACKGROUND: The group of autoinflammatory syndromes associated with Pyoderma gangrenosum, Acne, and Suppurative Hidradenitis are poorly defined and difficult to control with currently available treatment modalities. OBJECTIVES: We describe a patient with PASH syndrome and report about the successful multimodal treatment with infliximab, cyclosporine, and dapsone. METHODS: A review of the available literature to date about this group of autoinflammatory diseases was performed. We performed genetic analysis for PSTPIP1 mutations associated with PAPA syndrome. RESULTS: A 22-year-old woman presented to our department with pyoderma gangrenosum, concomitant acne, and suppurative hidradenitis. She had previously been treated unsuccessfully with etanercept, adalimumab, fumaric acid and the IL-1 receptor antagonist (IL-1RA) anakinra without prolonged remission. Treatment with intravenous infliximab in combination with cyclosporine and dapsone lead to sudden and prolonged improvement of the clinical symptoms that we classified as PASH syndrome. We review the literature about this group of diseases and report the third case of PASH syndrome to date. CONCLUSION: PASH syndrome and associated diseases should be considered whenever hidradenitis suppurativa is found in association with pyoderma gangrenosum. We provide a systematic overview about PASH syndrome and suggest a novel multimodal therapeutic regimen beyond isolated inhibition of TNF or IL-1.

Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts.

The stromal compartment surrounding epithelial-derived pancreatic tumors is thought to have a key role in the aggressive phenotype of this malignancy. Emerging evidence suggests that cancer-associated fibroblasts (CAFs), the most abundant cells in the stroma of pancreatic tumors, contribute to the tumor's invasion, metastasis and resistance to therapy, but the precise molecular mechanisms that regulate CAFs behavior are poorly understood. In this study, we utilized immortalized human pancreatic CAFs to investigate molecular pathways that control the matrix-remodeling and invasion-promoting activity of CAFs. We showed previously that palladin, an actin-associated protein, is expressed at high levels in CAFs of pancreatic tumors and other solid tumors, and also in an immortalized line of human CAFs. In this study, we found that short-term exposure of CAFs to phorbol esters reduced the number of stress fibers and triggered the appearance of individual invadopodia and invadopodial rosettes in CAFs. Molecular analysis of invadopodia revealed that their composition resembled that of similar structures (that is, invadopodia and podosomes) described in other cell types. Pharmacological inhibition and small interfering RNA knockdown experiments demonstrated that protein kinase C, the small GTPase Cdc42 and palladin were necessary for the efficient assembly of invadopodia by CAFs. In addition, GTPase activity assays showed that palladin contributes to the activation of Cdc42. In mouse xenograft experiments using a mixture of CAFs and tumor cells, palladin expression in CAFs promoted the rapid growth and metastasis of human pancreatic tumor cells. Overall, these results indicate that high levels of palladin expression in CAFs enhance their ability to remodel the extracellular matrix by regulating the activity of Cdc42, which in turn promotes the assembly of matrix-degrading invadopodia in CAFs and tumor cell invasion. Together, these results identify a novel molecular signaling pathway that may provide new molecular targets for the inhibition of pancreatic cancer metastasis.

A consensus linkage map identifies genomic regions controlling fruit maturity and beta-carotene-associated flesh color in melon (Cucumis melo L.).

The nutritional value and yield potential of US Western Shipping melon (USWS; Cucumis melo L.) could be improved through the introgression of genes for early fruit maturity (FM) and the enhancement of the quantity of beta-carotene (QbetaC) in fruit mesocarp (i.e., flesh color). Therefore, a set of 116 F(3) families derived from the monoecious, early FM Chinese line 'Q 3-2-2' (no beta-carotene, white mesocarp) and the andromonoecious, late FM USWS line 'Top Mark' (possessing beta-carotene, orange mesocarp) were examined during 2 years in Wisconsin, USA to identify quantitative trait loci (QTL) associated with FM and QbetaC. A 171-point F(2-3) based map was constructed and used for QTL analysis. Three QTL associated with QbetaC were detected, which explained a significant portion of the observed phenotypic variation (flesh color; R (2) = 4.0-50.0%). The map position of one QTL (beta-carM.E.9.1) was uniformly aligned with one carotenoid-related gene (Orange gene), suggesting its likely role in QbetaC in this melon population and putative relationship with the melon white flesh (wf) gene. Two major (FM.6.1 and FM.11.1; R (2) >or= 20%) and one minor QTL (FM.2.1; R (2) = 8%) were found to be associated with FM. This map was then merged with a previous recombinant inbred line (RIL)-based map used to identify seven QTL associated with QbetaC in melon fruit. This consensus map [300 molecular markers (187 co-dominant melon and 14 interspecific; 10 LG)] provides a framework for the further dissection and cloning of published QTL, which will consequently lead to more effective trait introgression in melon.

Mapping of genetic loci that regulate quantity of beta-carotene in fruit of US Western Shipping melon (Cucumis melo L.).

Melon (Cucumis melo L.) is highly nutritious vegetable species and an important source of beta-carotene (Vitamin A), which is an important nutrient in the human diet. A previously developed set of 81 recombinant inbred lines (RIL) derived from Group Cantalupensis US Western Shipper market type germplasm was examined in two locations [Wisconsin (WI) and California (CA), USA] over 2 years to identify quantitative trait loci (QTL) associated with quantity of beta-carotene (QbetaC) in mature fruit. A moderately saturated 256-point RIL-based map [104 SSR, 7 CAPS, 4 SNP in putative carotenoid candidate genes, 140 dominant markers and one morphological trait (a) spanning 12 linkage groups (LG)] was used for QbetaC-QTL analysis. Eight QTL were detected in this evaluation that were distributed across four LG that explained a significant portion of the associated phenotypic variation for QbetaC (R (2) = 8 to 31.0%). Broad sense heritabilities for QbetaC obtained from RIL grown in WI. and CA were 0.56 and 0.68, respectively, and 0.62 over combined locations. The consistence of QbetaC in high/low RIL within location across years was confirmed in experiments conducted over 2 years. QTL map positions were not uniformly associated with putative carotenoid genes, although one QTL (beta-car6.1) interval was located 10 cM from a beta-carotene hydroxylase gene. These results suggest that accumulation of beta-carotene in melon is under complex genetic control. This study provides the initial step for defining the genetic control of QbetaC in melon leading to the development of varieties with enhanced beta-carotene content.

A role for candidate tumor-suppressor gene TCEAL7 in the regulation of c-Myc activity, cyclin D1 levels and cellular transformation.

The pathophysiological mechanisms that drive the development and progression of epithelial ovarian cancer remain obscure. Recently, we identified TCEAL7 as a transcriptional regulatory protein often downregulated in epithelial ovarian cancer. However, the biological significance of such downregulation in cancer is not currently known. Here, we show that TCEAL7 is downregulated frequently in many human cancers and that in immortalized human ovarian epithelial cells this event promotes anchorage-independent cell growth. Mechanistic investigations revealed that TCEAL7 associates with cyclin D1 promoter containing Myc E-box sequence and transcriptionally represses cyclin D1 expression. Moreover, downregulation of TCEAL7 promotes DNA-binding activity of Myc-Max, and upregulates the promoter activity of c-Myc-target gene, ornithine decarboxylase (ODC), whereas enhanced expression of TCEAL7 inhibits Myc-induced promoter activity of ODC. Our findings suggest that TCEAL7 may restrict ovarian epithelial cell transformation by limiting Myc activity. These results also suggest a potential, alternative mechanism by which c-Myc activity may be deregulated in cancer by the downregulation of TCEAL7.

Detection of QTL for yield-related traits using recombinant inbred lines derived from exotic and elite US Western Shipping melon germplasm.

The inheritance of yield-related traits in melon (Cucumis melo L.; 2n = 2x = 24) is poorly understood, and the mapping of quantitative trait loci (QTL) for such traits has not been reported. Therefore, a set of 81 recombinant inbred lines (RIL) was developed from a cross between the monoecious, highly branched line USDA 846-1 and a standard vining, andromonoecious cultivar, 'Top Mark'. The RIL, parental lines, and three control cultivars ('Esteem', 'Sol Dorado', and 'Hales Best Jumbo') were grown at Hancock, WI and El Centro, CA in 2002, and evaluated for primary branch number (PB), fruit number per plant (FN), fruit weight per plant (FW), average weight per fruit (AWF), and percentage of mature fruit per plot (PMF). A 190-point genetic map was constructed using 114 RAPD, 43 SSR, 32 AFLP markers, and one phenotypic trait. Fifteen linkage groups spanned 1,116 cM with a mean marker interval of 5.9 cM. A total of 37 QTL were detected in both locations (PB = 6, FN = 9, FW = 12, AWF = 5, and PMF = 5). QTL analyses revealed four location-independent factors for PB (pb1.1, pb1.2, pb2.3, and pb10.5), five for FN (fn1.1, fn1.2, fn1.3, fn2.4, and fn8.8), four for FW (fw5.8, fw6.10, fw8.11, and fw8.12), two for AWF (awf1.3 and awf8.5), and one for PMF (pmf10.4). The significant (P

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance.

To investigate the mechanism by which HSulf-1 expression is downregulated in ovarian cancer, DNA methylation and histone acetylation of HSulf-1 was analysed in ovarian cancer cell lines and primary tumors. Treatment of OV207 and SKOV3 by 5-aza-2'-deoxycytidine resulted in increased transcription of HSulf-1. Sequence analysis of bisulfite-modified genomic DNA from ovarian cell lines and primary tumors without HSulf-1 expression revealed an increase in the frequency of methylation of 12 CpG sites in exon 1A. Chromatin immunoprecipitation assays showed an increase in histone H3 methylation in cell lines without HSulf-1 expression. To assess the significance of HSulf-1 downregulation in ovarian cancer, OV167 and OV202 cells were transfected with HSulf-1 siRNA. Downregulation of HSulf-1 expression in OV167 and OV202 cells lead to an attenuation of cisplatin-induced cytotoxicity. Moreover, patients with ovarian tumors expressing higher levels of HSulf-1 showed a 90% response rate (27/30) to chemotherapy compared to a response rate of 63% (19/30) in those with weak or moderate levels (P=0.0146, chi(2) test). Collectively, these data indicate that HSulf-1 is epigenetically silenced in ovarian cancer and that epigenetic therapy targeting HSulf-1 might sensitize ovarian tumors to conventional first-line therapies.

Molecular phylogeny of Cucumis species as revealed by consensus chloroplast SSR marker length and sequence variation.

To investigate phylogenetic relationships in the genus Cucumis, 9 consensus chloroplast simple sequence repeat (ccSSR) primer pairs (ccSSR3, 9, 11, 13, 14, 17, 20, 21, and 23) were employed for DNA fragment length variation and 5 amplified fragments, ccSSR4, 12, 13, 19, and 20, were sequenced using total DNA from 13 accessions representing 7 African Cucumis species (x = 12), 3 Cucumis melo L. (x = 12) accessions, 2 Cucumis sativus L. (x = 7) accessions, and 1 Cucumis hystrix Chakr. (x = 12) accession. A Citrullus lanatus (Thunb.) Matsum. & Nakai (x = 11) accession was used as an outgroup. While fragment length analysis revealed the existence of 3 major species clusters (i.e., a group of African Cucumis species, a group composed of C. melo accessions, and a group containing C. sativus and C. hystrix species), sequence variation analysis identified 2 major species clusters (i.e., a group of African Cucumis species and a group composed of C. melo, C. sativus, and C. hystrix species). Comparative analysis using nuclear DNA (previous studies) and cpDNA sequence substitution data resulted in the placement of C. melo and C. sativus in different cluster groupings. Thus, both nuclear and cytoplasmic DNA should be employed and compared when a putative progenitor or specimens of an ancestral Cucumis species lineage is investigated. In addition, C. ficifolius (2x) and C. aculeatus (4x) of the African Cucumis species clustered together in this study. This result does not agree with reported isozyme analyses, but does agree with previously characterized chromosome homologies between these 2 species. Although African Cucumis species and C. hystrix do not share a close relationship, genetic affinities between C. sativus and C. hystrix are considerable. Combined evidence from previously published studies and data presented herein lend support to the hypothesis that C. hystrix is either a progenitor species of C. sativus or that they at least share a common ancestral lineage.

Pro-A-type and N-terminal pro-B-type natriuretic peptides in different thyroid function states.

QUESTIONS UNDER STUDY: Natriuretic peptides are produced predominantly in the heart and secreted in response to volume expansion and pressure overload. A wide spectrum of cardiac changes is observed in thyroid dysfunctions. This study investigates mid regional pro A-type (proANP) and N-terminal pro-B-type natriuretic peptide (NTproBNP) levels in different thyroid states and evaluates the effect of L-thyroxine treatment on natriuretic peptides in patients with subclinical hypothyroidism. METHODS: Case-control and double-blind, placebo-controlled trial. Sera from 161 female patients (35 with overt, 63 with subclinical hypothyroidism; 10 with overt, 14 with subclinical hyperthyroidism; 40 euthyroid controls) were analysed. ProANP and NT-proBNP were measured at baseline and 48 weeks after L-thyroxine treatment in subclinical hypothyroidism. RESULTS: Circulating proANP and NT-proBNP levels were higher in hyperthyroid patients than in hypothyroid and euthyroid patients (p <0.001). Plasma proANP levels tended to be lower in overt hypothyroidism than in subclinical hypothyroidism. ProANP and NT-proBNP levels correlated weakly to thyroid stimulating hormone (TSH) (r = -0.3 and -0.2, respectively). The natriuretic peptide levels of subclinical and overt hypothyroid subjects showed no difference with those of euthyroid subjects. L-thyroxine treatment had no effect on natriuretic peptide levels in subclinical hypothyroidism. CONCLUSION: Natriuretic peptide levels are altered in different thyroid states with a more pronounced effect in hyperthyroidism than in hypothyroidism. Hyperthyroidism should be considered in patients presenting with unclear symptoms and mildly elevated natriuretic peptide levels, as overt hyperthyroidism results in increased serum A- and B-type natriurectic peptide levels, typically seen in mild heart failure.

Construction of two BAC libraries from cucumber (Cucumis sativus L.) and identification of clones linked to yield component quantitative trait loci.

Two bacterial artificial chromosome (BAC) libraries were constructed from an inbred line derived from a cultivar of cucumber (Cucumis sativus L.). Intact nuclei were isolated and embedded in agarose plugs, and high-molecular-weight DNA was subsequently partially digested with BamHI or EcoRI. Ligation of double size-selected DNA fragments with the pECBAC1 vector yielded two libraries containing 23,040 BamHI and 18,432 EcoRI clones. The average BamHI and EcoRI insert sizes were estimated to be 107.0 kb and 100.8 kb, respectively, and BAC clones lacking inserts were 1.3% and 14.5% in the BamHI and EcoRI libraries, respectively. The two libraries together represent approximately 10.8 haploid cucumber genomes. Hybridization with a C(0)t-1 DNA probe revealed that approximately 36% of BAC clones likely carried repetitive sequence-enriched DNA. The frequencies of BAC clones that carry chloroplast or mitochondrial DNA range from 0.20% to 0.47%. Four sequence-characterized amplified region (SCAR), four simple sequence repeat, and an randomly amplified polymorphic DNA marker linked with yield component quantitative trait loci were used either as probes to hybridize high-density colony filters prepared from both libraries or as primers to screen an ordered array of pooled BAC DNA prepared from the BamHI library. Positive BAC clones were identified in predicted numbers, as screening by polymerase chain reaction amplification effectively overcame the problems associated with an overabundance of positives from hybridization with two SCAR markers. The BAC clones identified herein that are linked to the de (determinate habit) and F (gynoecy) locus will be useful for positional cloning of these economically important genes. These BAC libraries will also facilitate physical mapping of the cucumber genome and comparative genome analyses with other plant species.

Long-term treatment of gastro-oesophageal reflux disease patients with frequent symptomatic relapses using rabeprazole: on-demand treatment compared with continuous treatment.

BACKGROUND: On-demand treatment may be an alternative in the long-term treatment of non-severe gastro-oesophageal reflux disease in patients with frequent symptomatic relapses. AIM: To compare the efficacy of on-demand treatment with rabeprazole 10 mg versus continuous treatment in the long-term treatment of patients with frequent symptomatic relapses of mild to moderate gastro-oesophageal reflux disease. METHODS: This randomized, open-label study enrolled patients diagnosed with non-erosive reflux disease or oesophagitis grade 1 or 2 (Savary-Miller classification) reporting frequent symptomatic relapses (requiring > or =2 courses of antisecretory therapy during the previous year), whose intensity is rated at least moderate (>2 on a 5-point Likert scale). After a 4-week selection phase with rabeprazole 10 mg once daily, patients reporting symptom relief (Likert score < or =2) were randomized to receive either rabeprazole 10 mg continuous treatment or on-demand treatment for 6 months. The main evaluation criterion was the rate of symptom relief (scored on the Likert scale) after 6 months. RESULTS: One hundred and seventy-six patients were enrolled in the 4-week selection phase (men, 53%; mean age, 49 years; non-erosive reflux disease, 36.4%; gastro-oesophageal reflux disease 1, 53.4%; gastro-oesophageal reflux disease 2, 10.2%). Rabeprazole relieved symptoms in 88.6% of patients. Of this group, 152 were randomized to the comparative phase to receive rabeprazole 10 mg continuous treatment (once daily) or on-demand treatment (continuous treatment, n = 81; on-demand treatment, n = 71). At month 6 (end point), the symptom relief rate was slightly higher for patients in the continuous treatment group compared with those in the on-demand treatment group: 86.4% versus 74.6%, respectively. This difference was not statistically significant (P = 0.065). For the overall quality of life score, there was no difference between the continuous treatment and on-demand treatment groups (86.25 and 84.94). Mean daily consumption of rabeprazole was significantly lower in the on-demand treatment group versus the continuous treatment group (0.31 tablets versus 0.96 tablets; P < 0.0001). CONCLUSION: On-demand therapy with rabeprazole 10 mg provides an alternative to continuous therapy in patients with mild to moderate gastro-oesophageal reflux disease suffering from frequent symptomatic relapses.

Comparative analysis of response to phenotypic and marker-assisted selection for multiple lateral branching in cucumber ( Cucumis sativus L.).

Yield increase in processing cucumber ( Cucumis sativus L.) is positively correlated with an increase in number of fruit-bearing branches. Multiple lateral branching (MLB) is a metric trait controlled by at least five effective factors. Breeding efficacy might be improved through marker-assisted selection (MAS) for MLB. Experiments were designed to independently confirm previously determined linkage of molecular markers (L18-2-H19A SNP, CSWTAAA01 SSR, CSWCT13 SSR, W7-2 RAPD and BC-551 RAPD) to MLB, and to determine their utility in MAS. These markers were present in significantly higher frequency than expected (1, presence:3, absence; p < 0.001) in BC(2) plants selected based on a high MLB phenotype (BC(2)PHE). However, markers that were considered selectively neutral fit the expected segregation of donor parent DNA in BC(2) progeny. Markers linked to MLB were used in MAS of BC(1) and BC(2) plants to produce BC(2)MAS, and BC(3)MAS progeny. Means for MLB in MAS populations were compared with backcross populations developed through phenotypic selection (BC(2)PHE, BC(3)PHE) and by random mating where no selection had been applied (BC(2)RND, BC(3)RND). Statistical analysis showed no significant differences ( p < 0.001) between means of phenotypic (BC(2)PHE = 3.02, BC(3)PHE = 3.29) and marker-aided selection (BC(2)MAS = 3.12, BC(3)MAS = 3.11) for MLB. However, both phenotypic and MAS population means were significantly higher than the random control (BC(2)RND = 2.27, BC(3)RND = 2.41) for MLB. Thus, given the observed response to selection and the rapid life-cycle of cucumber (4 months), markers linked to MLB when used in MAS will most likely be effective tools in cucumber improvement.

Genetic analysis of Spanish melon ( Cucumis melo L.) germplasm using a standardized molecular-marker array and geographically diverse reference accessions.

Genetic relationships among 125 Spanish melon ( Cucumis melo L.) accessions from a Spanish germplasm collection were assessed using a standard molecular-marker array consisting of 34 random amplified polymorphic DNA (RAPD) markers bands (19 primers) and 72 reference accessions drawn from previous studies. The reference accession array consisted of a broad range [Japanese (19) Crete (17), African (15), and USA and Europe (US/EU, 21)] of horticultural groupings (Group Cantalupensis, Group Conomon, Group Inodorus, Group Flexuosus, and Group Chito), and of melon market classes (e.g., Charentais, U.S. Western and European Shipper types, Ogen, and Galia, Honeydew, and Casaba). Spanish melon accessions (largely Casaba, Group Inodorus) were genetically distinct from the reference accessions and other Group Inodorus melons of different origins. Most African accessions showed common genetic affinities, and grouped with the Group Chito and the Group Conomon accessions examined. Those accession groupings were distinct from all other accessions belonging to Group Cantalupensis, Flexuosus, and Inodorus accessions originating from Crete, Japan, Europe, and the U.S. Genetic diversity was highest in accessions of African origin and lowest in accessions of Spanish origin. Additional RAPD markers (49 primers, 141 bands) and 22 selected agronomic traits (quantitative and qualitative) were then used to assess the genetic diversity among Spanish accessions. While cluster analysis using fruit characteristics grouped accessions into cultivars, RAPD-based genetic-distance estimate did not provide consistent accession groupings either by cultivar or geographic origin. While the highest level of polymorphism was detected among melons originating from the central region of Spain, and in the Rochet cultivar, accessions from the Andalucía region and Green cultivars were comparatively less diverse. These results indicate that the Spanish melon accessions could be used to broaden the genetic base of local and foreign Casaba germplasm, to enhance the genetic diversity of U.S and European commercial melon germplasm, and to delineate collection strategies for acquisition of additional Spanish landraces.

Genetic mapping and QTL analysis of horticultural traits in cucumber ( Cucumis sativus L.) using recombinant inbred lines.

A set of 171 recombinant inbred lines (RIL) were developed from a narrow cross in cucumber ( Cucumis sativus L.; 2n = 2 x = 14) using the determinate ( de), gynoecious ( F), standard-sized leaf line G421 and the indeterminate, monoecious, little-leaf ( ll) line H-19. A 131-point genetic map was constructed using these RILs and 216 F(2) individuals to include 14 SSRs, 24 SCARs, 27 AFLPs, 62 RAPDs, 1 SNP, and three economically important morphological [ F (gynoecy), de (determinate habit), ll (little leaf)] markers. Seven linkage groups spanned 706 cM with a mean marker interval of 5.6 cM. The location of F and de was defined by genetic linkage and quantitative trait locus (QTL) analysis to be associated with SSR loci CSWCT28 and CSWCTT14 at 5.0 cM and 0.8 cM, respectively. RIL-based QTL analysis of the number of lateral branches in three environments revealed four location-independent factors that cumulatively explained 42% of the observed phenotypic variation. QTLs conditioning lateral branching (mlb1.1), fruit length/diameter ratio (ldr1.2) and sex expression (sex1.2) were associated with de. Sex expression was influenced by three genomic regions corresponding to F and de both on linkage Group 1, and a third locus (sex6.1) on linkage Group 6. QTLs conditioning the number of fruit per plant (fpl1.2), the number of lateral branches (mlb1.4) and fruit length/diameter ratio (ldr1.3) were associated with ll. The potential value of these marker-trait associations (i.e., yield components) for plant improvement is portended by the relatively high LOD scores (2.6 to 13.0) and associated R(2) values (1.5% to 32.4%) that are affiliated with comparatively few genetic factors (perhaps 3 to 10).

A nonlinear compartmental model of Sr metabolism. I. Non-steady-state kinetics and model building.

A model of Sr metabolism was developed by using plasma and urinary Sr kinetic data obtained in groups of postmenopausal women who received four different oral doses of Sr and collected during the Sr administration period (25 days) and for 28 days after cessation of treatment. A nonlinear compartmental formalism that is appropriate for study of non-steady-state kinetics and allows dissociation of variables pertaining to Sr metabolism (system 1) from those indirectly operating on it (system 2) was used. At each stage of model development, the dose-dependent model response was fitted to the four sets of data considered simultaneously (1 set per dose). A seven-compartment model with internal Sr distribution and intestinal, urinary, and bone metabolic pathways was selected. It includes two kinds of nonlinearities: those accounting for saturable intestinal and bone processes, which behave as intrinsic nonlinearities because they are directly dependent on Sr, and extrinsic nonlinearities (dependent on system 2), which suggest the cooperative involvement of plasma Sr changes in modulating some intestinal and bone mineral metabolic pathways. With the set of identified parameter values, the initial steady-state model predictions are relevant to known physiology, and some peculiarities of model behavior for long-term Sr administration were simulated.

A nonlinear compartmental model of Sr metabolism. II. Its physiological relevance for Ca metabolism.

We have studied the peculiarities of the nonlinear compartmental model for human Sr metabolism (Staub JF, Foos E, Courtin B, Jochemsen R, and Perault-Staub AM. Am J Physiol Regul Integr Comp Physiol 284: R819-R834, 2003), including its physiological reliability in the context of Sr-Ca similarity-dissimilarity. We found it to be relevant to Ca metabolism, except for discrimination against Sr relative to Ca at urinary and intestinal levels. The main findings are as follows: 1) the saturable part of intestinal absorption, shared by Sr and Ca, does not seem to be responsible for the discrimination of the transcellular pathway; 2) although there is little discrimination in bone, the physicochemical behaviors of Sr and Ca at the bone surface differ, at least quantitatively; and 3) Sr behaves as a "tracer" for Ca metabolic pathways and, under non-steady-state conditions, can also reveal self-regulatory processes. It is suggested that they depend on Ca2+ (cationic)-sensing receptors that are apparently more sensitive to Sr than to Ca. Acting on gastrointestinal and osteoblast lineage cells, these slow processes might contribute to adaptive, rather than homeostatic, regulation of Ca metabolism. Understanding these features could help clarify the pharmacological and therapeutic effects of oral Sr.

Reproduction and cytogenetic characterization of interspecific hybrids derived from Cucumis hystrix Chakr. x Cucumis sativus L.

Interspecific hybrids between Cucumis hystrix Chakr. (2n = 2 x = 24) and Cucumis sativus L. (2n = 2 x = 14) were produced by means of F(1) (2n = 19) embryo rescue and subsequent chromosome doubling. The hybridity was confirmed by genomic in situ hybridization (GISH) and chromosome analysis. The amphidiploid (2n = 38) was self-pollinated and backcrossed to cucumber resulting in lines with improved crossability to C. sativus. Examination of shape, stainability, and germination rate of pollen grains and yield as a function of mature fruit set per ten pollinated flowers indicated a tendency for increased fertility in BC(1)S(1) progeny when compared to F(1) and amphidiploid offspring. Cytogenetic characterization of F(1) and amphidiploid progeny was performed. Generally normal meioses produced viable pollen grains, and fertilization resulted in partial fertility restoration in amphidiploid progeny. Chromosome anomalies such as "frying-pan trivalent", chromosome lagging and spindle mis-orientation were also observed. In most of the PMCs of the F(1) diploid hybrid progeny, 19 univalents were observed at diakinesis and MI. In the amphidiploid, more than 90% of the configurations at MI consisted of the predicted 19 bivalents and less than 5% contained multivalents [trivalents (2.3%) + quadrivalents (0.3%)], suggesting the presence of preferential pairing, and a distinctive parental genome as well. The chiasmata observed between homoeologous chromosomes further demonstrated the introgression of the C. hystrix genome into that of C. sativus.