Effects of 24 Weeks of a Supervised Walk Training on Knee Muscle Strength and Quality of Life in Older Female Total Knee Arthroplasty: A Retrospective Cohort Study.

Poor supervision, impaired exercise adherence, and low compliance with exercise regimens result in inconsistent effects regarding exercise interventions. A supervised-walk training regimen (9 km/week) may have a positive effect on functional recovery in female total knee arthroplasty (TKA). This study aimed to evaluate the effect of a supervised walking regimen on lower limb muscle strength, functional fitness, and patient-reported outcomes in female TKA. Twenty-eight female TKA were allocated into a control (CON) (n = 14) or walk training (WT) (n = 14) group. WT on treadmills was initiated 12 weeks after TKA. All patients were examined for lower muscle strength (including extension and flexion of hip and knee), physical function (including a 6-min walk test, 8-foot up-and-go test, and 30-s chair stand test), and Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Knee flexor (WT: CON; 64.4 ± 4.1 nm/kg: 43.7±3.3 nm/kg; p = 0.001; effect size: 5.62) and extensor strengths (WT: CON; 73.1 ± 7.5 nm/kg: 48.2 ± 2.4 nm/kg; p = 0.001; effect size: 4.47) statistically increased in the WT group compared to the CON group. The 6-min walk test (from 341.3 ± 20.5 m to 405.5 ± 30.7 m; p = 0.001; effect size: 2.46) and 8-foot up-and-go test (from 9.5 ± 0.7 s to 8.3 ± 0.7 s; p = 0.002; effect size: 1.71) tests also showed significant improvements in the WT group in the follow-up compared to the baseline. An increase in quality of life score according to the KOOS questionnaire (WT: CON; 91.0 ± 2.8: 68.1 ± 5.8; p = 0.001; effect size: 5.02) was noted in the WT group compared to the CON group in the follow-up. WT facilitated improvements in knee muscle strength and functional outcomes in TKA patients.

Effect of resistance training on satellite cells in old mice - a transcriptome study : implications for sarcopenia.

AIMS: The decrease in the number of satellite cells (SCs), contributing to myofibre formation and reconstitution, and their proliferative capacity, leads to muscle loss, a condition known as sarcopenia. Resistance training can prevent muscle loss; however, the underlying mechanisms of resistance training effects on SCs are not well understood. We therefore conducted a comprehensive transcriptome analysis of SCs in a mouse model. METHODS: We compared the differentially expressed genes of SCs in young mice (eight weeks old), middle-aged (48-week-old) mice with resistance training intervention (MID+ T), and mice without exercise (MID) using next-generation sequencing and bioinformatics. RESULTS: After the bioinformatic analysis, the PI3K-Akt signalling pathway and the regulation of actin cytoskeleton in particular were highlighted among the top ten pathways with the most differentially expressed genes involved in the young/MID and MID+ T/MID groups. The expression of Gng5, Atf2, and Rtor in the PI3K-Akt signalling pathway was higher in the young and MID+ T groups compared with the MID group. Similarly, Limk1, Arhgef12, and Araf in the regulation of the actin cytoskeleton pathway had a similar bias. Moreover, the protein expression profiles of Atf2, Rptor, and Ccnd3 in each group were paralleled with the results of NGS. CONCLUSION: Our results revealed that age-induced muscle loss might result from age-influenced genes that contribute to muscle development in SCs. After resistance training, age-impaired genes were reactivated, and age-induced genes were depressed. The change fold in these genes in the young/MID mice resembled those in the MID + T/MID group, suggesting that resistance training can rejuvenate the self-renewing ability of SCs by recovering age-influenced genes to prevent sarcopenia. Cite this article: Bone Joint Res 2022;11(2):121-133.

Three-dimensional condylar changes from Herbst appliance and multibracket treatment: A comparison with matched Class II elastics.

INTRODUCTION: The purpose of this study was to quantify and qualify the 3-dimensional (3D) condylar changes using mandibular 3D regional superimposition techniques in adolescent patients with Class II Division 1 malocclusions treated with either a 2-phase or single-phase approach. METHODS: Twenty patients with Herbst appliances who met the inclusion criteria and had cone-beam computed tomography (CBCT) images taken before, 8 weeks after Herbst removal, and after the completion of multibracket appliance treatment constituted the Herbst group. They were compared with 11 subjects with Class II malocclusion who were treated with elastics and multibracket appliances and who had CBCT images taken before and after treatment. Three-dimensional models generated from the CBCT images were registered on the mandible using 3D voxel-based superimposition techniques and analyzed using semitransparent overlays and point-to-point measurements. RESULTS: The magnitude of lateral condylar growth during the orthodontic phase (T2-T3) was greater than that during the orthopedic phase (T1-T2) for all condylar fiducials with the exception of the superior condyle (P <0.05). Conversely, posterior condylar growth was greater during the orthopedic phase than the subsequent orthodontic phase for all condylar fiducials (P <0.05). The magnitude of vertical condylar development was similar during both the orthopedic (T1-T2) and orthodontic phases (T2-T3) across all condylar fiducials (P <0.05). Posterior condylar growth during the orthodontic phase (T2-T3) of the 2-phase approach decreased for all condylar fiducials with the exception of the posterior condylar fiducial (P <0.05) when compared with the single-phase approach. CONCLUSIONS: Two-phase treatment using a Herbst appliance accelerates condylar growth when compared with a single-phase regime with Class II elastics. Whereas the posterior condylar growth manifested primarily during the orthopedic phase, the vertical condylar gains occurred in equal magnitude throughout both phases of the 2-phase treatment regime.

3D assessment of mandibular skeletal effects produced by the Herbst appliance.

BACKGROUND: A functional appliance is commonly used to optimize the development of the facial skeleton in the treatment of Class II malocclusion. Recent three-dimensional(3D) image-based analysis offers numerous advantages in quantitative measurement and visualization in orthodontics. The aim of this study was to localize in 3D the skeletal effect produced by the Herbst appliance on the mandible using the geometric morphometric technique. METHODS: Twenty patients treated with a Herbst appliance and subsequent fixed appliances were included. Cone-beam computed tomography (CBCT) images were taken before treatment (T1), 8 weeks after Herbst appliance removal (T2), and after subsequent fixed appliance treatment (T3). Spatially dense morphometric techniques were used to establish the corresponding points of the mandible. The mandibular morphological changes from T1-T2, T2-T3, and T1-T3 were calculated for each patient by superimposing two mandibular models at two time points with robust Procrustes superimposition. These changes were then compared to the morphological changes estimated from normative mandibular growth curves over the same period. The proportion of cases exceeding the growth expression for controls was compared to a normal population using a one tailed binomial test. RESULTS: Approximately 1.5-2 mm greater condylar changes and 0.5 mm greater changes in the chin occurred from Tl to T2. This effect lasted until the completion of treatment (T1-T3), but there was no obvious skeletal effect during the orthodontic phase (T2-T3). Approximately 40-50% of the patient sample exceeded condylar growth by > 1.5 mm compared to untreated controls (p < .05). However, changes at the chin were not statistically significant. CONCLUSIONS: The principal skeletal effect of Herbst appliance treatment was additional increase in condylar length for about half of the sample. This inconsistency may relate to the degree of mandibular growth suppression associated with a specific malocclusion.

Reversible, orally available ADP receptor (P2Y12) antagonists Part I: Hit to lead process.

A hit to lead process to identify reversible, orally available ADP receptor (P2Y12) antagonists lead compounds is described. High throughput screening afforded 1. Optimization of 1, using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an orally available, competitive reversible antagonist (KB = 94 nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low, reasonable levels were achieved to merit extensive lead optimization of this structural class.

Impact of early versus late systemic lupus erythematosus diagnosis on clinical and economic outcomes.

BACKGROUND AND OBJECTIVES: Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease that often mimics symptoms of other illnesses, which complicates the ability of healthcare providers to make the diagnosis. The objective of this study was to assess clinical outcomes, resource utilization, and costs between patients with earlier versus later SLE diagnosis. METHODS: Patients aged 18-64 years were identified from a large US commercial claims database between January 2000 and June 2010. Confirmed SLE diagnosis with a claims-based algorithm required either three or more claims for a visit to a rheumatologist on separate dates with an SLE diagnosis (International Classification of Diseases [ICD-9] code 710.0x), two or more claims for visits to a rheumatologist at least 60 days apart with SLE diagnoses, or two or more claims for visits to rheumatologist less than 60 days apart with SLE diagnoses with at least one dispensing for a typical SLE medication. SLE probable onset date was identified during the 12-month baseline period by the second claim for antinuclear antibody tests or prodromal symptoms of SLE. Patients were stratified into early or late diagnosis groups based on time between probable SLE onset and diagnosis (<6 months or ≥6 months, respectively). Each patient observation period began on the date of the first medical claim, with a diagnosis code for SLE that satisfied the inclusion criteria, and ended on the earliest date between health plan disenrollment and 30 June 2010. Patients in each group were propensity-score matched on age, gender, diagnosis year, region, health plan type, and comorbidities. Flare rates and resource utilization were compared post-diagnosis between groups using rate ratios. All-cause and SLE-related costs (adjusted to 2010 US dollars) per patient per month (PPPM) were calculated. RESULTS: There were 4,166 matched patients per group. Post-SLE diagnosis, the early diagnosis group had lower rates of mild (rate ratio [RR] 0.95; 95 % CI 0.93-0.96), moderate (RR 0.96; 95 % CI 0.94-0.99), and severe (RR 0.87; 95 % CI 0.82-0.93) flares compared with the late diagnosis group. The rates of hospitalizations (RR 0.80; 95 % CI 0.75-0.85) were lower for the early diagnosis group than the late diagnosis group. Compared with late diagnosis patients, mean all-cause inpatient costs PPPM were lower for the early diagnosis patients (US$406 vs. US$486; p = 0.016). Corresponding SLE-related hospitalization costs were also lower for early compared with late diagnosis patients (US$71 vs. US$95; p = 0.013). Results were consistent for other resource use and cost categories. CONCLUSIONS: Patients diagnosed with SLE sooner may experience lower flare rates, less healthcare utilization, and lower costs from a commercially insured population perspective. This finding needs to be further explored within the context of background SLE disease activity.

Matching-adjusted indirect comparison of adalimumab vs etanercept and infliximab for the treatment of psoriatic arthritis.

OBJECTIVES: No head-to-head trial has compared the efficacy of adalimumab vs etanercept and infliximab for psoriatic arthritis (PsA). This study implements a matching-adjusted indirect comparison technique to address that gap. METHODS: Patient-level data from a placebo-controlled trial of adalimumab (ADEPT) were re-weighted to match average baseline characteristics from pivotal published trials of etanercept and infliximab. ADEPT patients were re-weighted by odds of enrollment in comparator trials, estimated using logistic regression. Matched-on characteristics included PsA duration, age, gender, severity, active psoriasis, and concomitant treatment. After matching, placebo-adjusted treatment arms were compared at weeks 12 (or 14) and 24. Outcomes included ACR20/50/70, PsARC, HAQ, and modified TSS. PASI50/75/90 were compared for patients with active psoriasis. Cost per responder (CPR) was assessed in the US and Germany using matching-adjusted end-points and drug list prices. Statistical significance was assessed using weighted t-tests. RESULTS: After matching, adalimumab-treated patients had greater placebo-adjusted rates of ACR70 and PASI50/75/90 at week 24 compared with etanercept (all p < 0.05). Adalimumab patients had a higher placebo-adjusted rate of ACR70 than infliximab at week 14 (p = 0.034). Adalimumab treatment had lower CPR for ACR70 and PASI50/75/90 compared with etanercept at week 24, in both the US and Germany (all p < 0.02). Adalimumab had lower CPR than infliximab for all outcomes at week 24 (all p < 0.05). CONCLUSION: Adalimumab is associated with higher ACR70 and PASI50/75/90 response rates than etanercept at week 24 and a higher ACR70 response rate than infliximab at week 14. Adalimumab has significant advantages over etanercept and infliximab in CPR across multiple end-points. KEY LIMITATIONS: The matching-adjusted indirect comparison method cannot account for unobserved differences in patient characteristics across trials, and only a head-to-head randomized clinical trial can fully avoid the limitations of indirect comparisons. CPR findings are limited to the US and German markets, and may not be generalizable to other markets with different relative pricing.

Risk of hepatotoxicity-related hospitalizations among patients treated with opioid/acetaminophen combination prescription pain medications.

OBJECTIVE: This study determined the risk of serious hepatotoxicity resulting in hospitalizations among patients prescribed opioid/acetaminophen combinations. METHODS: A retrospective cohort study using an insurance claims database was conducted. Adult patients with ≥1 claim for oxycodone/acetaminophen or hydrocodone/acetaminophen combinations were included (N = 1,228,356). A pre-post design was employed to compare serious hepatotoxicity risk before versus after initiation of opioid/acetaminophen combination. Serious hepatotoxicity risk between the opioid/acetaminophen group and a control group of opioid-alone users (N = 11,809) was also examined. Within the opioid/acetaminophen group, risk of hepatotoxicity-related hospitalizations pre- versus post-opioid/acetaminophen treatment was compared using the normal approximation with the binomial distribution. The incidence rate of hepatotoxicity-related hospitalizations for the opioid/acetaminophen group was compared with the opioid-alone group using multivariate Poisson regression adjusting for baseline differences between groups. RESULTS: Of the opioid/acetaminophen cohort, hepatotoxicity-related hospitalization risk in the 6-month post-opioid/acetaminophen period was lower than that in the pre-period with a risk reduction of 1.2 per 10,000 (pre-period = 0.12%; 95% confidence interval [CI], 0.12 to 0.13; post-period = 0.11%; 95% CI, 0.11 to 0.12). In the 12-month period, risk increased in the post-period by 2.4 per 10,000 (pre-period = 0.14%; 95% CI, 0.14 to 0.15; post-period = 0.17%; 95% CI, 0.16 to 0.18). After adjusting for confounders, the opioid-alone group did not demonstrate a lower rate of hepatotoxicity-related hospitalizations than the opioid/acetaminophen group (incidence rate ratio of opioid-alone over opioid/acetaminophen = 2.9; 95% CI, 1.8 to 4.7). CONCLUSIONS: There is no population data-based evidence supporting elevated risk of hepatotoxicity-related hospitalization associated with opioid/acetaminophen combinations.

Comparing healthcare costs of Medicaid patients with postherpetic neuralgia (PHN) treated with lidocaine patch 5% versus gabapentin or pregabalin.

OBJECTIVE: To compare healthcare resource utilization and costs of postherpetic neuralgia (PHN) patients initiating lidocaine patch 5% (lidocaine patch) or oral gabapentin/pregabalin. METHODS: Patients with PHN diagnosis, or herpes zoster diagnosis and ≥30 days PHN-recommended treatment were selected from de-identified Medicaid claims data from Florida, Iowa, Missouri, and New Jersey, 1999-2007. Patients initiated monotherapy with lidocaine patch or gabapentin/pregabalin after PHN diagnosis, had continuous eligibility 6 months before (baseline) and 6 months after (study period) medication index date, and were ≥18 years old. Lidocaine patch patients were matched to gabapentin/pregabalin patients based on their propensity to initiate treatment. Study period resource utilization and costs from a Medicaid perspective were compared between treatment groups using univariate analysis. RESULTS: Matched patients were on average 61.3 years old, approximately 73% were women, and 55% had other painful conditions during the baseline period. 6-month per patient PHN-related prescription drug costs were similar for matched lidocaine patch (n=312) and gabapentin/pregabalin (n=312) patients ($854 vs. 820, p=0.75), while PHN-related medical costs appeared lower in the lidocaine patch group ($145 vs. 353, p=0.12). Furthermore, there were no statistically significant differences between treatment groups during the observation period in overall resource utilization, total prescription drug costs, and total medical costs per patient. CONCLUSIONS: In spite of higher list prices, PHN patients treated with lidocaine patch cost no more than patients treated with gabapentin or pregabalin in terms of overall healthcare costs over the 6-month study period. The study suggests that PHN-related medical costs may be lower among lidocaine patch patients. LIMITATIONS: Findings are based on a Medicaid sample and may not be generalizable to all PHN patients.

Descriptive analysis of Medicaid patients with postherpetic neuralgia treated with lidocaine patch 5%.

OBJECTIVES: To compare demographic and comorbidity profiles and healthcare costs of Medicaid patients with postherpetic neuralgia (PHN) treated with lidocaine patch 5% (lidocaine patch) versus patients not treated with the lidocaine patch. Repeat comparison for the subset of patients treated in long-term care (LTC) settings. METHODS: Patients, age≥18 years, with PHN diagnosis, or PHN-likely patients with herpes zoster diagnosis and ≥30 days of PHN-recommended treatment, were identified in Medicaid claims from Florida, Iowa, Missouri, and New Jersey (1999-2007). Patients had continuous eligibility 6 months before (baseline) and 12 months after (study period) the PHN index date. Patients with ≥1 claim for a lidocaine patch during the study period (n=872) were compared to patients without a lidocaine patch claim (comparison group). Baseline characteristics, study period treatment and healthcare costs (reimbursements by Medicaid for medical services and prescription drugs) were compared between groups using univariate analyses. RESULTS: PHN patients in the lidocaine patch group were older (64.5 vs. 62.2 years; p=0.002) and had higher rates of pain-related comorbidities (e.g., back/neck pain, osteoarthritis) than comparison patients. Average PHN-related drug costs per patient were higher ($1994 vs. 1137; p<0.0001) among lidocaine patch patients, with lidocaine patch accounting for $505 of the difference. PHN-related medical costs appeared lower in the lidocaine patch group, although not statistically significant ($983 vs. 1294; p=0.1348). No significant differences were found in total healthcare costs ($20,175 vs. 19,124; p=0.3720) across groups, despite higher total prescription drug costs among lidocaine patch patients. A similar pattern was observed among LTC patients. CONCLUSIONS: Despite higher rates of comorbidities and prescription drug costs, lidocaine patch patients had similar study period healthcare costs as comparison patients. The cost of the lidocaine patch represented a small fraction of overall costs incurred over the study period. LIMITATIONS: Findings are based on a Medicaid sample and may not be generalizable to all PHN patients.

Differential expression of proteins induced by lead in the Dwarf Sunflower Helianthus annuus.

The Dwarf Sunflower (Helianthus annuus) is a hyperaccumulator of toxic metals including cadmium (Cd), mercury (Hg), nickel (Ni), and lead (Pb). In order to identify stress response to Pb, plants were exposed to a mixture of 30 mg/l of three ions, Cd, Cr, and Ni, with and without Pb. Soluble proteins were resolved by two-dimensional gel electrophoresis. Four proteins were differentially expressed and very abundant in the leaf samples after plants were exposed to all these four metals. The first protein spot contained two proteins: chitinase and a chloroplast drought-induced stress protein CDSP-34. The second spot contained a thaumatin-like protein. Two proteins in spot 3 were identified as heat-shock cognate 70-1 and the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase. Several peptides were identified in spot 4 but none could be matched to any sequence in the NCBI database.

Spinal learning in the adult mouse using the Horridge paradigm.

The spinal cord is endogenously capable of several forms of adaptive plasticity and learning, including functional re-training, instrumental, and Pavlovian learning. Understanding the mechanisms of spinal plasticity could lead to improved therapies for spinal cord injury and other neuromotor disorders. We describe and demonstrate techniques for eliciting spinal learning in the adult mouse using the Horridge paradigm. In the Horridge paradigm, instrumental learning occurs when a nociceptive leg stimulus is made to be contingent on leg position and the spinal cord learns to maintain the ankle in a flexed position. Using fine-wire intramuscular stimulating electrodes, an inexpensive real-time video tracking system, and DC current stimulation, we were able to elicit instrumental spinal learning from mouse lumbrosacral spinal cords that were functionally isolated from the brain. This technique makes it more feasible to use the powerful genetic manipulations available in mice to better understand the processes of spinal learning, memory, and plasticity.

Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A4 hydrolase.

The synthesis and biological evaluation of a series of N-alkyl glycine amide analogs as LTA(4)-h inhibitors and the importance of the introduction of a benzoic acid group to the potency and pharmacokinetic parameters of our analogs are described. The lead compound in the series, 4q, has excellent potency and oral bioavailability.

Discovery of novel and potent aryl diamines as leukotriene A4 hydrolase inhibitors.

The synthesis and biological evaluation of a series of aryl diamines as inhibitors of LTA(4)-h inhibitors are described. The optimization which led to the identification of the optimal para-substitution on the diphenyl ether moiety and diamine spacer is discussed. The resulting compounds such as 3l have excellent enzyme and cellular potency as well as desirable pharmacokinetic properties.

Hydroponic phytoremediation of Cd, Cr, Ni, As, and Fe: can Helianthus annuus hyperaccumulate multiple heavy metals?

Sundance sunflowers were subjected to contaminated solutions containing 3, 4, or 5 heavy metals, with and without EDTA. The sunflowers exhibited a metal uptake preference of Cd=Cr>Ni, Cr>Cd>Ni>As and Fe>>As>Cd>Ni>Cr without EDTA and Cr>Cd>Ni, Fe>>As>Cd>Cr>Ni with EDTA. As uptake was not affected by other metals, but it decreased Cd and Ni concentration in the stems. The presence of Fe improved the translocation of the other metals regardless of whether EDTA was present. In general, EDTA served as a hindrance to metal uptake. For the experiment with all five heavy metals, EDTA decreased Cd in the roots and stems from 2.11 to 1.36 and from 2.83 to 2.3 2mg g(-1) biomass, respectively. For the same conditions, Ni in the stems decreased from 1.98 to 0.94 mg g(-1) total metal uptake decreased from 14.95 mg to 13.89 mg, and total biomass decreased from 2.38 g to 1.99 g. These results showed an overall negative effect in addition of EDTA. However it is unknown whether the negative effect was due to toxicity posed by EDTA or the breaking of phytochelatin-metal bonds. The most important finding was the ability of Sundance sunflowers to achieve hyperaccumulator status for both As and Cd under all conditions studied. Ni hyperaccumulator status was only achieved in the presence of three metals without EDTA.

Occurrence and distribution of polycyclic aromatic hydrocarbons (PAHs) in Bolgoda and Beira Lakes, Sri Lanka.

The pollution of polycyclic aromatic hydrocarbons (PAHs) has been widely used to assess the potential impact of anthropogenic activities on aquatic environments because their occurrence in water is closely tied to urban activities. Many PAHs possess mutagenic and carcinogenic properties (Menzie et al. 1992). PAH distribution and toxic potentials have therefore been the focus of numerous studies in waterways including the Great Lakes (USEPA Report 1994), Yanisei Bay (Dahle et al., 2003), and the Fraser River basin (Yunker et al., 2002). Sri Lanka, a small island nation with a dense population of about 20 million people, faces a multitude of environmental stresses ranging from deforestation to traffic congestion and the deterioration of water quality. This study was undertaken to understand the occurrence, sources, and potential impacts of PAHs in the waterways of Sri Lanka. Two lakes, Beira and Bolgoda, were selected for the study due to their economic value and high level of pollution. Beira Lake, situated in downtown Colombo, the capital city of Sri Lanka, is highly polluted. Sources of pollution are multifarious. For instance, clusters of communities have sprung up along the edges of the lake in recent times and many shacks have been built. These communities are generally not connected to municipal sewer systems and substantial quantities of domestic sewage and untreated wastewaters are discharged directly into the lake. Small industries have also grown rapidly around the lakes, most of which are not believed to have adequate facilities to treat industrial wastewater, especially organic wastes. In addition, Sri Lanka has experienced an upsurge of motor vehicles, including millions of three-wheelers and minivans that are powered by leaded gasoline and diesel fuels. Traffic congestion and severe air pollution due to vehicle emissions are now common daily occurrences and are considered a major potential source of PAHs in the lakes. Although Bolgoda Lake is situated some distance from Colombo, it is heavily polluted due to the growing number of towns with an attendant increase in small businesses and various industries along its shores. These new developments have undoubtedly impacted the lake through the discharge of PAHs and other anthropogenic chemicals present in industrial wastewater and from street runoffs. The lake, additionally, receives a large quantity of pollutants from the industrial zone in the north. The pollution caused by PAHs has led to various studies on the distribution and origin of PAHs in the environment (Yunker et al., 1996; Budzinski et al., 1997). Based on the proportions of different PAHs, most studies aim to distinguish PAHs of petrogenic sources from those of pyrolytic origins. The PAHs of petrogenic origin, prevalent in coals and fossil fuels, are formed from diagenesis of sedimentary organic material under low to moderate temperature and tend to consist of low-molecular-weight PAHs with two to three aromatic rings (Potter et al., 1998). The pyrolytic PAHs, on the other hand, are formed at much higher temperatures (greater than 500 degrees C for example) and consist mainly of four or more aromatic rings (Commins, 1969). Thus, an increase in the proportion of higher-molecular-weight PAHs is taken to be indicative of contaminations of mainly pyrolytic origin. The prevalence of high-molecular-weight PAHs in the urban dusts (Wise et al., 1988) and in atmospheric particles (Sicre et al., 1987) illustrates the chemistry of their formation at high temperature. The purpose of this study was to determine the PAH concentrations and distribution with respect to sampling location, origin and sources in two polluted lakes.

Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.

BACKGROUND: Neoplasia can be driven by mutations resulting in dysregulation of transcription. In the mesenchymal neoplasm, aggressive fibromatosis, subtractive hybridization identified sterile alpha motif domain 9 (SAMD9) as a substantially down regulated gene in neoplasia. SAMD9 was recently found to be mutated in normophosphatemic familial tumoral calcinosis. In this study, we studied the gene structure and function of SAMD9, and its paralogous gene, SAMD9L, and examined these in a variety of species. RESULTS: SAMD9 is located on human chromosome 7q21.2 with a paralogous gene sterile alpha motif domain 9 like (SAMD9L) in the head-to-tail orientation. Although both genes are present in a variety of species, the orthologue for SAMD9 is lost in the mouse lineage due to a unique genomic rearrangement. Both SAMD9 and SAMD9L are ubiquitously expressed in human tissues. SAMD9 is expressed at a lower level in a variety of neoplasms associated with beta-catenin stabilization, such as aggressive fibromatosis, breast, and colon cancers. SAMD9 and SAMD9L contain an amino-terminal SAM domain, but the remainder of the predicted protein structure does not exhibit substantial homology to other known protein motifs. The putative protein product of SAMD9 localizes to the cytoplasm. In vitro data shows that SAMD9 negatively regulates cell proliferation. Over expression of SAMD9 in the colon cancer cell line, SW480, reduces the volume of tumors formed when transplanted into immune-deficient mice. CONCLUSION: SAMD9 and SAMD9L are a novel family of genes, which play a role regulating cell proliferation and suppressing the neoplastic phenotype. This is the first report as far as we know about a human gene that exists in rat, but is lost in mouse, due to a mouse specific rearrangement, resulting in the loss of the SAMD9 gene.

1-(1,3-Benzodioxol-5-ylmethyl)-3-[4-(1H-imidazol-1-yl)phenoxy]-piperidine analogs as potent and selective inhibitors of nitric oxide formation.

A new series of 1-(1,3-benzodioxol-5-ylmethyl)-3-[4-(1H-Imidazol-1-yl)phenoxy]-piperidine analogs were designed and identified as potent and selective inhibitors of NO formation based both on the crystal structure of a murine iNOS Delta114 monomer domain/ inhibitor complex and inhibition of the NO formation in human A172 cell assays. Compound 12S showed high potency and high iNOS selectivity versus nNOS and eNOS.

Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.

By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.

CCR5 receptor antagonists: discovery and SAR of novel 4-hydroxypiperidine derivatives.

The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, 1, with an IC(50) of 840 nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative, 6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of 10h, a potent CCR5 antagonist with an IC(50) of 11 nM.