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The Hoary Bat Chalinolobus nigrogriseus is the only species of the genus known from the island of New Guinea. A new species of Chalinolobus from Papua New Guinea is described based on DNA sequence and morphological criteria using material previously assigned to C. nigrogriseus. The new species most resembles the eastern Australian subspecies of the Hoary Bat C. n. nigrogriseus in general size and appearance but is easily distinguished by an enlarged, rather than rudimentary lobe at the terminal outer ear margin. The new species might also be confused on external characters with smaller individuals of Australian Gould's Wattle Bat C. gouldii, from which it differs in having bifid first upper incisors and uniform dark dorsal fur. The inclusion of C. nigrogriseus in the bat fauna of New Guinea is now in doubt, pending a re-assessment of the identity of Chalinolobus specimens in world museum collections. Locality records of all Chalinolobus spp. from Papua New Guinea are reviewed. Most localities are below 60 m elevation in coastal savannah and woodlands. The identity of specimens of C. nigrogriseus and C. gouldii from northern Australia should be reviewed to determine whether the new species also occurs in Australia.

Primatologists have a long-standing interest in the study of maternal care and nonmaternal handling (NH) of infants stemming from recognition that early social relationships can have enduring consequences. Though maternal care and NH often include expression of similar behaviors, they are regularly studied in isolation from each other with nonoverlapping terminology, thereby overlooking possible interplay between them and obfuscating potential developmental ramifications that ensue from trade-offs made between maternal (MH) and NH during infancy. To that end, identifying how MH and NH patterns interact and contribute to the total handling (TH) infants receive is a critical first step. We present durational handling data collected from 25 wild Colobus vellerosus infants from 2016 to 2017 and assess the relationships between TH, MH, and NH. Patterns of social affiliation are shaped in part by surrounding context, and therefore, we also assess whether NH and TH differ in their responsivity to various infant and social group characteristics. Ninety-four percent of observed handling was MH, while just 5.5% was NH. Young infants who received more MH (excluding nursing) also received more NH; there was no relationship between the two in older infants. Infants in larger groups participated in more handling of all types. Additionally, NH time was associated with infant sex and group stability. Non-nursing TH time was associated with group stability and infant cohort size. Though NH variation likely confers social-networking advantage, in this population NH is not a major contributor to TH and would not effectively replace reduced MH. The positive association between MH and NH during early infancy suggests that colobus mothers may play a mediating role in shaping infant socialization. This is a first step in elucidating how different forms of handling relate to one another in wild primates and in identifying the impact of handling on infant socialization., (© 2024 The Authors. American Journal of Primatology published by Wiley Periodicals LLC.)

Analysis of glucocorticoid profiles serves as a valuable, multi-faceted tool for insight into the behavior and physiology of wild populations. Recently, the measurement of fecal glucocorticoid metabolites (FCMs) has exploded in popularity due to its compatibility with noninvasive techniques and remote environments A critical first step is to perform a biological validation to ensure that the assay accurately reflect changes in FCM levels. We use an enzyme immunoassay (EIA) to perform a biological validation on samples collected from two males and six females in a wild population of Colobus vellerosus in response to three naturally occurring potential stressors. We also describe the FCM response pattern in the week following parturition in three females and examine the influence of sex, reproductive state, and time of day on the concentrations of baseline samples collected daily from 13 adult individuals over a period of four months. We validated the assay: FCM levels increase in response to natural stressors with a two-day lag. In the two days surrounding parturition, FMC levels increased. Baseline concentrations were affected by collection time and female reproductive state, with lactating females having lower concentrations than pregnant or cycling females. Thus, we successfully carried out the first validation and characterization of FCMs in a wild African colobine. This will serve as an essential foundation for future studies of C. vellerosus and similar wild primates whose objective is to investigate the role glucocorticoids play in responses to social and ecological challenges., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

X chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is an iconic example of epigenetic regulation. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here, we examine genome-wide signatures of DNA methylation across fives tissues from a male and female koala ( Phascolarctos cinereus ), and present the first whole-genome, multi-tissue marsupial 'methylome atlas'. Using these novel data, we elucidate divergent versus common features of representative marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in koalas primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx , the primary lnc RNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-specific (and presumably inactive X chromosome-specific) expression. Finally, we use the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5%) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.

Purpose: Chondroblastoma is a cartilaginous neoplasm which rarely presents in the spine, where it has been shown to exhibit aggressive behavior. We present a case of a late diagnosis of a T12 chondroblastoma causing paraparesis in an 11-year-old girl. Several missed classical radiographic and clinical features are highlighted., Methods: We reviewed clinical, imaging, and pathology data from the time of transfer to our institution, followed by review of all outside clinical records and imaging data from 14 months prior to admission until onset of paraplegia., Results: The patient was transferred to our center for emergent treatment of a large, expansile, exophytic lesion compressing the spinal cord at T12. Intravenous steroids improved her neurologic status to ASIA Grade B, and an en bloc posterior element resection was performed emergently within 24 h. She rapidly improved to an ASIA Grade E. After obtaining all prior imaging during detailed histopathologic work-up, the final diagnosis was that of spinal chondroblastoma. Subsequent anterior en bloc resection was performed. The patient remains disease-free with a stable, residual scoliosis 7 years postoperatively., Conclusions: Detailed review of radiographs is essential for scoliosis patients. Earlier recognition of the "winking owl" sign, a kyphotic sagittal alignment, and more concern about a child with a painful curve may have resulted in earlier diagnosis before the onset of neurologic deficits.

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC 50  = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC 50  = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

With the goal of safety and efficiency in health care delivery, enhanced recovery protocols (ERPs) continue to gain traction throughout various surgical disciplines, including in pediatric scoliosis surgery. The growing body of literature reporting decreased length of stay and cost with no change in readmissions or complications has brought these protocols to the forefront. The key components of ERPs include preoperative patient counseling, perioperative pain management, and early patient mobilization. In this review, the authors aim to describe the foundational history and major components of ERPs following pediatric spine deformity surgery. [Orthopedics. 2020;43(5):e338-e344.]., (Copyright 2020, SLACK Incorporated.)

System x c - exchanges extracellular cystine for intracellular glutamate across the plasma membrane of many cell types. One of the physiological roles of System x c - is to provide cystine for synthesis of the antioxidant glutathione. Here we report that hydrogen peroxide (H 2 O 2 ) triggers the translocation of System x c - to the plasma membrane within 10 min of the initial exposure. Specifically, we observed a three-fold increase in 35 S-l-cystine uptake following a 10 min exposure to 0.3 mM H 2 O 2 . This effect was dose-dependent with an EC 50 for H 2 O 2 of 65 μM. We then used cell surface biotinylation analysis to test the hypothesis that the increase in activity is due to an increased number of transporters on the plasma membrane. We demonstrated that the amount of transporter protein, xCT, localized to the plasma membrane doubles within 10 min of H 2 O 2 exposure as a result of an increase in its delivery rate and a reduction in its internalization rate. In addition, we demonstrated that H 2 O 2 triggered a rapid decrease in total cellular glutathione which recovered within 2 h of the oxidative insult. The kinetics of glutathione recovery matched the time course for the recovery of xCT cell surface expression and System x c - activity following removal of the oxidative insult. Collectively, these results suggest that oxidants acutely modulate the activity of System x c - by increasing its cell surface expression, and that this process may serve as an important mechanism to increase de novo glutathione synthesis during periods of oxidative stress., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Post-traumatic heterotopic ossification (HO) is the formation of ectopic bone in non-osseous structures following injury. The precise mechanism for bone development following trauma is unknown; however, early onset of HO may involve the production of pro-osteogenic serum factors. Here we evaluated serum from a cohort of civilian and military patients post trauma to determine early induction gene signatures in orthopaedic trauma induced HO. To test this, human adipose derived stromal/stem cells (hASCs) were stimulated with human serum from patients who developed HO following trauma and evaluated for a gene panel with qPCR. Pathway gene analysis ontology revealed that hASCs stimulated with serum from patients who developed HO had altered gene expression in the activator protein 1 (AP1) and AP1 transcriptional targets pathways. Notably, there was a significant repression in FOS gene expression in hASCs treated with serum from individuals with HO. Furthermore, the mitogen-activated protein kinase (MAPK) signaling pathway was activated in hASCs following serum exposure from individuals with HO. Serum from both military and civilian patients with trauma induced HO had elevated downstream genes associated with the MAPK pathways. Stimulation of hASCs with known regulators of osteogenesis (BMP2, IL6, Forskolin, and WNT3A) failed to recapitulate the gene signature observed in hASCs following serum stimulation, suggesting non-canonical mechanisms for gene regulation in trauma induced HO. These findings provide new insight for the development of HO and support ongoing work linking the systemic response to injury with wound specific outcomes., (© 2018 Wiley Periodicals, Inc.)

Stromal/stem cell differentiation is controlled by a vast array of regulatory mechanisms. Included within these are methods of mRNA gene regulation that occur at the level of epigenetic, transcriptional, and/or posttranscriptional modifications. Current studies that evaluate the posttranscriptional regulation of mRNA demonstrate microRNAs (miRNAs) as key mediators of stem cell differentiation through the inhibition of mRNA translation. miRNA expression is enhanced during both adipogenic and osteogenic differentiation; however, the mechanism by which miRNA expression is altered during stem cell differentiation is less understood. Here we demonstrate for the first time that adipose-derived stromal/stem cells (ASCs) induced to an adipogenic or osteogenic lineage have differences in strand preference (-3p and -5p) for miRNAs originating from the same primary transcript. Furthermore, evaluation of miRNA expression in ASCs demonstrates alterations in both miRNA strand preference and 5'seed site heterogeneity. Additionally, we show that during stem cell differentiation there are alterations in expression of genes associated with the miRNA biogenesis pathway. Quantitative RT-PCR demonstrated changes in the Argonautes (AGO1-4), Drosha, and Dicer at intervals of ASC adipogenic and osteogenic differentiation compared to untreated ASCs. Specifically, we demonstrated altered expression of the AGOs occurring during both adipogenesis and osteogenesis, with osteogenesis increasing AGO1-4 expression and adipogenesis decreasing AGO1 gene and protein expression. These data demonstrate changes to components of the miRNA biogenesis pathway during stromal/stem cell differentiation. Identifying regulatory mechanisms for miRNA processing during ASC differentiation may lead to novel mechanisms for the manipulation of lineage differentiation of the ASC through the global regulation of miRNA as opposed to singular regulatory mechanisms.

Osteomyelitis of the clavicle is a rare entity with a broad differential diagnosis and high potential for complications if not diagnosed promptly and treated appropriately. The threshold for surgical intervention should be low to prevent osteonecrosis and bony resorption. In addition, although rare, life-threatening complications have been reported. This report describes primary osteomyelitis of the clavicle that was diagnosed in a 22-month-old girl on her third clinical evaluation after 4 days of symptoms. She presented to a children's tertiary care emergency department with fever and acute pain and swelling of her right shoulder and arm. The diagnosis was confirmed through clinical, laboratory, and imaging studies including ultrasound; these revealed subperiosteal abscess formation, which may have developed in part as the result of a delayed diagnosis from the 2 prior emergency department visits. The patient was treated initially with intravenous antibiotics and underwent therapeutic as well as diagnostic needle-guided tissue aspiration under ultrasound guidance. This ruled out malignancy but was not curative, and the subperiosteal abscess recurred within 24 hours, prompting formal operative irrigation and debridement. The patient was seen for 12-month follow-up and has had no complications or evidence of recurrence. This case emphasizes the need for a high index of suspicion to prevent diagnostic delays as well as the importance of a low threshold for surgical debridement to minimize the potential for complications that could prolong the treatment course. [Orthopedics. 2016; 39(4):e760-e763.]., (Copyright 2016, SLACK Incorporated.)

Since inflammatory mechanisms have been postulated to link obesity to osteoarthritis, the current study evaluated the ratio of immune cells to multipotent stromal cells within the infrapatellar fat pad (IPFP) and subcutaneous adipose tissue (SQ) of the knee; each depot has potential as a source of regenerative cells. The immunophenotypes of stromal vascular fraction (SVF) and adipose-derived stem cells (ASCs) of the IPFP and SQ were determined in tissues from osteoarthritic subjects (n = 7) undergoing total knee replacement. Based on a subset of surface antigens, the immunophenotype of ASCs from SQ of OA subjects was not significantly different from that of relatively healthy and leaner subjects undergoing elective liposuction surgery. Flow-cytometry comparison of SVF cell populations in the IPFP of OA subjects resembled those within the subject's own matched SQ, with the exception of the endothelial marker CD31(+) , which was significantly greater in cells from SQ. In the OA subjects, lower numbers of capillary-like structures and higher numbers of stromal and alkaline phosphatase colony-forming units in the IPFP vs SQ were consistent with this finding; however, ASCs from both depots in OA subjects exhibited comparable adipogenic and osteogenic differentiation potential. Thus, the IPFP contains an ASC and immune cell population similar to that of donor-matched SQ, making it an alternative ASC source for tissue regeneration. Further studies will be needed to determine whether IPFP immune cell infiltrates play an aetiological role in osteoarthritis equivalent to that shown in diabetes associated with obesity., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: The koala, Phascolarctos cinereus, is a biologically unique and evolutionarily distinct Australian arboreal marsupial. The goal of this study was to sequence the transcriptome from several tissues of two geographically separate koalas, and to create the first comprehensive catalog of annotated transcripts for this species, enabling detailed analysis of the unique attributes of this threatened native marsupial, including infection by the koala retrovirus., Results: RNA-Seq data was generated from a range of tissues from one male and one female koala and assembled de novo into transcripts using Velvet-Oases. Transcript abundance in each tissue was estimated. Transcripts were searched for likely protein-coding regions and a non-redundant set of 117,563 putative protein sequences was produced. In similarity searches there were 84,907 (72%) sequences that aligned to at least one sequence in the NCBI nr protein database. The best alignments were to sequences from other marsupials. After applying a reciprocal best hit requirement of koala sequences to those from tammar wallaby, Tasmanian devil and the gray short-tailed opossum, we estimate that our transcriptome dataset represents approximately 15,000 koala genes. The marsupial alignment information was used to look for potential gene duplications and we report evidence for copy number expansion of the alpha amylase gene, and of an aldehyde reductase gene.Koala retrovirus (KoRV) transcripts were detected in the transcriptomes. These were analysed in detail and the structure of the spliced envelope gene transcript was determined. There was appreciable sequence diversity within KoRV, with 233 sites in the KoRV genome showing small insertions/deletions or single nucleotide polymorphisms. Both koalas had sequences from the KoRV-A subtype, but the male koala transcriptome has, in addition, sequences more closely related to the KoRV-B subtype. This is the first report of a KoRV-B-like sequence in a wild population., Conclusions: This transcriptomic dataset is a useful resource for molecular genetic studies of the koala, for evolutionary genetic studies of marsupials, for validation and annotation of the koala genome sequence, and for investigation of koala retrovirus. Annotated transcripts can be browsed and queried at http://koalagenome.org.

Purpose: Two noninvasive delivery strategies for VEGF/PDGF receptor tyrosine kinase inhibitors (RTKI) were explored that exploited uveal retention as a means for establishing an ocular drug depot: a single oral "loading" dose and topical administration., Methods: Melanin binding was confirmed by centrifugation and mass spectrometry. Ocular retention was examined in pigmented and albino rats. Ocular release kinetics were measured 3 to 28 days postdosing in pigmented rats. Microautoradiography was used to demonstrate retention of RTKI in the uveal tract. A uveal drug depot of pazopanib was created by a single oral dose prior to induction of laser choroidal neovascularization (CNV). Choroid/retinal pigmented epithelium (RPE) retention of a related RTKI with enhanced topical bioavailability, GW771806, was confirmed by bioanalytics, and its ability to regress CNV compared with pazopanib., Results: Pazopanib and GW771806 directly bound melanin and were retained within the uveal tract of pigmented rats for weeks following a single oral dose. Pazopanib was undetectable systemically following a single oral administration prior to CNV induction, and reduced CNV as well as twice daily dosing. Topical ocular delivery of GW771806 at 5 mg/mL led to high choroidal/RPE exposure and significantly regressed CNV lesions; 2 mg/mL prevented lesion progression., Conclusions: Uveal retention of drugs such as pazopanib can be used to create a sustained-release depot. Topical GW771806 regressed CNV. These data indicate that topical or infrequent oral loading dose treatment with VEGF/PDGF RTKI retained in the choroid/RPE might allow noninvasive treatments for ocular neovascular disease.

Using next-generation sequencing technology, we describe the complete mitochondrial genomes for 5 Australian passerine birds (Epthianura albifrons, Petroica phoenicea, Petroica goodenovii, Petroica boodang, and Eopsaltria australis). We successfully assemble each mitogenome de novo using just 1/8th of a Roche GL FSX 454 pyrosequencing plate. From the assembled mitogenomes, we identify 2 different mitochondrial gene arrangements in the region spanning 5'-3' from Cytochrome B to 12s RNA. These gene arrangements represent 2 of the 4 known avian mitochondrial gene arrangements. Our results, together with other previously described avian mitogenomes, highlight that certain mitochondrial rearrangements appear to have arisen multiple times.

Neovascularization in the eye is a major cause of irreversible vision loss. The present study was undertaken to determine mechanisms through which pazopanib, a drug that targets multiple receptor tyrosine kinases such as VEGF receptors, inhibits angiogenesis and experimental choroidal neovascularization (CNV). Pazopanib inhibited VEGF expression by retinal pigment epithelium (RPE) cells and choroidal endothelial cells (CEC), decreased VEGF-induced cellular migration in a dose-dependent manner and suppressed extracellular signal-regulated kinase (ERK)-1/-2 phosphorylation. To assess the impact of pazopanib in vivo, CNV was induced in rats by rupturing the Bruch's membrane by laser coagulation. These experiments demonstrated that twice-daily topical eye drop treatment significantly (P<0.001) decreased leakage from photocoagulated lesions by 89.5%. Furthermore, the thickness of the developed CNV lesions was significantly inhibited by 71.7% (P<0.001) in pazopanib-treated eyes, and immunoreactivity of VEGF was lower than in control eyes. Our data suggest that pazopanib is a promising inhibitor of angiogenesis leading to an effective inhibition of CNV development in vivo. This activity can be largely ascribed to the down-regulation of VEGF release in the retina as well as to impaired VEGF-induced signaling and chemotaxis. Using a convenient topical dosing regimen, pazopanib may prove useful for treating a variety of ocular neovascular diseases such as neovascular age-related macular degeneration., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Myelosuppression has been observed with several multikinase angiogenesis inhibitors in clinical studies, although the frequency and severity varies among the different agents. Inhibitors targeting vascular endothelial growth factor receptor (VEGFR) often inhibit other kinases, which may contribute to their adverse-event profiles., Methods: Kinase selectivity of pazopanib, sorafenib, and sunitinib was evaluated in a panel of 242 kinases. Cellular potency was measured using autophosphorylation assays. Effect on human bone marrow progenitor growth in the presence of multiple growth factors was evaluated and correlated with the kinase selectivity., Results: Sunitinib inhibited more kinases than pazopanib and sorafenib, at potencies within 10-fold of VEGFR-2. All three compounds potently inhibited VEGFR-2, platelet-derived growth factor receptor-beta and c-Kit, However, pazopanib was less active against Flt-3 in both kinase and cellular assays. The inhibitory properties of pazopanib, sorafenib, and sunitinib were dependent on the growth factor used to initiate bone marrow colony formation. Addition of stem cell factor and/or Flt-3 ligand with granulocyte-macrophage colony stimulating factor resulted in significant shifts in potency for sorafenib and sunitinib but less so for pazopanib., Conclusion: Activity against c-kit and Flt-3 by multikinase angiogenesis inhibitors provide a potential explanation for the differences in myelosuppression observed with these agents in patients.

Objective: To investigate pazopanib hydrochloride, a multitargeted kinase inhibitor, for treatment of choroidal neovascularization (CNV)., Methods: Choroidal neovascularization was induced in mice by rupture of Bruch membrane with laser photocoagulation. Mice were treated with pazopanib by gavage or periocular injection, and the area of CNV was measured., Results: Twice-daily gavage of pazopanib, 100 mg/kg, suppressed the development of CNV by 93%. Treatment of established CNV between days 7 and 14 with 8, 40, or 200 mg/kg per day reduced CNV by 0%, 58%, and 71%, respectively. Substantial regression (40%) of CNV was also achieved after periocular injection of pazopanib. A single oral dose of 4 or 100 mg/kg resulted in an area under the curve from time 0 to the last quantifiable concentration of 129.6 and 752.0 microg x h/mL, respectively. After 7 days of 4, 20, or 100 mg/kg twice a day by gavage, plasma levels were 1300, 4900, and 5800 ng/mL and levels in the retina/choroid were 4800, 28 800, and 38 000 ng/g of tissue., Conclusions: Orally administered pazopanib has good bioavailability to the retina/choroid and strongly suppresses CNV in mice. Treatment with pazopanib after CNV is established causes dose-dependent regression of CNV., Clinical Relevance: Pazopanib may be useful for treatment of CNV in humans.

The pharmacokinetics and brain penetration of the novel neurokinin (NK)-1 receptor antagonist casopitant [1-piperidinecarboxamide, 4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-, (2R,4S)-; GW679769] were examined in ferrets. The ferret is known to respond to the full spectrum of agents recognized to induce emesis in humans, and the cisplatin-induced emesis models in the ferret have been used to establish the antiemetic potential of casopitant. Following single i.p. dosing to the ferret, casopitant was rapidly absorbed, with plasma and brain concentrations being approximately equal at 2 h postdose. The predominant radioactive component present in the ferret brain after a single dose of [(14)C]casopitant was parent compound, accounting for approximately 76% of the radioactivity. The major metabolites present in brain tissue following administration of [(14)C]casopitant were hydroxylated casopitant (M1) and the corresponding ketone product of the M1 metabolite (M2), which accounted for approximately 19 and 3% of the radioactivity in the brain extracts, respectively. All three molecules had relatively similar potency against ferret brain cortical NK-1, suggesting that the pharmacologic activity of casopitant in the ferret is largely attributable to parent compound and, to a lesser extent, to its oxidative metabolites. Because casopitant is intended to be administered in combination with ondansetron and because therapeutic synergy has been observed with this combination in the ferret, a drug interaction study was conducted. The additional pharmacodynamic benefit of the combination dose was not because of an alteration in the pharmacokinetics of either agent but is likely the result of the complementary mechanisms of pharmacologic action of the two drugs.

Mobilized peripheral blood hematopoietic stem cells (PBSCs) demonstrate accelerated engraftment compared with bone marrow; however, mechanisms responsible for enhanced engraftment remain unknown. PBSCs mobilized by GRObeta (GRObeta(Delta4)/CXCL2(Delta4)) or the combination of GRObeta(Delta4) plus granulocyte colony-stimulating factor (G-CSF) restore neutrophil and platelet recovery faster than G-CSF-mobilized PBSCs. To determine mechanisms responsible for faster hematopoietic recovery, we characterized immunophenotype and function of the GRObeta-mobilized grafts. PBSCs mobilized by GRObeta(Delta4) alone or with G-CSF contained significantly more Sca-1(+)-c-kit(+)-lineage(-) (SKL) cells and more primitive CD34(-)-SKL cells compared with cells mobilized by G-CSF and demonstrated superior competitive long-term repopulation activity, which continued to increase in secondary and tertiary recipients. GRObeta(Delta4)-mobilized SKL cells adhered better to VCAM-1(+) endothelial cells compared with G-CSF-mobilized cells. GRObeta(Delta4)-mobilized PBSCs did not migrate well to the chemokine stromal derived factor (SDF)-1alpha in vitro that was associated with higher CD26 expression. However, GRObeta(Delta4)-mobilized SKL and c-Kit(+) lineage(-) (KL) cells homed more efficiently to marrow in vivo, which was not affected by selective CXCR4 and CD26 antagonists. These data suggest that GRObeta(Delta4)-mobilized PBSCs are superior in reconstituting long-term hematopoiesis, which results from differential mobilization of early stem cells with enhanced homing and long-term repopulating capacity. In addition, homing and engraftment of GRObeta(Delta4)-mobilized cells is less dependent on the SDF-1alpha/CXCR4 axis.

Ovariectomized (OVX) ewes were assigned to receive vehicle, progesterone (P4, 0.9-g controlled internal drug release vaginal implants), estradiol-17beta (E2, 5 microg/kg bolus + 6 microg kg(-1) day(-1)), or P4 + E2 for 10 days (n = 3/group). Uterine artery endothelial proteins were mechanically isolated on Day 10. The samples were used for protein expression profiling by the Ciphergen Proteinchip system and immunoblotting analysis of endothelial nitric oxide synthase (NOS3, also termed eNOS) and caveolin 1. Uterine artery rings were cut and analyzed by immunohistochemistry to localize NOS3 and caveolin 1 expression. With the use of the IMAC3 protein chip with loading as little as 2 microg protein/sample, many protein peaks could be detected. Compared to vehicle controls, a approximately 133.1-kDa protein was identified to be upregulated by 2- to 4-fold in OVX ewes receiving E2, P4, and their combination, whereas a approximately 22.6-kDa protein was downregulated by 2- to 4-fold in OVX ewes receiving E2 and E2/P4, but not P4 treatments. Western blot analysis revealed that E2, P4, and their combination all increased NOS3 protein, whereas E2 and its combination with P4, but not P4 alone, downregulated caveolin 1 expression. Immunohistochemical analysis revealed that NOS3 was mainly localized in the endothelium and upregulated by E2, whereas caveolin 1 was localized in both endothelium and smooth muscle and downregulated by E2. Thus, our data demonstrate that uterine artery endothelial NOS3 and caveolin 1 are regulated reciprocally by estrogen replacement therapy. In keeping with the facts that E2, but not P4, causes uterine vasodilatation and that E2 and P4 increase NOS3 expression, but only E2 decrease caveolin 1 expression, our current study suggests that both increased NOS3 expression and decreased caveolin 1 expression are needed to facilitate estrogen-induced uterine vasodilatation.

Emesis may be modulated via multiple mechanisms. The actions of ghrelin suggest an ability to couple an induction of hunger with preparation of the stomach for ingestion of food. Such a process might reduce any tendency to vomit, so an anti-emetic activity of ghrelin was investigated in the ferret cisplatin-induced emesis model. In controls, intra-peritoneal cisplatin (10 mg/kg) induced 41.4+/-8.4 episodes of emesis comprising 310.4+/-55.3 retches and 28.8+/-6.9 vomits during the 6h observation; the latency to onset of the first emetic episode was 108.9+/-4.8 min. Intra-peritoneal ghrelin (1mg/kg, split as a 30 min pre- and 30 min-post dose) did not induce a change in behaviour or modify cisplatin-induced emesis (p>0.05). Intracerebroventricular (i.c.v.) administration (third ventricle) was achieved via a pre-implanted cannula. At the first emetic episode following cisplatin, ghrelin or vehicle (20 microl saline) was administered i.c.v. During the 30 min following the initial episode of emesis, control animals exhibited 18.0+/-2.6 emetic episodes comprising 160.3+/-24.1 retches and 13.8+/-2.7 vomits. Ghrelin 10 microg i.c.v. reduced the number of retches by 61.5% (p<0.05) and at a dose of 30 microg i.c.v. ghrelin reduced the number of episodes, individual retches and vomits by 74.4 (p<0.05), 80.4 (p<0.01), and 72.5% (p<0.05), respectively. At subsequent time periods there were no differences between ghrelin- or saline-treated animals (p>0.05). An ability of ghrelin to reduce emesis is consistent with a role in modulating gastro-intestinal functions and identifies a novel approach to the treatment of emesis.

The anti-emetic activity of selective NK-1 receptor antagonism is well established. However, little is known of the possibility that other NK receptors might also be involved in the emetic reflex. Given the reported location of NK-3 receptors within the rat brainstem vagal motor and sensory nuclei, we investigated the ability of SB-222200, a brain-penetrant NK-3 receptor antagonist, to interfere with emesis evoked in ferrets by the emetogenic cytotoxic agent cisplatin. In contrast to control anti-emetic experiments using the 5-HT3 receptor antagonist ondansetron, SB-222200 was found to have no effects on cisplatin-induced vomiting or on the associated reductions in feeding and drinking behaviors at any dose tested. We suggest that if NK-3 receptors are involved in the mechanisms of cisplatin-induced nausea and vomiting, they play only a minor role, relative to the major anti-emetic activity exhibited by 5-HT3 or NK-1 receptor antagonism.

Study Design: Time series monitoring changes in titanium and stainless steel rod curvature kept at a constant temperature of 37 C as a function of time., Objectives: To assess the possibility of loss of curvature in titanium rods after scoliosis surgery., Summary of Background Data: Titanium rods have gained use in scoliosis surgery due to their excellent biocompatibility, while allowing medical personnel to obtain undistorted magnetic resonance imaging scans following surgery. However, the impression of several clinicians has been that when screw pullout and/or loss of sagittal balance occurs, it may be due to the rods losing some of their curvature., Methods: Five 6-mm rods of differing compositions and lengths (titanium 300 and 100 mm, stainless steel 300 and 100 mm, prebent titanium 85 mm) were bent at room temperature with a 3-point rod bender, then placed in an incubator at 37 C. Digital photographs were taken every 2 weeks and analyzed to extract the radius of curvature of each rod., Results: The Ti rods had a significantly decreasing curvature with time. The prebent Ti and stainless steel rods did not exhibit significant change in curvature., Conclusions: Titanium rods bent at room temperature and then exposed to body temperature over time tend to exhibit "metal memory"; they gradually revert to their original shape. This may result in loss of sagittal balance and/or proximal screw pullout.

Mobilized peripheral blood stem cells (PBSCs) are widely used for transplantation, but mechanisms mediating their release from marrow are poorly understood. We previously demonstrated that the chemokines GRObeta/CXCL2 and GRObetaT/CXCL2Delta4 rapidly mobilize PBSC equivalent to granulocyte colony-stimulating factor (G-CSF) and are synergistic with G-CSF. We now show that mobilization by GRObeta/GRObetaT and G-CSF, alone or in combination, requires polymorphonuclear neutrophil (PMN)-derived proteases. Mobilization induced by GRObeta/GRObetaT is associated with elevated levels of plasma and marrow matrix metalloproteinase 9 (MMP-9) and mobilization and MMP-9 are absent in neutrophil-depleted mice. G-CSF mobilization correlates with elevated neutrophil elastase (NE), cathepsin G (CG), and MMP-9 levels within marrow and is partially blocked by either anti-MMP-9 or the NE inhibitor MeOSuc-Ala-Ala-Pro-Val-CMK. Mobilization and protease accumulation are absent in neutrophil-depleted mice. Synergistic PBSC mobilization observed when G-CSF and GRObeta/GRObetaT are combined correlates with a synergistic rise in the level of plasma MMP-9, reduction in marrow NE, CG, and MMP-9 levels, and a coincident increase in peripheral blood PMNs but decrease in marrow PMNs compared to G-CSF. Synergistic mobilization is completely blocked by anti-MMP-9 but not MeOSuc-Ala-Ala-Pro-Val-CMK and absent in MMP-9-deficient or PMN-depleted mice. Our results indicate that PMNs are a common target for G-CSF and GRObeta/GRObetaT-mediated PBSC mobilization and, importantly, that synergistic mobilization by G-CSF plus GRObeta/GRObetaT is mediated by PMN-derived plasma MMP-9.

Objective: The Siglec family of proteins consists of at least 10 members with immunoglobulin and lectin domains and with similar sialic acid-binding properties. Many Siglec family members are expressed on hematopoietic cells and are involved in cell/cell interactions. Some family members are suspected of regulating cellular processes through specific signaling pathways. Monoclonal antibodies were generated against specific epitopes of Siglec-5 (CD170) and were used to determine expression of Siglec-5 on normal blood and marrow cells and cell lines. The antibodies also were used to elucidate functional activity for Siglec-5 on blood neutrophils., Methods: Flow cytometry and ELISA were used to determine the specificity of the monoclonal antibodies for Siglec-5 and to determine expression patterns. Chemiluminescence assays were employed to measure the oxidative burst activity of whole blood or purified neutrophils following treatment with the anti-Siglec-5 antibodies., Results: Cell surface expression analysis demonstrated that the protein was expressed on gated human neutrophil and monocyte populations, both in the blood and bone marrow. Expression on neutrophils was enhanced by one-hour treatment with fMLP or TNF-alpha. Epitope-specific anti-Siglec-5 monoclonal antibodies did not directly activate human neutrophils; however, antibody binding augmented neutrophil oxidative burst activity as determined by fMLP-induced luminol-dependent chemiluminescence., Conclusion: Data demonstrating expression of Siglec-5 on cells of the myelomonocytic lineage and alteration of its expression by inflammatory stimuli suggest a role for this protein in cell/cell interactions following microbial exposure.

Using computed tomography of lumbar spine pedicles, pedicle morphology was documented in 30 patients with adolescent idiopathic scoliosis. Lumbar pedicles are relatively symmetrical in patients with adolescent idiopathic scoliosis; however, a statistically significant difference was found between males and females at L2-L4. A trend for increased transverse pedicle width was observed on the concavity versus the convexity. At levels L3-L5, 90% of the pedicles were >5.5 mm but pedicles Li and 12 were smaller, only >5.5 mm in 34% and 42%, respectively. Safe insertion of 5.5-mm screws is possible at 13-15, but more cephalic pedicles necessitate caution.

Chemokines induce rapid hematopoietic stem and progenitor cell mobilization and synergize with hematopoietic cytokines in mobilizing stem and progenitor cells. These proteins alone and in combination offer new paradigms for autologous and allogeneic peripheral blood stem cell transplantation (PBSCT). The mechanisms responsible for hematopoietic stem cell (HSC) mobilization either with growth factors or chemokines are largely unknown, but a better understanding of these mechanisms will permit the development of novel, more rapid and efficacious regimens. Studies presented herein indicate that the CXCR2 chemokine receptor that interacts with selective chemokine ligands, particularly GRObeta/CXCL2 and GRObeta-T, may be the dominant receptor mediating hematopoietic cell mobilization, and that polymorphonuclear neutrophils may be the primary CXCR2 expressing target cell for stem and progenitor cell mobilization.

The most immature lymphoid-committed progenitors in both the bone marrow (common lymphoid progenitor) and thymus (proT1) maintain a latent granulocyte/macrophage (G/M) differentiation potential that can be initiated by signals emanating from exogenously expressed IL-2 receptors. In this study, we investigate at which developmental stage thymocytes lose this G/M differentiation potential. We demonstrate that the next maturational stage after proT1 cells (proT2), but not preT (TN3) cells, can convert cell fate from lymphoid to myeloid in response to ectopic IL-2 receptor signaling in human IL-2Rbeta transgenic mice. It is significant that approximately 10% of clonogenic G/M colonies derived from proT cells of IL-2Rbeta transgenic mice have DJ rearrangement specifically at the Dbeta1 but not Dbeta2 segment in the TCRbeta locus. No TCR gene rearrangement is observed in G/M cells from nontransgenic mice, suggesting that the G/M cells we observe in this system were truly lymphoid-committed before stimulation with IL-2. In addition, Dbeta1 and Dbeta2 DJ rearrangement of the TCRbeta gene may be differentially regulated and thus serve as markers for distinct proT cell maturational stages.

There is increasing evidence that neuronal factors can affect hematopoietic cell proliferation. Endogenous opioids with specificity for several opioid receptor classes were tested for their ability to inhibit murine and human hematopoietic progenitor cell proliferation. Tyr-MIF, an opioid tetrapeptide (H-Tyr-Pro-Leu-Gly-NH2), demonstrated a dose-dependent inhibition of colony formation at concentrations < 10 uM, inhibiting M-CSF and G-CSF-responsive progenitor cells equally. Tyr-MIF did not inhibit the number of colonies responsive to recombinant interleukin 3 (rmIL-3) or recombinant murine granulocyte-macrophage colony stimulating factor (rmGM-CSF), but significantly reduced colony size of GM-CSF responsive colonies. Colony formation by human low density and CD34+ marrow cells in response to G-CSF was also inhibited by Tyr-MIF and was more sensitive to inhibition than murine progenitor cells. Colony formation by single CD34+ cells was also inhibited by Tyr-MIF, indicating an effect directly on progenitor cells. Incubation of marrow cells in liquid culture and removal of Tyr-MIF prior to quantitating progenitor cell proliferation demonstrated that opioid-induced inhibition was reversible. The inhibitory effect of Tyr-MIF was not blocked by naloxone, a mu receptor specific antagonist, or diminished in mu opioid receptor deficient mice. HPLC analysis of cell-free culture medium containing Tyr-MIF showed no presence of the parent peptide after 24 h while progenitor cell inhibitory activity was retained. Analysis of potential degradation products of Tyr-MIF indicated that only H-Gly-NH9 or H-Gly-NH2 containing peptides inhibited colony forming unit (CFU) proliferation. These results indicate that Tyr-MIF is a reversible inhibitor of mature hematopoietic progenitor cell proliferation, and that this effect is most likely mediated by the degradation product H-Gly-NH2. Potential applications including protection of myeloid cells after cytosuppresive therapy are discussed.

The recent application of new techniques, such as multi-color cell sorting and the production of transgenic and gene-knockout mice, has contributed to a better understanding of lymphocyte development from hematopoietic stem cells. Now that we can purify progenitors at different maturational stages during lymphocyte development, the challenge is to understand the processes that govern each developmental stage transition.

We mapped transcription start sites for ten unrelated protein-encoding Pyrobaculum aerophilum genes by primer extension and S(1) nuclease mapping. All of the mapped transcripts start at the computationally predicted translation start codons, two of which were supported by N-terminal protein sequencing. A whole genome computational analysis of the regions from -50 to +50 nt around the predicted translation starts codons revealed a clear upstream pattern matching the consensus sequence of the archaeal TATA box located unusually close to the translation starts. For genes with the TATA boxes that best matched the consensus sequence, the distance between the TATA box and the translation start codon appears to be shorter than 30 nt. Two other promoter elements distinguished were also found unusually close to the translation start codons: a transcription initiator element with significant elevation of C and T frequencies at the -1 position and a BRE element with more frequent A bases at position -29 to -32 (counting from the translation start site). We also show that one of the mapped genes is transcribed as the first gene of an operon. For a set of genes likely to be internal in operons the upstream signal extracted by computer analysis was a Shine-Dalgarno pattern matching the complementary sequence of P. aerophilum 16 S rRNA. Together these results suggest that the translation of proteins encoded by single genes or genes that are first in operons in the hyperthermophilic crenarchaeon P. aerophilum proceeds mostly, if not exclusively, through leaderless transcripts. Internal genes in operons are likely to undergo translation via a mechanism that is facilitated by ribosome binding to the Shine-Dalgarno sequence., (Copyright 2001 Academic Press.)

SB-251353 is an N-terminal truncated form of the human CXC chemokine GRObeta. Recombinant SB-251353 was profiled in murine and rhesus monkey peripheral blood stem cell mobilization and transplantation models. SB-251353 rapidly and transiently mobilized hematopoietic stem cells and neutrophils into the peripheral blood after a single subcutaneous injection. Transplantation of equivalent numbers of hematopoietic stem cells mobilized by SB-251353 into lethally irradiated mice resulted in faster neutrophil and platelet recovery than stem cells mobilized by granulocyte colony-stimulating factor (G-CSF). A single injection of SB-251353 in combination with 4 days of G-CSF administration resulted in augmented stem and progenitor cell mobilization 5-fold greater than G-CSF alone. Augmented stem cell mobilization could also be demonstrated in mice when a single injection of SB-251353 was administered with only one-day treatment with G-CSF. In addition, SB-251353, when used as a single agent or in combination with G-CSF, mobilized long-term repopulating stem cells capable of hematopoietic reconstitution of lethally irradiated mice. In rhesus monkeys, a single injection of SB-251353 induced rapid increases in peripheral blood hematopoietic progenitor cells at a 50-fold lower dose than in mice, which indicates a shift in potency. These studies provide evidence that the use of SB-251353 alone or in combination with G-CSF mobilizes hematopoietic stem cells with long-term repopulating ability. In addition, this treatment may (1) reduce the number of apheresis sessions and/or amount of G-CSF required to collect adequate numbers of hematopoietic stem cells for successful peripheral blood cell transplantation and (2) improve hematopoietic recovery after transplantation.

In vitro colony forming unit (CFU) assays have been used to measure the effects of compounds that regulate the growth of hematopoietic progenitor cells. These assays are time consuming and subjective and are therefore not amenable to high throughput of large numbers of compounds. Here we have shown that the traditional murine bone marrow CFU assay can be modified into a robust non-subjective colorimetric assay format. 3-[4,5-Dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) was added after colony formation in an agar based 96-well plate culture system. Optical density correlated with increasing cell input concentrations in the presence of growth factor. The linearity of this response was equivalent to the standard CFU assay. Several hematopoietic inhibitors were tested in both assays. Effects on colony number and size were compared to optical density. Compounds that reduced colony numbers with little effect on colony size had identical IC(50) values in both the colorimetric assay and CFU assay. The IC(50) values of compounds that also decreased colony size did not correlate in the two assays. These results demonstrate the utility of the colorimetric assay to rapidly screen for compounds that specifically inhibit hematopoietic progenitor cell colony formation in vitro.

The primary role of cytokines in haemato-lymphopoiesis is thought to be the regulation of cell growth and survival. But the instructive action of cytokines in haematopoiesis has not been well addressed. Here we show that a clonogenic common lymphoid progenitor, a bone marrow-resident cell that gives rise exclusively to lymphocytes (T, B and natural killer cells), can be redirected to the myeloid lineage by stimulation through exogenously expressed interleukin (IL)-2 and GM-CSF (granulocyte/macrophage colony-stimulating factor) receptors. Analysis of mutants of the beta-chain of the IL-2 receptor revealed that the granulocyte- and monocyte-differentiation signals are triggered by different cytoplasmic domains, showing that the signalling pathway(s) responsible for these unique developmental outcomes are separable. Finally, we show that the endogenous myelomonocytic cytokine receptors for GM-CSF and macrophage colony-stimulating factor (M-CSF) are expressed at low to moderate levels on the more primitive haematopoietic stem cells, are absent on common lymphoid progenitors, and are upregulated after myeloid lineage induction by IL-2. We conclude that cytokine signalling can regulate cell-fate decisions and propose that a critical step in lymphoid commitment is downregulation of cytokine receptors that drive myeloid cell development.

Study Design: Review of 27 consecutive patients who underwent video-assisted thoracoscopic surgery (VATS) in the prone position for anterior release and discectomy., Objectives: To convey the benefits and safety of this new technique for treating spinal deformities through VATS., Summary of Background Data: All reports using VATS for spinal deformities describe the patient in the lateral position. This is the first study to demonstrate the benefits and safety of the prone position., Methods: The patient is positioned prone, prepared, and draped allowing room for lateral portals on the convexity of the curve. Traditionally, a double-lumen endotracheal tube is used to deflate the ipsilateral lung. Prone positioning eliminates this need, because gravity aids in retraction of the lung., Results: All procedures were successfully performed using the VATS technique with the patient prone. After the anterior release and discectomy, posterior instrumentation (n = 27), costoplasty (n = 16), and fusion (n = 27) were performed. The time (n = 20) and blood loss (n = 16) for the anterior approach averaged 129 +/- 35 minutes and 221 +/- 231 mL, respectively. The mean number of disks resected was 3.3 +/- 0.7 (range, 2-5)., Conclusion: The prone position is both safe and effective for VATS when treating spinal deformity. The current results confirm that there is no need to insert a double-lumen tube, there is gravity-assisted correction of kyphosis when the patient is prone, and significant operative time is saved with the elimination of repositioning and redraping before the posterior procedure. Surgical times and blood loss compare very favorably with those reported for VATS in the lateral position.

The STIF (spinopelvic transiliac fixation) technique for lumbosacral fusion was developed by the authors as an alternative to the Luque-Galveston technique. The results observed in this initial series of 27 neuromuscular scoliosis patients treated with the STIF technique are reported. With a minimum of 24 months of radiographic follow-up in 19 patients, the percentage of correction of scoliosis curvature and pelvic obliquity was superior to that reported in the literature. The rates of complications and pseudarthrosis in this series are typical for this patient population. The STIF technique facilitates compression across the sacroiliac joints, which promotes sacroiliac joint fusion and can provide a stable base for curvature correction and lumbosacral fusion. Despite the severe coronal and sagittal plane curves in this group of patients, total operative time also compares favorably to that reported in the literature. The STIF technique requires a well-developed posterior iliac apophysis, which may not be present in younger pediatric patients.

We have identified a novel regulatory erythroid kinase (REDK) that is homologous to a family of dual-specificity kinases. The yeast homolog of REDK negatively regulates cell division, suggesting a similar function for REDK, which is primarily localized in the nucleus. REDK is present in hematopoietic tissues, such as bone marrow and fetal liver, but the RNA is expressed at significant levels only in erythroid or erythropoietin (EPO)-responsive cells. Two novel forms of cDNA (long and short) for REDK have been isolated that appear to be alternative splice products and imply the presence of polypeptides with differing amino termini. The ratio of short-to-long forms of REDK increases dramatically in CD34(+) cells cultured with EPO, suggesting differing regulation and function for each form. REDK is predominantly found in nuclear, rather than cytoplasmic, protein extracts, and immunoprecipitated REDK is active in phosphorylating histones H2b, H3, myelin basic protein, and other coimmunoprecipitated proteins. Antisense REDK oligonucleotides promote erythroid colony formation by human bone marrow cells, without affecting colony-forming unit (CFU)-GM, CFU-G, or CFU-GEMM numbers. Maximal numbers of CFU-E and burst-forming unit-erythroid were increased, and CFU-E displayed increased sensitivity to suboptimal EPO concentrations. The data indicate that REDK acts as a brake to retard erythropoiesis. (Blood. 2000;95:2838-2846)

SK&F 107647, a previously described synthetic immunomodulatory peptide, indirectly stimulates bone marrow progenitor cells and phagocytic cells, and enhances host defense effector mechanisms in bacterial and fungal infection models in vivo. In vitro, SK&F 107647 induces the production of a soluble mediator that augments colony forming cell (CFU-GM) formation in the presence of CSFs. In this paper we purified and sequenced the stromal cell-derived hematopoietic synergistic factors (HSF) secreted from both murine and human cell lines stimulated with SK&F 107647. Murine HSF is an N-terminal 4-aa truncated form of the CXC chemokine, KC, while human HSF was identified as an N-terminal 4-aa truncated form of the CXC chemokine, GRO beta. In comparison to their full-length forms, truncated KC and truncated GRO beta were 10 million times more potent as synergistic growth stimulants for CFU-GM. Enhanced potency of these novel truncated chemokines relative to their full-length forms was also demonstrated in respiratory burst assays, CD11b Ag expression, and intracellular killing of the opportunistic pathogen, Candida albicans. Administration of truncated KC significantly enhanced survival of mice lethally infected with C. albicans. The results reported herein delineate the biological mechanism of action of SK&F 107647, which functions via the induction of unique specific truncated forms of the chemokines KC and GRO beta. To our knowledge, this represents the first example where any form of KC or GRO beta were purified from marrow stromal cells. Additionally, this is the first demonstration of in vivo efficacy of a CXC chemokine in an animal infectious fungal disease model.

The activity of a novel series of peptidomimetic hematoregulatory compounds, designed based on a pharmacophore model inferred from the structure activity relationships of a peptide SK&F 107647 (1), is reported. These compounds induce a hematopoietic synergistic factor (HSF) which in turn modulates host defense. The compounds may represent novel therapeutic agents in the area of hematoregulation.