Topical Semisolid Drug Product Critical Quality Attributes with Relevance to Cutaneous Bioavailability and Pharmacokinetics: Part I-Bioequivalence of Acyclovir Topical Creams.

PURPOSE: To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT). METHODS: Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system. RESULTS: A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams. CONCLUSIONS: This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies.

Social Determinants of Health among Older Adults with Dementia in Urban and Rural Areas.

BACKGROUND: Social determinants of health (SDOH) may influence health in people living with dementia. Little is known about SDOH differences in urban compared to rural dwelling people living with dementia. OBJECTIVES: To explore urban-rural differences in SDOH in people living with mild cognitive impairment (MCI) and dementia. DESIGN: Descriptive study. SETTING/PARTICIPANTS: People ≥55 years with MCI or dementia empaneled to Community Internal Medicine at Mayo Clinic (Rochester, MN, USA) who completed SDOH questions between June 1, 2019 and June 30, 2021 were included. MEASUREMENTS: SDOH questions addressed education, depression, alcohol use, financial strain, food insecurity, physical activity, social connections, stress and transportation. SDOH data were compared by location based on Rural-Urban Commuting Areas Codes. RESULTS: Of 3552 persons with MCI (n=1495) or dementia (n=2057), 62% lived in urban areas, 19% in large rural, 10% in small rural and 9% in isolated areas. Approximately 60% were physically inactive, 20% socially isolated and 30% had stress concerns. Rural patients experienced greater financial strain (p=0.003). CONCLUSION: Social isolation, stress and physical inactivity are common in people living with MCI and dementia across urban and rural areas. Targeted interventions to improve physical and psychosocial health could have great impact in this population.

Expression of human thrombomodulin by GalTKO.hCD46 pigs modulates coagulation cascade activation by endothelial cells and during ex vivo lung perfusion with human blood.

Thrombomodulin is important for the production of activated protein C (APC), a molecule with significant regulatory roles in coagulation and inflammation. To address known molecular incompatibilities between pig thrombomodulin and human thrombin that affect the conversion of protein C into APC, GalTKO.hCD46 pigs have been genetically modified to express human thrombomodulin (hTBM). The aim of this study was to evaluate the impact of transgenic hTBM expression on the coagulation dysregulation that is observed in association with lung xenograft injury in an established lung perfusion model, with and without additional blockade of nonphysiologic interactions between pig vWF and human GPIb axis. Expression of hTBM was variable between pigs at the transcriptional and protein level. hTBM increased the activation of human protein C and inhibited thrombosis in an in vitro flow perfusion assay, confirming that the expressed protein was functional. Decreased platelet activation was observed during ex vivo perfusion of GalTKO.hCD46 lungs expressing hTBM and, in conjunction with transgenic hTBM, blockade of the platelet GPIb receptor further inhibited platelets and increased survival time. Altogether, our data indicate that expression of transgenic hTBM partially addresses coagulation pathway dysregulation associated with pig lung xenograft injury and, in combination with vWF-GP1b-directed strategies, is a promising approach to improve the outcomes of lung xenotransplantation.

The Complete Genome Sequence of the Simalia boeleni, the Boelen's Python.

The Boelen's Python (Simalia boeleni) is a python endemic to the mountains of New Guinea. We present the whole genome sequence of this species. Illumina sequencing was performed on a genetic sample from a single individual. The reads were assembled using a de novo method followed by a series of references from related species for finishing. The raw and assembled data is publicly available via Genbank: Sequence Read Archive (SRR19167501) and assembled genome (JANKYG000000000).

The Complete Genome Sequence of Morelia viridis, the Green Tree Python.

The Green Tree Python (Morelia viridis) is a snake native to New Guinea, some islands in Indonesia, and the Cape York Peninsula in Australia. We present the whole genome sequence for this species. Illumina sequencing was performed on a genetic sample from a single individual. The reads were assembled using a de novo method followed by a series of references from related species for finishing. The raw and assembled data are publicly available via Genbank: Sequence Read Archive (SRR19167500) and genome (JANHOE000000000).

Crop uptake of heavy metals in response to the environment and agronomic practices on land near mine tailings in the Zambian Copperbelt Province.

A field experiment was undertaken on farmers' fields adjacent to a large mine tailings dam in the Zambian mining town of Kitwe. Experimental plots were located close to the tailings (≤ 200 m) or further away (300-400 m) within the demarcated land farmed by the same community. This study evaluated the uptake of Cd, Cu, Ni, Pb and Zn by pumpkin leaves and maize grown in soil amended with lime and manure applied at agronomic rates, and the subsequent risk of dietary exposure to the local community, typical of many similar situations across the Zambian Copperbelt. Treatments, combinations of lime and manure (present or absent), were applied to subplots selected independently and randomly within each main plot, which represented variable geochemistry across this study site as a result of windblown/rain-driven dust from the tailings. Total elemental concentrations in crops were determined by ICP-MS following microwave-assisted acid digestion. Concentrations of Cu and Pb in pumpkin leaves were above the prescribed FAO/WHO safe limits by 60-205% and by 33-133%, respectively, while all five metals were below the limit for maize grain. Concentration of metals in maize grain was not affected by the amendments. However, lime at typical agronomic application rates significantly reduced concentrations of Cd, Cu, Pb and Zn in the pumpkin leaves by 40%, 33%, 19% and 10%, respectively, and for manure Cd reduced by 16%, while Zn increased by 35%. The uptake of metals by crops in locations further from the tailings was greater than closer to the tailings because of greater retention of metals in the soil at higher soil pH closer to the tailings. Crops in season 2 had greater concentrations of Cu, Ni, Pb and Zn than in season 1 due to diminished lime applied only in season 1, in line with common applications on a biannual basis. Maize as the staple crop is safe to grow in this area while pumpkin leaves as a readily available commonly consumed leafy vegetable may present a hazard due to accumulation of Cu and Pb above recommended safe limits.

Lead, Zinc and Cadmium Accumulation, and Associated Health Risks, in Maize Grown near the Kabwe Mine in Zambia in Response to Organic and Inorganic Soil Amendments.

Health risks due to heavy metal (HM) contamination is of global concern. Despite concerns of high levels of HMs in soils near Kabwe mine in Zambia, edible crop production is common, posing potential health risks. This study assessed the potential of chicken manure (CM), triple superphosphate (TSP) and a blended fertilizer (BF; consisting of Nitrogen, Phosphorous and Potassium (NPK) fertilizer and composted chicken manure) to reduce lead (Pb), zinc (Zn) and cadmium (Cd) in soils and their accumulation in maize grown near the Kabwe mine. Maize was grown to maturity and its HM concentrations and associated health risk indices were calculated. All soil amendments decreased bioavailable soil Pb concentrations by 29-36%, but only CM decreased Zn, while the amendments increased or had no effect on Cd concentrations compared to the control. The amendments reduced Pb (>25%) and Zn concentrations (>18%) in the maize stover and grain. However, Cd concentrations in maize grain increased in the BF and TSP treatments. Bioaccumulation factors showed that Cd had the highest mobility from the soil into maize stover and grain, indicating the need for greater attention on Cd in Kabwe despite its apparently lower soil concentration compared to Pb and Zn. The hazard quotients for Pb and Cd were much greater than one, indicating a high risk of possible exposure to toxic levels by people consuming maize grain grown in this area. This study demonstrated the significant potential of manure and phosphate-based amendments to reduce Pb and Zn, and to some extent Cd, uptake in maize grain and consequently reduce associated health risks.

Do soil amendments used to improve agricultural productivity have consequences for soils contaminated with heavy metals?

This study presents an analysis of the effects of manure and lime commonly used to improve agricultural productivity and evaluates the potential for such soil amendments to mobilise/immobilise metal fractions in soils contaminated from nearby mine tailings in the Zambian Copperbelt. Lime and manure were applied at the onset of the study, and their effects were studied over two planting seasons, i.e. 2016-17 and 2017-18. Operationally defined plant-available Cd, Cu, Ni, Pb and Zn in the soil, were determined by extraction with DTPA-TEA (diethylenetriaminepentaacetic acid-triethanolamine) and 0.01 M Ca(NO3)2, before, and after, applying the amendments. In unamended soils, Cd was the most available and Ni the least. Lime application decreased extractable Cd, Cu, Ni, Pb and Zn. The response to lime was greater in soils with an initially acidic pH than in those with approximately neutral pH values. Manure increased DTPA extractable Zn, but decreased DTPA and Ca(NO3)2 extractable Cd, Cu and Pb. Combined lime and manure amendment exhibited a greater reduction in DTPA extractable Cd, Ni, Pb, Zn, as well as for Ca(NO3)2 extractable Cd compared to separate applications of lime and manure. The amendments had a significant residual effect on most of the soil fractions between season 1 and 2. The results obtained in this study showed that soil amendment with minimal lime and manure whilst benefiting agricultural productivity, may significantly reduce the mobility or plant availability of metals from contaminated agricultural soils. This is important in contaminated, typical tropical soils used for crop production by resource poor communities affected by mining or other industrial activities.

Review: mine tailings in an African tropical environment-mechanisms for the bioavailability of heavy metals in soils.

Heavy metals are of environmental significance due to their effect on human health and the ecosystem. One of the major exposure pathways of Heavy metals for humans is through food crops. It is postulated in the literature that when crops are grown in soils which have excessive concentrations of heavy metals, they may absorb elevated levels of these elements thereby endangering consumers. However, due to land scarcity, especially in urban areas of Africa, potentially contaminated land around industrial dumps such as tailings is cultivated with food crops. The lack of regulation for land-usage on or near to mine tailings has not helped this situation. Moreover, most countries in tropical Africa have not defined guideline values for heavy metals in soils for various land uses, and even where such limits exist, they are based on total soil concentrations. However, the risk of uptake of heavy metals by crops or any soil organisms is determined by the bioavailable portion and not the total soil concentration. Therefore, defining bioavailable levels of heavy metals becomes very important in HM risk assessment, but methods used must be specific for particular soil types depending on the dominant sorption phases. Geochemical speciation modelling has proved to be a valuable tool in risk assessment of heavy metal-contaminated soils. Among the notable ones is WHAM (Windermere Humic Aqueous Model). But just like most other geochemical models, it was developed and adapted on temperate soils, and because major controlling variables in soils such as SOM, temperature, redox potential and mineralogy differ between temperate and tropical soils, its predictions on tropical soils may be poor. Validation and adaptation of such models for tropical soils are thus imperative before such they can be used. The latest versions (VI and VII) of WHAM are among the few that consider binding to all major binding phases. WHAM VI and VII are assemblages of three sub-models which describe binding to organic matter, (hydr)oxides of Fe, Al and Mn and clays. They predict free ion concentration, total dissolved ion concentration and organic and inorganic metal ion complexes, in soils, which are all important components for bioavailability and leaching to groundwater ways. Both WHAM VI and VII have been applied in a good number of soils studies with reported promising results. However, all these studies have been on temperate soils and have not been tried on any typical tropical soils. Nonetheless, since WHAM VII considers binding to all major binding phases, including those which are dominant in tropical soils, it would be a valuable tool in risk assessment of heavy metals in tropical soils. A discussion of the contamination of soils with heavy metals, their subsequent bioavailability to crops that are grown in these soils and the methods used to determine various bioavailable phases of heavy metals are presented in this review, with an emphasis on prospective modelling techniques for tropical soils.

Inappropriate Medication Use in Hospitalized Patients Diagnosed with Parkinson's Disease.

The purpose of this study was to evaluate the rate at which potentially inappropriate medications were administered for patients diagnosed with Parkinson's disease (PD). This is a single-center, retrospective, case cohort study with data collected at an academic medical center between January 2010 and December 2013. Participants included all adult patients with admission diagnosis codes for PD. Included patients were screened for administrations of 27 potentially inappropriate medications and two potentially appropriate medications to be used for comparison. There were 1736 patients who met inclusion criteria with 175 documented administrations of potentially inappropriate medications to 77 patients. Patients who received potentially inappropriate medications had a longer mean duration of stay than the baseline population of PD patients (3.3 days vs. 1.9 days, p-value < 0.001). Despite recommendations to avoid certain medications in PD patients, a substantial number of administrations still occurred. The use of these medications can have clinical implications and our findings demonstrate increases in duration of stay. The findings from this study can assist in developing technological alerts to reduce inappropriate prescribing to PD patients. Larger prospective studies are warranted to further investigate the administration of inappropriate medications to patients diagnosed with PD.

Fourteen days of etoricoxib 60 mg improves pain, hyperalgesia and physical function in individuals with knee osteoarthritis: a randomized controlled trial.

OBJECTIVE: Mounting evidence points to the heterogeneity of osteoarthritis (OA) pain, increasing the need for more comprehensive assessment of the efficacy of standard interventions. This study investigated whether 14 days of the selective Cox-2 inhibitor etoricoxib (60 mg/day) would modify self-report of pain intensity and quality, and physical measures of hyperalgesia and function in individuals with knee OA. DESIGN: This double-blind placebo-controlled trial included 80 community-recruited volunteers with painful knee OA (≥3/10 VAS), randomly allocated to Active or Placebo groups. Self-report measures of pain, stiffness, function Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and pain quality (PainDETECT, Pain Quality Assessment Scale [PQAS]) and physical measures of locomotion and local (knee) and widespread (elbow) hyperalgesia were assessed at Days 0, 4 and 14. Repeated Measures ANOVA analysed group differences. RESULTS: Significant group × time interaction effects were found for all measures of pain (all p < 0.001), with WOMAC pain sub-score improving by 30.7% by Day 14 and index knee mechanical hyperalgesia improving by 32.6%, whilst Placebo group values worsened. Both self-report and physical tests of function improved (p < 0.001-p = 0.006): WOMAC-function by 28.4%, sit-to-stand and walk time by 13%, pain during locomotion tasks by 12.4-32.6%. Pain quality also significantly improved for the Active and declined for the Placebo group (p < 0.001): PainDETECT score reduced by 23.6% and PQAS paroxsysmal and surface sub-scores by 36.9% and 29.4%. There were also significant improvements in local cold hyperalgesia and widespread mechanical hyperalgesia (10-13.8%). CONCLUSION: Just 14 days of etoricoxib significantly improves pain intensity and quality, function and local and widespread hyperalgesia, measured by both self-report and physical tests.

Human skin penetration and local effects of topical nano zinc oxide after occlusion and barrier impairment.

Public health concerns continue to exist over the safety of zinc oxide nanoparticles that are commonly used in sunscreen formulations. In this work, we assessed the effects of two conditions which may be encountered in everyday sunscreen use, occlusion and a compromised skin barrier, on the penetration and local toxicity of two topically applied zinc oxide nanoparticle products. Caprylic/capric triglyceride (CCT) suspensions of commercially used zinc oxide nanoparticles, either uncoated or with a silane coating, were applied to intact and barrier impaired skin of volunteers, without and with occlusion for a period of six hours. The exposure time was chosen to simulate normal in-use conditions. Multiphoton tomography with fluorescence lifetime imaging was used to noninvasively assess zinc oxide penetration and cellular metabolic changes that could be indicative of toxicity. We found that zinc oxide nanoparticles did not penetrate into the viable epidermis of intact or barrier impaired skin of volunteers, without or with occlusion. We also observed no apparent toxicity in the viable epidermis below the application sites. These findings were validated by ex vivo human skin studies in which zinc penetration was assessed by multiphoton tomography with fluorescence lifetime imaging as well as Zinpyr-1 staining and toxicity was assessed by MTS assays in zinc oxide treated skin cryosections. In conclusion, applications of zinc oxide nanoparticles under occlusive in-use conditions to volunteers are not associated with any measurable zinc oxide penetration into, or local toxicity in the viable epidermis below the application site.

Analysing the skin barrier from down under.

Over the past 40 years the Australian contribution to the field of skin science has been led by Michael Roberts. One of his earliest papers on membrane permeation was published in Nature, setting the scene for his huge contribution to both the fundamental understanding of skin permeability and the application of that knowledge to improved clinical outcomes, new delivery technologies and minimizing toxicological risk. His work has been characterized by a mechanistic, mathematical approach to defining skin permeation. He defined the parameters important to skin permeation, established structure-penetration relationships and demonstrated the importance of maximum flux from a clinical and toxicological viewpoint. Through his systematic approach, Mike showed a parabolic relationship between maximum flux and lipophilicity, and established that this is driven mainly by variations in solubility of the solute in the stratum corneum. One of the significant strengths of Mike's work is the ability to express biological concepts in mathematical terms. He has developed mathematical models that enhance our understanding of epidermal, dermal, deep tissue permeation and follicular transport. Throughout his career Mike has been involved in pioneering new technologies both for analysing the skin barrier and influencing permeation across it. His fundamental work in the area of iontophoresis provided models that defined the parameters influencing its permeation enhancement. Mike's research has been translated into improved clinical outcomes, reduced toxicological risk and changes to the regulation of skin products. This article provides an insight into Mike Roberts and the Australian contribution to skin science.

Effect of angiotensin II type I receptor blocker losartan on bone deterioration in orchiectomized male hypertensive and normotensive rats.

BACKGROUND: Epidemiological study showed that the use of angiotensin-converting enzyme inhibitors was associated with higher bone mineral density (BMD) in older people, especially male subjects, which suggested that angiotensin II may have a detrimental effect on bone. Therefore, blocking its effect may have a beneficial effect on bone health. METHODS: Six-month-old male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) were used. Animals of each model were randomly assigned to the following four groups: Group 1, SHAM operated+vehicle; Group 2, orchidectomy (ORX)+vehicle; Group 3, ORX+low-dose losartan (10 mg×kg(-1)×d(-1)); and Group 4, ORX+high-dose losartan (25 mg×kg(-1)×d(-1)). Blood pressure was recorded weekly. SHAM and ORX operations were performed, followed by daily losartan and vehicle treatment from day 4 after operation for 16 weeks. Serum and 24-hour urine samples were collected for measurement of bone turnover markers before euthanasia and then the left femur was collected for measurements of BMD and microarchitecture before mechanical test. RESULTS: Urine deoxypyridinoline/urine creatinine (DPD/Cr) ratio was significantly higher in SHR than in WKY. BMD and microarchitecture parameters also showed bone deterioration in SHR. After ORX, serum osteocalcin concentration decreased and urine DPD/Cr ratio increased significantly accompanied by a significant decrease in cortical and trabecular BMD and cortical bone thickness in both WKY and SHR. High-dose losartan significantly increased DPD in urine in both SHR and WKY. Apart from marginal favorable changes in bone architecture in WKY treated with high-dose losartan, losartan did not show significant effect on BMD, bone area, bone microarchitecture, and mechanical properties in both SHR and WKY. CONCLUSION: Angiotensin II type I receptor blocker losartan was not able to demonstrate significant effect on ORX-induced bone deterioration in both hypertensive and normotensive rats.

Targeted DNA methylation analysis by high throughput sequencing in porcine peri-attachment embryos.

The purpose of this experiment was to implement and evaluate the effectiveness of a next-generation sequencing-based method for DNA methylation analysis in porcine embryonic samples. Fourteen discrete genomic regions were amplified by PCR using bisulfite-converted genomic DNA derived from day 14 in vivo-derived (IVV) and parthenogenetic (PA) porcine embryos as template DNA. Resulting PCR products were subjected to high-throughput sequencing using the Illumina Genome Analyzer IIx platform. The average depth of sequencing coverage was 14,611 for IVV and 17,068 for PA. Quantitative analysis of the methylation profiles of both input samples for each genomic locus showed distinct differences in methylation profiles between IVV and PA samples for six of the target loci, and subtle differences in four loci. It was concluded that high throughput sequencing technologies can be effectively applied to provide a powerful, cost-effective approach to targeted DNA methylation analysis of embryonic and other reproductive tissues.

Effect of angiotensin II type I receptor blocker losartan on bone deterioration in orchiectomized male hypertensive and normotensive rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Epidemiological study showed that the use of angiotensin-converting enzyme inhibitors was associated with higher bone mineral density (BMD) in older people, especially male subjects, which suggested that angiotensin II may have a detrimental effect on bone. Therefore, blocking its effect may have a beneficial effect on bone health.</p><p><b>METHODS</b>Six-month-old male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) were used. Animals of each model were randomly assigned to the following four groups: Group 1, SHAM operated+vehicle; Group 2, orchidectomy (ORX)+vehicle; Group 3, ORX+low-dose losartan (10 mg×kg(-1)×d(-1)); and Group 4, ORX+high-dose losartan (25 mg×kg(-1)×d(-1)). Blood pressure was recorded weekly. SHAM and ORX operations were performed, followed by daily losartan and vehicle treatment from day 4 after operation for 16 weeks. Serum and 24-hour urine samples were collected for measurement of bone turnover markers before euthanasia and then the left femur was collected for measurements of BMD and microarchitecture before mechanical test.</p><p><b>RESULTS</b>Urine deoxypyridinoline/urine creatinine (DPD/Cr) ratio was significantly higher in SHR than in WKY. BMD and microarchitecture parameters also showed bone deterioration in SHR. After ORX, serum osteocalcin concentration decreased and urine DPD/Cr ratio increased significantly accompanied by a significant decrease in cortical and trabecular BMD and cortical bone thickness in both WKY and SHR. High-dose losartan significantly increased DPD in urine in both SHR and WKY. Apart from marginal favorable changes in bone architecture in WKY treated with high-dose losartan, losartan did not show significant effect on BMD, bone area, bone microarchitecture, and mechanical properties in both SHR and WKY.</p><p><b>CONCLUSION</b>Angiotensin II type I receptor blocker losartan was not able to demonstrate significant effect on ORX-induced bone deterioration in both hypertensive and normotensive rats.</p>

Potential reproductive toxicity of Largehead Atractylodes Rhizome, the most commonly used Chinese medicine for threatened miscarriage.

BACKGROUND: Largehead Atractylodes Rhizome (LAR) is the most commonly used Chinese medicine to prevent early pregnancy loss due to threatened miscarriage. However, its safety profile during pregnancy is still not available. Here we aimed to identify the potential adverse effects of LAR on embryo-fetal development as well as prenatal and post-natal growth. METHODS: Pregnant mice, rats and rabbits were orally administered with LAR extracts in various doses (from 1×, 2×, 3× and up to 6× clinical doses) at different gestational periods (implantation, gastrulation, organogenesis, maturation and whole gestation). Maternal effects on weight loss, implantation failure and fetal resorption and perinatal effects on developmental delay, growth restriction and congenital malformations were studied. RESULTS: In mice, with early LAR exposure, a significant decrease in fetal growth parameters and a significant increase in post-implantation loss were identified. With late LAR exposure, significant increases in gestational duration as well as prenatal and post-natal mortality were found. At high clinical doses, congenital skeletal malformations were recorded. In rabbits, fetal resorption, hydrops fetalis and short ear anomaly were observed. No significant adverse effects were found in rats. CONCLUSIONS: Potential reproductive toxicity of LAR in pregnant animals was identified within the clinical dose. Caution should be taken in clinical applications of LAR during pregnancy.

A novel statistical morphometry imaging method for differentiating long bone geometry: methodological development and application with adolescent idiopathic scoliosis (AIS) patients.

Non-invasive quantification of bone shape is crucial in orthopaedic research. The primary objective of this study was to develop an automated statistical morphometry method for comparing the cross-sectional images of normal and diseased bones. The secondary objective involved demonstrating the effectiveness of the proposed method in distinguishing AIS patients from normal controls. This framework is composed of bone segmentation followed by measurements of maximum and minimum bone diameters, inter-group and intra-group statistical morphometry, and statistical analysis of bone thickness. The proposed framework was applied to detect bone morphological abnormality in adolescent idiopathic scoliosis (AIS) patients. The forearm bones in cross-sectional peripheral quantitative computed tomography (pQCT) images from 23 AIS patients and 16 normal controls were analyzed. The radius outer contour was found to be rounder and the radius cortical bone was thinner in AIS patients compared to normal controls.

Neutralizing IL-17 prevents obliterative bronchiolitis in murine orthotopic lung transplantation.

Obliterative bronchiolitis (OB) is the key impediment to the long-term survival of lung transplant recipients and the lack of a robust preclinical model precludes examining OB immunopathogenesis. In the current study, lungs from C57BL/10 H-2(b) mice that are MHC compatible, but minor histocompatability antigen incompatible, were transplanted into C57BL/6 mice. Histological features and cytokine profiles of OB were assessed. Moderate rejection (grade A3) developed by day 14, with evidence of OB at that time point. At 21 days, OB was present in 55% of grafts and moderate to severe rejection (grade A3-A4) was present in all mice. At 28 days, OB was present in 44% of mice and severe rejection (grade A4) was present in all. IL-17A, but not IL-17F, splenic mRNA transcripts and serum protein levels were increased only in mice that developed OB, whereas IL-10 transcripts and protein were increased only in non-OB mice. Neutralizing IL-17 prevented OB, down regulated acute rejection, and upregulated systemic IL-10. Collectively, these data show that transplantation of minor histoincompatible lungs from C57BL/10 mice into C57BL/6 mice results in a highly reproducible preclinical model of OB. In addition, these data indicate that neutralizing IL-17A or augmenting IL-10 could be therapeutic interventions to prevent OB.