Nanoapatite-Loaded κ-Carrageenan/Poly(vinyl alcohol)-Based Injectable Cryogel for Hemostasis and Wound Healing.

Immediate control of excessive bleeding and prevention of infections are of utmost importance in the management of wounds. Cryogels have emerged as promising materials for the rapid release of medication and achieving hemostasis. However, their quick release properties pose the challenge of exposing patients to high concentrations of drugs. In this study, hybrid nanocomposites were developed to address this issue by combining poly(vinyl alcohol) and κ-carrageenan with whitlockite nanoapatite (WNA) particles and ciprofloxacin, aiming to achieve rapid hemostasis and sustained antibacterial effects. A physically cross-linked cryogel was obtained by subjecting a blend of poly(vinyl alcohol) and κ-carrageenan to successive freezing-thawing cycles, followed by the addition of WNA. Furthermore, ciprofloxacin was introduced into the cryogel matrix for subsequent evaluation of its wound healing properties. The resulting gel system exhibited a 3D microporous structure and demonstrated excellent swelling, low cytotoxicity, and outstanding mechanical properties. These characteristics were evaluated through analytical and rheological experiments. The nanocomposite cryogel with 4% whitlockite showed extended drug release of 71.21 ± 3.5% over 21 days and antibacterial activity with a considerable growth inhibition zone (4.19 ± 3.55 cm). Experiments on a rat model demonstrated a rapid hemostasis property of cryogels within an average of 83 ± 4 s and accelerated the process of wound healing with 96.34% contraction compared to the standard, which exhibited only ∼78% after 14 days. The histopathological analysis revealed that the process of epidermal re-epithelialization took around 14 days following the skin incision. The cryogel loaded with WNAs and ciprofloxacin holds great potential for strategic utilization in wound management applications as an effective material for hemostasis and anti-infection purposes.

A novel protocol for rapid deployment of heart rate data storage tags in Atlantic bluefin tuna Thunnus thynnus reveals cardiac responses to temperature and feeding.

The Atlantic bluefin tuna (ABFT) is a highly prized species of large pelagic fish. Studies of their environmental physiology may improve understanding and management of their populations, but this is difficult for mature adults because of their large size. Biologging of heart rate holds promise in investigating physiological responses to environmental conditions in free-swimming fishes but it is very challenging to anesthetize large ABFT for invasive surgery to place a tag in the body cavity near to the heart. We describe a novel method for rapid deployment of a commercially available heart-rate tag on ABFT, using an atraumatic trocar to implant it in the musculature associated with the cleithrum. We performed three sequential experiments to show that the tagging method (1) is consistently repeatable and reliable, (2) can be used successfully on commercial fishing boats and does not seem to affect fish survival, and (3) is effective for long-term deployments. In experiment 3, a tag logged heart rate over 80 days on a 60-kg ABFT held in a farm cage. The logged data showed that heart rate was sensitive to prevailing seasonal temperature and feeding events. At low temperatures, there were clear responses to feeding but these all disappeared above a threshold temperature of 25.5°C. Overall, the results show that our method is simple, rapid, and repeatable, and can be used for long-term experiments to investigate physiological responses by large ABFT to environmental conditions.

[99mTc]Tc-DTPA-Bis(cholineethylamine) as an Oncologic Tracer for the Detection of Choline Transporter (ChT) and Choline Kinase (ChK) Expression in Cancer.

OBJECTIVE: The elevated choline transporters (ChT), choline kinase (ChK), choline uptake, and phosphorylation in certain tumor cells have influenced the development of radiolabeled choline derivatives as diagnostic probes for imaging cell membrane proliferation. We, therefore, aimed to develop a choline-based moiety for imaging choline kinase-overexpressed tumors by single-photon emission tomography (SPECT). A novel choline-based diagnostic probe was synthesized and evaluated preclinically in various ChT- and ChK-overexpressed tumor models for SPECT imaging applications. METHODS: The synthesis of diethylenetriaminepentaacetic acid-bis-choline ethylamine [DTPA-bis(ChoEA)] featured the conjugation of dimethylaminoethanol to a bifunctional chelator DTPA anhydride. [99mTc]Tc-DTPA-bis(ChoEA) was prepared, and its in vivo characteristics were evaluated in BALB/c mice and tumor-xenografted PC3, A549, and HCT116 athymic mouse models. The in vitro parameters, including cell binding and cytotoxicity, were assessed in PC3, A549, and HCT116 cell lines. To evaluate the specificity of the radioprobe, competitive binding studies were performed. Small-animal SPECT/CT diagnostic imaging was performed for in vivo evaluation. The mouse biodistribution data was further investigated to estimate the radiation dose in humans. RESULTS: In silico studies suggested high binding with enhanced specificity. A standard radiolabeling procedure using stannous chloride as a reducing agent showed a labeling yield of 99.5 ± 0.5%. The in silico studies suggested high binding with enhanced specificity. [99mTc]Tc-DTPA-bis(ChoEA) showed high in vitro stability and specificity. The pharmacokinetic studies of [99mTc]Tc-DTPA-bis(ChoEA) in mice showed an increased tumor-to-background ratio after few minutes of intravenous administration. The first-in-human trial was also conducted. The effective dose was estimated to be 0.00467 mSv/MBq (4.67 mSv/GBq), resulting in a radiation dose of up to 1.73 mSv for the 370 MBq injection of [99mTc]Tc-DTPA-bis(ChoEA). CONCLUSIONS: The synthesized radioprobe [99mTc]Tc-DTPA-bis(ChoEA) accumulates specifically in choline kinase-overexpressed tumors with a high signal-to-noise ratio. The preclinical and first-in-man data suggested that [99mTc]Tc-DTPA-bis(ChoEA) could potentially be used as a diagnostic SPECT tracer in the monitoring and staging of cancer.

Amifostine analog, DRDE-30, alleviates radiation induced lung damage by attenuating inflammation and fibrosis.

BACKGROUND: Radiotherapy of thoracic neoplasms and accidental radiation exposure often results in pneumonitis and fibrosis of lungs. Here, we investigated the potential of amifostine analogs: DRDE-07, DRDE-30, and DRDE-35, in alleviating radiation-induced lung damage. METHODS: C57BL/6 mice were exposed to 13.5 Gy thoracic irradiation, 30 min after intraperitoneal administration of the analogs, and assessed for modulation of the pathological response at 12 and 24 weeks. KEY FINDINGS: DRDE-07, DRDE-30 and DRDE-35 increased the survival of irradiated mice from 20% to 30%, 80% and 70% respectively. Reduced parenchymal opacity (X-ray CT) in the lungs of DRDE-30 pre-treated mice corroborated well with the significant decrease in Ashcroft score (p < 0.01). Two-fold increase in SOD and catalase activities (p < 0.05), coupled with a 50% increase in GSH content and a 60% decrease in MDA content (p < 0.05) suggested restoration of the antioxidant defence system. A 20% to 40% decrease in radiation-induced apoptotic and mitotic death in the lung tissue (micronuclei: p < 0.01), resulted in attenuated lung and vascular permeability (FITC-Dextran leakage) by 50% (p < 0.01), and a commensurate reduction (~50%) in leukocyte infiltration in the injured tissue (p < 0.05). DRDE-30 abrogated the activation of pro-inflammatory NF-κB and p38/MAPK signaling cascades, suppressing the release of pro-inflammatory cytokines (IL-1ß: p < 0.05; TNF-α: p < 0.05; IL-6: p < 0.05) and up-regulation of CAMs on the endothelial cell surface. Reduction in hydroxyproline content (p < 0.01) and collagen suggested inhibition of lung fibrosis which was associated with attenuation of TGF-ß/Smad pathway-mediated-EMT. CONCLUSION: DRDE-30 could be a potential prophylactic agent against radiation-induced lung injury.

DNA binding and antiradical potential of ethyl pyruvate: Key to the DNA radioprotection.

DNA is the store house of all necessary hereditary information for growth of cells and tissues. Physiological functionality of DNA depends on its 3D helical structure and any distortion in a structure may lead to mutation and genomic instability that may translate into disease like cancer. In order to prevent DNA damage, an exogenous compound is required that can either scavenge the excess free radicals or enhance the structural integrity of DNA through binding. In the present study, the binding mechanism of ethyl pyruvate (EP) with DNA models using different spectroscopic techniques was investigated for their structural integrity. Besides, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays were performed to determine the antioxidant scavenging of EP. Plasmid DNA relaxation assay was performed to assess the radioprotection efficacy of EP in the plasmid DNA. Circular dichroism (CD) and UV-Vis absorbance spectroscopic data confirmed the conformation change in ctDNA upon binding with EP. The molecular docking visualized that EP stacks between the DNA bases with a glide score of -2.117 kcalmol while EP binds in the minor groove region of DNA with the glide score of -1.414 kcalmol . DPPH and FRAP data confirmed that EP scavenges significantly radicals at higher concentrations. In vitro radioprotection study in plasmid DNA pBR322 showed that EP retained the supercoiled form of plasmid DNA at 50 Gy radiation dose.

Amifostine Analog, DRDE-30, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Bleomycin (BLM) is an effective curative option in the management of several malignancies including pleural effusions; but pulmonary toxicity, comprising of pneumonitis and fibrosis, poses challenge in its use as a front-line chemotherapeutic. Although Amifostine has been found to protect lungs from the toxic effects of radiation and BLM, its application is limited due to associated toxicity and unfavorable route of administration. Therefore, there is a need for selective, potent, and safe anti-fibrotic drugs. The current study was undertaken to assess the protective effects of DRDE-30, an analog of Amifostine, on BLM-induced lung injury in C57BL/6 mice. Whole body micro- computed tomography (CT) was used to non-invasively observe tissue damage, while broncheo-alveolar lavage fluid (BALF) and lung tissues were assessed for oxidative damage, inflammation and fibrosis. Changes in the lung density revealed by micro-CT suggested protection against BLM-induced lung injury by DRDE-30, which correlated well with changes in lung morphology and histopathology. DRDE-30 significantly blunted BLM-induced oxidative stress, inflammation and fibrosis in the lungs evidenced by reduced oxidative damage, endothelial barrier dysfunction, Myeloperoxidase (MPO) activity, pro-inflammatory cytokine release and protection of tissue architecture, that could be linked to enhanced anti-oxidant defense system and suppression of redox-sensitive pro-inflammatory signaling cascades. DRDE-30 decreased the BLM-induced augmentation in BALF TGF-ß and lung hydroxyproline levels, as well as reduced the expression of the mesenchymal marker α-smooth muscle actin (α-SMA), suggesting the suppression of epithelial to mesenchymal transition (EMT) as one of its anti-fibrotic effects. The results demonstrate that the Amifostine analog, DRDE-30, ameliorates the oxidative injury and lung fibrosis induced by BLM and strengthen its potential use as an adjuvant in alleviating the side effects of BLM.

Evidence for long-term change in length, mass and migration phenology of anadromous spawners in French Atlantic salmon Salmo salar.

This study provides new data on Atlantic salmon Salmo salar life-history traits across France. Using a long-term recreational angling database (1987-2013) covering 34 rivers in three regions (genetic units), a decline in individual length, mass and a delayed adult return to French rivers was reported. Temporal similarities in trait variations between regions may be attributed to common change in environmental conditions at sea. The relative rate of change in phenotypic traits was more pronounced in early maturing fish [1 sea-winter (1SW) fish] than in late maturing fish (2SW fish). Such contrasted response within populations highlights the need to account for the diversity in life histories when exploring mechanisms of phenotypic change in S. salar. Such detailed life-history data on returning S. salar have not previously been reported from France. This study on French populations also contributes to reducing the gap in knowledge by providing further empirical evidence of a global pattern in S. salar across its distribution range. Results are consistent with the hypothesis that the observed changes in life-history traits are primarily associated with environmental changes in the North Atlantic Ocean. They also emphasize the presence of less important, but still significant contrasts between region and life history.

Benzopyran derivative CDRI-85/287 induces G2-M arrest in estrogen receptor-positive breast cancer cells via modulation of estrogen receptors α- and ß-mediated signaling, in parallel to EGFR signaling and suppresses the growth of tumor xenograft.

In an endeavor to develop novel and improved selective estrogen receptor modulators as anti-breast cancer agents, the benzopyran compounds have been synthesized and identified which act as potent anti-estrogen at uterine level. The present study evaluates the anti-tumor activity of 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) and explores the mechanism of action with a view to describe its potential to inhibit proliferation in ER-positive breast cancer cells MCF-7 and T47D. The compound decreased the expression of ERα while increased the expression of ERß thereby altering ERα/ERß ratio in both cell lines. Although the compound showed low binding affinity to ERs, it acted as ERα antagonist and ERß agonist in decreasing ERE- or AP-1-mediated transcriptional activation in these cells. Transactivation studies in ERα/ß-transfected MDA-MB231 cells suggested that at cyclin D1 promoter, compound antagonized the action of ERα-mediated E2 response while acted as estrogen agonist via ERß. Further, the compound led to decreased expression of ERα-dependent proliferation markers and ERß-dependent cell cycle progression markers. The expression of cell cycle inhibitory protein p21 was increased leading to G2/M phase arrest. In parallel, compound also interfered with EGFR activation, caused inhibition of PI-3-K/Akt pathway and subsequent induction of apoptosis via intrinsic pathway. A significant reduction in tumor mass and volume was observed in 85/287-treated mice bearing MCF-7 xenograft. We conclude that compound 85/287 exhibits significant anti-tumor activity via modulation of genomic as well as non-genomic mechanisms involved in cellular growth and arrested the cells in G2 phase in both MCF-7 and T47D breast cancer cells. Study suggests that CDRI-85/287 may have therapeutic potential in ER-positive breast cancer.

Shoulder fusion after a self-inflicted gunshot wound: an injury pattern and treatment option.

Gunshot injuries to the shoulder are rare and difficult to manage. We present a case series of seven patients who sustained a severe shoulder injury to the non-dominant side as a result of a self-inflicted gunshot wound. We describe the injury as 'suicide shoulder' caused by upward and outward movement of the gun barrel as the trigger is pulled. All patients were male, with a mean age of 32 years (21 to 48). All were treated at the time of injury with initial repeated debridement, and within four weeks either by hemiarthroplasty (four patients) or arthrodesis (three patients). The hemiarthroplasty failed in one patient after 20 years due to infection and an arthrodesis was attempted, which also failed due to infection. Overall follow-up was for a mean of 26 months (12 to 44). All four hemiarthroplasty implants were removed with no feasible reconstruction ultimately possible, resulting in a poor functional outcome and no return to work. In contrast, all three primary arthrodeses eventually united, with two patients requiring revision plating and grafting. These patients returned to work with a good functional outcome. We recommend arthrodesis rather than replacement as the treatment of choice for this challenging injury.

Population differences in response to hypoxic stress in Atlantic salmon.

Understanding whether populations can adapt to new environmental conditions is a major issue in conservation and evolutionary biology. Aquatic organisms are increasingly exposed to environmental changes linked with human activities in river catchments. For instance, the clogging of bottom substratum by fine sediments is observed in many rivers and usually leads to a decrease in dissolved oxygen concentrations in gravel beds. Such hypoxic stress can alter the development and even be lethal for Atlantic salmon (Salmo salar) embryos that spend their early life into gravel beds. In this study, we used a common garden experiment to compare the responses to hypoxic stress of four genetically differentiated and environmentally contrasted populations. We used factorial crossing designs to measure additive genetic variation of early life-history traits in each population. Embryos were reared under normoxic and hypoxic conditions, and we measured their survival, incubation time and length at the end of embryonic development. Under hypoxic conditions, embryos had a lower survival and hatched later than in normoxic conditions. We found different hypoxia reaction norms among populations, but almost no population effect in both treatments. We also detected significant sire × treatment interactions in most populations and a tendency for heritability values to be lower under stressful conditions. Overall, these results reveal a high degree of phenotypic plasticity in salmon populations that nevertheless differ in their adaptive potential to hypoxia given the distinct reaction norms observed between and within populations.

[French hospital discharge database: data production, validity, and origins of errors in the field of severe maternal morbidity]. / Le programme de médicalisation du système d'information (PMSI) - processus de production des données, validité et sources d'erreurs dans le domaine de la morbidité maternelle sévère.

BACKGROUND: The organization of obstetric care in France brings all women in contact with the hospital system. Thus, hospital discharge data from the Program of Medicalization of the Information System (PMSI) constitute a potentially valuable source of information, particularly regarding rare events such as severe maternal morbidity. These data cover a large population but their quality has not been assessed in that field. Our objectives were to study the processes of production and the validity of PMSI data related to severe maternal morbidity. METHODS: The study was conducted in four French tertiary teaching hospitals (Caen, Cochin [AP-HP, Paris], Grenoble and Lille). First, the organization of each step of the medical information process -production, formatting, verification and processing- was detailed in each center with a standardized form. Second, the validation study was based on the comparison of data related to severe maternal morbid events in the PMSI from these centers for 2006 and 2007, with the content of medical records which constituted the gold standard. Indicators of sensitivities and positive predictive values of PMSI were calculated. RESULTS: The processes of PMSI data production showed major differences between the four centers. In hospital discharge data, diagnoses (eclampsia and pulmonary embolism) had a high proportion of false-positives (68%). Inversely, procedures (four procedures for management of severe haemorrhage) had less than 1% of false-positives, but a low sensitivity with 37% false-negatives which could be corrected in 95%. Regarding intensive care provision, all indicators of hospital data quality were very high. In addition, the validity of hospital data in centers 1 and 2 was higher for all events. CONCLUSION: The heterogeneity of the process of PMSI data production is associated with a variable quality of these data. Intensive care provision can be used in the PMSI, as well as procedures after correction. For diagnoses, the quality of the PMSI data is better in centers having both computerized medical records and steps for verification of medical information.

Effect of water temperature and density of juvenile salmonids on growth of young-of-the-year Atlantic salmon Salmo salar.

A von Bertalanffy growth model for young-of the-year Atlantic salmon Salmo salar in a small French coastal stream was fitted using water temperatures and densities of juvenile salmonids (S. salar and brown trout Salmo trutta) as covariates influencing daily growth rate. The Bayesian framework was used as a template to integrate prior information from external data sets. The relative influence of the covariates on parr growth was quantified and results showed that growth of S. salar juveniles depended on both water temperatures and densities, but that most of the spatiotemporal variability of growth resulted from local spatiotemporal variations of 0+ age salmonid (S. salar and S. trutta) densities. Further analysis revealed that the fluctuations in young-of-the-year salmonid densities are likely to dominate the effects of potential future warming of water temperature due to climate change. It is concluded that factors that could affect salmonid densities might well have a greater effect on S. salar population dynamics than factors influencing water temperatures.

[Mortality and morbidity conference: A tool for quality and safety of care continuous improvement]. / La Revue de mortalité et morbidité : une méthode d'amélioration continue de la qualité et la sécurité des soins.

OBJECTIVE: The mortality and morbidity conference (MMC) is one of the keystones in the evaluation of quality of care. The objective of this work was to describe a MMC by presenting a case report. CASE REPORT: A 16-year old man suffering from chronic anaemia had to be transfused with two units of red blood cells in an outpatient unit. Although the transfusion went well for the first unit, the patient presented haemolysis during the transfusion of the second unit because the nurse administered the wrong unit. The incident was analysed during a mortality and morbidity conference with the attendance of the hemovigilance local correspondent. Immediate causes of the event were the failure to respect the transfusion procedure: in advance compatibility testing, failure to check the patient and blood component identification just before the transfusion. Factors contributing to the event were the deviation of transfusion practices, poor working conditions of nurses, linked to inadequate staff in relation to the activity. The discussion of the incident led to develop an action plan. DISCUSSION: This case shows the interest for staff members to discuss an adverse event. However, a well-defined methodology for conducting mortality and morbidity conferences is lacking and leads to a wide heterogeneity between teams. Major differences refer to criteria for case selection and quality of participants. This heterogeneity is likely to have an impact of the efficacy of mortality and morbidity conferences regarding the quality and safety of care.

Compliance with recommendations and clinical outcomes for formal and informal infectious disease specialist consultations.

The purpose of this study was to compare compliance with recommendations and clinical outcomes between formal and informal infectious disease specialist consultations. Six hundred twenty-seven consecutive adult inpatients who received an infectious disease consultation in a university-affiliated hospital were included. After adjusting for quintile of propensity score, we compared compliance with the consultant's recommendations and clinical outcomes for 443 (70.7%) and 184 (29.3%) formal and informal consultations. Informal and formal consultations were associated with comparable levels of compliance with recommendations for antimicrobial treatment (86.5% vs 88.9%; adjusted odds ratio [aOR], 0.63; 95% confidence interval, 0.34-1.14; P = 0.13) and diagnostic or monitoring tests (72.6% vs 72.0%; aOR, 0.91 [0.53-1.57]; P = 0.73). The rates of early clinical improvement (58.2% vs 58.6%; aOR, 1.11 [0.70-1.74]; P = 0.66), subsequent consultation (34.2% vs 36.3%; aOR, 0.80 [0.53-1.21]; P = 0.29), in-hospital mortality (4.9% vs 8.4%; aOR, 0.55 [0.24-1.24]; P = 0.15), and the median length of stay (23 vs 20 days; aOR of discharge, 0.90 [0.74-1.10]; P = 0.30) did not differ depending on the type of consultation. This study provides observational evidence that informal consultations result in levels of compliance with recommendations comparable to formal consultations, without compromising patient safety. Further study is needed to refine the criteria for requesting or providing informal rather than formal consultations.

[Preterm births circumstances in babies born before 35 weeks in French Alpes: PREMALP study]. / Etude des circonstances de naissance prématurée avant 35SA dans le sillon alpin : étude PREMALP.

OBJECTIVES: In a regional study of preterm infants born before 35weeks of gestation, the aim was to propose a new classification of preterm births into three groups, and to describe the pregnancy complications and fetal disorders in each group. PATIENTS AND METHODS: In two areas covered by a perinatal network, all preterm births, live births and stillbirths, which occurred between 22 and 34 completed weeks were recorded over a 21-month period. Each case was classified either in the medically-indicated preterm birth (I) group, or in the accepted spontaneous preterm birth (ASp) group or in the non-accepted spontaneous preterm birth (NASp) group. RESULTS: One thousand and sixty cases of preterm births were included; among them, 981 were live births or ended with per partum infant death. Forty-nine percent of these births were medically indicated, 32 % were ASp and 19 % were NASp. The distribution of pregnancy complications and fetal disorders differed between preterm birth groups: ischemic placental diseases were present in 38,2 % of medically-indicated births; preterm premature rupture of membranes occurred twice more often in I and ASp preterm births than in NASp preterm births. CONCLUSION: This classification is based on the medical decision; it allows to compare medical practices in given obstetrical situations. It appears to be reproducible and easy to use.

[Evaluation of a remote infectious disease consultation]. / Evaluation d'une consultation mobile d'infectiologie.

OBJECTIVES: The aims of our study were to characterize the activity of a remote infectious diseases consultation (RIDC) in a teaching hospital and to assess physician observance to advice. DESIGN: All demands received by the RIDC for initial advice and the given answers were recorded during one month. Advice given for inpatients was followed up 72 hours after to evaluate the physician's observance. RESULTS: Six hundred and nineteen demands were recorded: 47% came from our teaching hospital and 53% came from community practice. Hospital demands came mostly from surgical (47%) and medical (41%) units. Most of them (92%) were related to the treatment of an infection or diagnostic help. Outside calls came from doctors (85%) either private or working in a health care institution. Prophylaxis (47%) and treatment of an infection or a diagnostic help (43%) were the most frequent issues. Among the 176 pieces of advice requested for inpatients, 87% were completely observed. Advice was more followed when it was given by experienced specialists (p=0.02) or by phone (p=0.03) and less followed for patients presenting a nosocomial infection (p=0.03). CONCLUSIONS: The RIDC is very useful for the medical community and its advice is usually followed. Informal consultations account for an important part of its activity.

Synthesis and biochemical evaluation of guanidino-alkyl-ribitol derivatives as nucleoside hydrolase inhibitors.

Nucleoside hydrolase (NH) is a key enzyme in the purine salvage pathway. The purine specificity of the IAG-NH from Trypanosoma vivax is at least in part due to cation-pi-stacking interactions. Guanidinium ions can be involved in cation-pi-stacking interactions, therefore a series of guanidino-alkyl-ribitol derivatives were synthesized in order to examine the binding affinity of these compounds towards the target enzyme. The compounds show moderate to good inhibiting activity towards the IAG-NH from T. vivax.

Diagnosis of Parkinsonian disorders using a channelized Hotelling observer model: proof of principle.

Imaging dopamine transporters using PET and SPECT probes is a powerful technique for the early diagnosis of Parkinsonian disorders. In order to perform automated accurate diagnosis of these diseases, a channelized Hotelling observer (CHO) based model was developed and evaluated using the SPECT tracer [Tc-99m]TRODAT-1. Computer simulations were performed using a digitized striatal phantom to characterize early stages of the disease (20 lesion-present cases with varying lesion size and contrast). Projection data, modeling the effects of attenuation and geometric response function, were obtained for each case. Statistical noise levels corresponding to those observed clinically were added to the projection data to obtain 100 noise realizations for each case. All the projection data were reconstructed, and a subset of the transaxial slices containing the striatum was summed and used for further analysis. CHO models, using the Laguerre-Gaussian functions as channels, were designed for two cases: (1) By training the model using individual lesion-present samples and (2) by training the model using pooled lesion-present samples. A decision threshold obtained for each CHO model was used to classify the study population (n = 40). It was observed that individual lesion trained CHO models gave high diagnostic accuracy for lesions that were larger than those used to train the model and vice-versa. On the other hand, the pooled CHO model was found to give a high diagnostic accuracy for all the lesion cases (average diagnostic accuracy = 0.95 +/- 0.07; p < 0.0001 Fisher's exact test). Based on our results, we conclude that a CHO model has the potential to provide early and accurate diagnosis of Parkinsonian disorders, thereby improving patient management.

1,2,3-Triazolylalkylribitol derivatives as nucleoside hydrolase inhibitors.

A range of novel 1,2,3-triazolylalkylribitol derivatives were synthesized and evaluated as nucleoside hydrolase inhibitors. The most active compound (11a) has low micromolar potency and is structurally diverse from previously reported nucleoside hydrolase inhibitors, which, along with the simplicity of the chemistry involved in its synthesis, makes it a good lead for the further development of novel nucleoside hydrolase inhibitors.

Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family.

Chemokines coordinate many aspects of leukocyte migration. As chemoattractants they play an important role in the innate and acquired immune response. There is good experimental evidence that N-terminal truncation by secreted or cell surface proteases is a way of modulating chemokine action. The localization of CD26/dipeptidyl peptidase IV on cell surfaces and in biological fluids, its primary specificity, and the type of naturally occurring truncated chemokines are consistent with such a function. We determined the steady-state catalytic parameters for a relevant selection of chemokines (CCL3b, CCL5, CCL11, CCL22, CXCL9, CXCL10, CXCL11, and CXCL12) previously reported to alter their chemotactic behavior due to CD26/dipeptidyl peptidase IV-catalyzed truncation. The results reveal a striking selectivity for stromal cell-derived factor-1alpha (CXCL12) and macrophage-derived chemokine (CCL22). The kinetic parameters support the hypothesis that CD26/dipeptidyl peptidase IV contributes to the degradation of certain chemokines in vivo. The data not only provide insight into the selectivity of the enzyme for specific chemokines, but they also contribute to the general understanding of CD26/dipeptidyl peptidase IV secondary substrate specificity.