A Brief Review on Murraya paniculata (Orange Jasmine): pharmacognosy, phytochemistry and ethanomedicinal uses.

Objectives: Murraya paniculata (family-Rutaceae), popularly known as orange jasmine, is the most important evergreen plant. The Rutaceae family is economically significant due to its diverse edible fruits and essential oils. Methods: Murraya paniculata extracts (MPE) of leaf have been shown to include phenolic compounds, highly oxygenated flavonoids, flavanones, sesquiterpenoids, polymethoxy glycosides, and coumarins. Cyclocitral, methyl salicylate, trans-nerolidol, cubenol, isogermacrene, -cadinol, and cubeb-11-ene are all abundant in MPE. The usages of various parts of this plant, such as bark, leaves and flower, as a remedy for a variety of ailments as widely recorded in the traditional literature. The plant has anti-diabetic, anti-obesity, antibacterial, anti-implantation, anti-oxidative, cytotoxic, anti-diarrheal, antidepressant and anti-anxiety properties and many others. Results: The goal of the review is to reignite interest in this potential plant, encouraging researchers to continue their research in order to uncover novel therapeutic compounds for the treatment and management of a range of infections. The current review provided a comprehensive overview of this traditional unique plant. Conclusion: The review paves a way for exploring its active chemical elements with substantial pharmacological values further for potential benefits of mankind.

Referrals to Home Visiting: Current Practice and Unrealized Opportunities.

INTRODUCTION: Evidence supports ongoing investment in maternal and early childhood home visiting in the US. Yet, a small fraction of eligible families accesses these services, and little is known about how families are referred. This report describes priority populations for home visiting programs, the capacity of programs to enroll more families, common sources of referrals to home visiting, and sources from which programs want to receive more referrals. METHODS: We conducted a secondary analysis of data from a national web-based survey of members of the Home Visiting Applied Research Collaborative (HARC), focusing on a small set of items that directly addressed study aims. Survey respondents (N = 87) represented local programs implementing varying home visiting models diverse in size and geographic context. RESULTS: Programs prioritized enrollment of pregnant women; parents with mental health, substance abuse or intimate partner violence concerns; teen parents; and children with developmental delays or child welfare involvement. Most respondents reported capacity to enroll more families in their programs. Few reported receiving any referrals from pediatric providers, child welfare, early care and education, or TANF/other social services. Most desired more referrals, especially from healthcare providers, WIC, and TANF/other social services. DISCUSSION: Given that most programs have the capacity to serve more families, this study provides insights regarding providers with whom home visiting programs might strengthen their referral systems.

The Need for Improved Collaboration between Schools and Child Death Review Teams.

BACKGROUND: Schools are essential public health partners for safeguarding students' health. Child Death Review (CDR) is one public health activity where collaboration with schools is integral for developing strategies to prevent child death but the degree of collaboration is unknown. This study assessed school participation in CDR and the prevalence of school problems in reviewed child death cases, comparing non-suicide and suicide-related deaths. METHODS: Using the National Fatality Review-Case Reporting System, we created a dataset of school-aged children (5 to 20 years) whose death was reviewed from 2005 to 2017 and used frequencies, proportions, and chi-squared statistics on selected measures. RESULTS: Educational representatives infrequently participated in CDRs (24.9%). School records were rarely accessed for reviewed deaths (5.2%). Less than half (41.2%) of reviewed deaths had any school information and of these, 35.5% of children were indicated as having problems in school. Compared with non-suicide deaths, a larger proportion of suicide deaths had school representatives attend CDRs (28.4% vs 24.1%, P < .0001), and access to educational records (4.2% vs 9.2%, P < .0001). IMPLICATIONS: Efforts are needed to address potential barriers to systems integration, including state policies and federal educational privacy laws. CONCLUSIONS: School participation in CDRs is lacking for both suicide and non-suicide deaths.

Fixed dose combination of low dose pregabalin and duloxetine, or pregabalin monotherapy for neuropathic pain: A double-blind, randomized, parallel-group study.

Background: Treatment of neuropathic pain is challenging. Pregabalin and duloxetine are used as first-line therapy. Various international guidelines recommend a combination of first-line agents for the management of neuropathic pain. The objective of this study was to evaluate the efficacy and safety of a fixed-dose combination (FDC) of low-dose pregabalin and duloxetine compared to pregabalin monotherapy at week 7 in patients with moderate to severe neuropathic pain. Methods: This was a phase 3, randomized, double-blind, double-dummy parallel-group non-inferiority study conducted at 17 sites across India. Three hundred and twenty-eight adult patients with moderate to severe neuropathic pain were randomized in a ratio of 1:1 to receive a FDC of pregabalin and duloxetine or pregabalin monotherapy for 7 weeks followed by a one-week follow-up. The pregabalin-duloxetine combination was initiated at 50 plus 20 mg per day and gradually titrated to a maximum of 75mg plus 30mg twice daily. Pregabalin was initiated at 75mg/day and gradually titrated to a maximum of 150mg twice daily. The main efficacy outcome was a mean change in pain intensity at the end of 7 weeks. Results: Two hundred and ninety-eight patients completed the study, 148 in the pregabalin-duloxetine group and 150 in the pregabalin group. The mean change in daily pain at 7 weeks was as follows: -4.49 with FDC and -4.66 with pregabalin (p<0.0001). The non-inferiority of a low-dose FDC compared to pregabalin monotherapy was demonstrated at the end of the study. The incidence of dizziness and somnolence was comparable between both treatments. A higher frequency of peripheral oedema was observed with pregabalin monotherapy than in the FDC group (p>0.05). Conclusions: A FDC of low doses of pregabalin and duloxetine and high dose of pregabalin monotherapy achieved similar analgesia with dizziness, and somnolence as the most frequent adverse event. Trial registration: CTRI/2020/09/027555.

Child Health Status and Health Care Use in Grandparent- Versus Parent-Led Households.

OBJECTIVES: To use a nationally representative sample to compare children in grandparent-led versus parent-led households with regard to diagnosed child health conditions, receipt of timely health care, and burden of caregiving responsibilities. METHODS: We used 4 years of pooled data from the National Survey of Children's Health, representative of United States children ages 0 to 17 years, and applied bivariate analyses and logistic regressions adjusted for sociodemographic confounders to compare grandparent- and parent-led households on key measures of interest. RESULTS: Compared with children in parent-led households, those in grandparent-led households had increased physical health conditions (oral health problems: 18.9% vs 13.1%, P = .0006; overweight/obesity: 40.3% vs 29.7%, P = .0002); emotional, mental, and developmental health conditions (attention deficit hyperactivity disorder: 16.3% vs 8.0%; behavioral/conduct problems: 13.9% vs 6.1%; depression: 6.6% vs 3.1%; learning disability: 13.9% vs 6.2%, P < .0001 for all); and special health care needs (28.2% vs 17.8%, P < .0001). They also had decreased prevalence of health care utilization (usual source of sick care: 65.7% vs 79.5%, preventive checkups: 64.6% vs 77.1%; preventive dental visits: 73.8% vs 80.6%; specialty care: 78.6% vs 90.2%, P ≤ .0001 for all) and increased prevalence of forgone care (5.9% vs 2.8%, P = .0020). After adjustment, the associations with caregiver type remained statistically significant for all emotional, mental, and developmental conditions listed; special health care needs; usual source of sick care and preventive checkups. CONCLUSIONS: Grandparent caregivers may benefit from additional support to ensure that grandchildren receive timely health care services.

TRC150094, a Novel Mitochondrial Modulator, Reduces Cardio-Metabolic Risk as an Add-On Treatment: a Phase-2, 24-Week, Multi-Center, Randomized, Double-Blind, Clinical Trial.

BACKGROUND: TRC150094, a novel mitochondrial modulator, reduces insulin resistance and is expected to improve the trinity of dysglycemia, dyslipidemia, and hypertension. In this multi-dose phase-2 study, we evaluated the safety and efficacy of TRC150094 in diabetic subjects with dyslipidemia receiving standard of care. METHODS: A randomized, multicenter, double-blind, placebo-controlled, parallel-group, Phase 2 study was conducted in 225 subjects from July 2013 to August 2015. The key inclusion criteria were body mass index of 23-35 kg/m2, age between 30 and 65 years, fasting glucose of ≥126 or glycated hemoglobin (HbA1c) of ≥6.4% stabilized on treatment with ≤2 oral hypoglycemic agents, apolipoprotein-B (apo-B) ≥100 mg/dL, serum triglyceride (TG) ≥150 mg/dL, systolic blood pressure (SBP) ≥130 mmHg, and diastolic blood pressure (DBP) ≥85 mmHg with/without antihypertensive treatment. The subjects were randomly assigned to one of three TRC150094 doses (25, 50, or 75 mg) or placebo for 24 weeks. The outcomes assessed included fasting plasma glucose (FPG), insulin, mean arterial blood pressure (MAP), and apoB. In addition, safety and tolerability were assessed. RESULTS: A reduction for dose up to 50 mg was noted for FPG in the range of 13.9 to 21.7 mg/dL (p < 0.05 for TRC150094 25 and 50 mg), fasting insulin reduction in the range 2.7 to 6.0 mU/L (all doses, p > 0.05), and improved HOMA-IR (-2.0 to -2.5) (all doses, p > 0.05) compared to placebo after 24 weeks of treatment. Furthermore, a significant reduction in MAP in the range 3.1 to 4.2 mmHg (p < 0.05 for TRC150094 25 and 75 mg) was noted. In addition, TRC150094 treatment was weight neutral, had a favorable effect on lowering atherogenic lipid fractions, including non-HDL cholesterol (-6.8 mg/dL at 50 mg dose). Adverse events were mild to moderate in nature and not dose-related. One adverse event not related to treatment led to the discontinuation of the study. Overall, TRC150094 was safe and well tolerated for up to 24 weeks. CONCLUSION: In this study, TRC150094 treatment in the dose range of 25 to 50 mg showed improvement in various components of CMBCD, ie, dysglycemia, dyslipidemia, and hypertension. TRIAL REGISTRATION: This study was registered in the Clinical Trial Registry of India. Trial registration number: CTRI/2013/03/003444. Date of registration: 4th March 2013.

Statistical features of an electromagnetic Gaussian-Schell model beam propagating through a smoke aerosol environment.

In this paper, we investigate both theoretically and experimentally the statistical properties of an electromagnetic Gaussian-Schell model (EMGSM) beam propagating through polluted atmosphere specifically containing smoke aerosol medium. Experimentally, a glass chamber of 1 m length is constructed to mimic the smoky atmosphere inside the laboratory, in which incense sticks are used for smoke aerosol production inside the chamber in a time-controlled manner. An input EMGSM beam having a variable degree of coherence and degree of polarization (DOP) propagates through the aerosol medium, and its coherence and polarization features after propagation are probed. The results show that the coherence features of the vectorial beam are modified significantly by the smoke aerosol medium, while, for the given propagation length of 1 m, the polarization features remain unaffected. We also investigate the coherence features of the EMGSM beam through smoke aerosols in a particular condition when the DOP of the beam is kept zero. These results are expected to provide insights into atmospheric effects on free-space optical communication in real situations when the medium contains air pollution.

Outcomes and Factors Associated With Prehospital Treatment of Pediatric Anaphylaxis.

OBJECTIVE: Anaphylaxis is a potentially life-threatening reaction requiring prompt treatment with intramuscular epinephrine (EPI). We sought to describe presenting features of pediatric anaphylaxis and compare patient characteristics and outcomes of children treated with prehospital EPI with those untreated. METHODS: We abstracted data from emergency department (ED) records for children meeting the National Institute of Allergy & Infectious Disease criteria for anaphylaxis (2015-2017) in one tertiary care children's hospital. We analyzed associations between patient characteristics and outcomes and receipt of prehospital EPI using descriptive statistics and multivariate logistic regression. RESULTS: Of 414 children presenting with anaphylaxis, 39.4% received IM EPI and 62.1% received antihistamines before hospital arrival. Children with Medicaid received pre-emergency department EPI less frequently than did children with private insurance (24.5% vs 43.8%, P = 0.001). Factors positively associated with prehospital EPI administration were history of food allergy (odds ratio [OR], 4.4 [95% confidence interval {CI}, 2.4-8.2]) or arrival by emergency medical services (OR, 8.0 [95% CI, 4.2-15.0]). Medicaid insurance was associated with decreased odds of prehospital EPI (OR, 0.33 [95% CI, 0.16-0.66]) and prehospital H1-antihistamine use (OR, 0.30 [95% CI, 0.17-0.56]). Prehospital EPI treatment was also associated with decreased rates of observation (37% vs 63%), inpatient admission (38% vs 62%), and intensive care unit admission (20% vs 80%) compared with no pretreatment (P = 0.03). CONCLUSIONS: Prehospital treatment with EPI remains low, and barriers to optimal treatment are more pronounced in children with public insurance. Prehospital treatment with EPI was associated with decreased morbidity including hospitalization and intensive care unit admission.

Safety, Tolerability, and Pharmacokinetics of a Novel Mitochondrial Modulator, TRC150094, in Overweight and Obese Subjects: A Randomized Phase-I Clinical Trial.

TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n = 46, in overweight/obese adult and elderly subjects. In addition, the effect of TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters. TRC150094 was rapidly absorbed, and the AUC of TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine. TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (-2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect. TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall, TRC150094 ensured safety and exhibited suitability for all subjects. Clinical Trial Registration: EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD).

Facilitating access to prenatal care through an interprofessional student-run free clinic.

INTRODUCTION: Addressing the persistent challenge of inadequate prenatal care requires innovative solutions. Student-run free health centers are poised to rise to this challenge. The Shade Tree Clinic Early Pregnancy Program, jointly operated by university medical and nursing programs, functions as an ongoing access-to-care portal for pregnant women without health insurance. The clinic is run by medical students and nurse-midwifery students and uses a service-based learning model that allows students to work and learn in supervised, interprofessional teams while providing evidence-based prenatal care. METHODS: All data reported in this paper were obtained from a retrospective chart review of women served by the prenatal clinic. These data are descriptive in nature, and include the patient demographics and services provided by the clinic to 152 women between the years of 2010-2013. RESULTS: During this time period, the clinic served a demographically diverse clientele. Approximately half lacked documentation of legal immigration status. The majority of women seeking care were in their first trimester of pregnancy and had previously given birth. Several women had medical or obstetric complications that required timely referral to specialist care; and many women received treatment for infection and other primary care concerns. DISCUSSION: Shade Tree Clinic provides the basic components of prenatal care and assists women with other medical needs. Women also receive help when applying for and accessing public maternity insurance, and the clinic facilitates entry to any necessary specialist care while that insurance is processed. In many cases, necessary and time-sensitive care would be delayed if Shade Tree Clinic's prenatal services were not available. In addition, the clinic presents a valuable opportunity for interprofessional socialization, increased respect, and improved collaboration between students in different but complementary professions, which is an important experience while we move to meet national goals for interprofessional care among health professionals. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health.

Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

An algorithm developed using the Brighton Collaboration case definitions is more efficient for determining diagnostic certainty.

The Brighton Collaboration is a global research network focused on vaccine safety. The Collaboration has created case definitions to determine diagnostic certainty for several adverse events. Currently nested within multi-page publications, these definitions can be cumbersome for use. We report the results of a randomized trial in which the case definition for anaphylaxis was converted into a user-friendly algorithm and compared the algorithm with the standard case definition. The primary outcomes were efficiency and accuracy. Forty medical students determined the Brighton Level of diagnostic certainty of a sample case of anaphylaxis using either the algorithm or the original case definition. Most participants in both groups selected the correct Brighton Level. Participants using the algorithm required significantly less time to review the case and determine the level of diagnostic certainty [mean difference=107 s (95% CI: 13-200; p=0.026)], supporting that the algorithm was more efficient without impacting accuracy.

Zebrafish screen identifies novel compound with selective toxicity against leukemia.

To detect targeted antileukemia agents we have designed a novel, high-content in vivo screen using genetically engineered, T-cell reporting zebrafish. We exploited the developmental similarities between normal and malignant T lymphoblasts to screen a small molecule library for activity against immature T cells with a simple visual readout in zebrafish larvae. After screening 26 400 molecules, we identified Lenaldekar (LDK), a compound that eliminates immature T cells in developing zebrafish without affecting the cell cycle in other cell types. LDK is well tolerated in vertebrates and induces long-term remission in adult zebrafish with cMYC-induced T-cell acute lymphoblastic leukemia (T-ALL). LDK causes dephosphorylation of members of the PI3 kinase/AKT/mTOR pathway and delays sensitive cells in late mitosis. Among human cancers, LDK selectively affects survival of hematopoietic malignancy lines and primary leukemias, including therapy-refractory B-ALL and chronic myelogenous leukemia samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for antineoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. Although our efforts focused on leukemia therapy, this screening approach has broad implications as it can be translated to other cancer types involving malignant degeneration of developmentally arrested cells.

Alcama mediates Edn1 signaling during zebrafish cartilage morphogenesis.

The zebrafish pharyngeal cartilage is derived from the pharyngeal apparatus, a vertebrate-specific structure derived from all three germ layers. Developmental aberrations of the pharyngeal apparatus lead to birth defects such as Treacher-Collins and DiGeorge syndromes. While interactions between endoderm and neural crest (NC) are known to be important for cartilage formation, the full complement of molecular players involved and their roles remain to be elucidated. Activated leukocyte cell adhesion molecule a (alcama), a member of the immunoglobulin (Ig) superfamily, is among the prominent markers of pharyngeal pouch endoderm, but to date no role has been assigned to this adhesion molecule in the development of the pharyngeal apparatus. Here we show that alcama plays a crucial, non-autonomous role in pharyngeal endoderm during zebrafish cartilage morphogenesis. alcama knockdown leads to defects in NC differentiation, without affecting NC specification or migration. These defects are reminiscent of the phenotypes observed when Endothelin 1 (Edn1) signaling, a key regulator of cartilage development is disrupted. Using gene expression analysis and rescue experiments we show that Alcama functions downstream of Edn1 signaling to regulate NC differentiation and cartilage morphogenesis. In addition, we also identify a role for neural adhesion molecule 1.1 (nadl1.1), a known interacting partner of Alcama expressed in neural crest, in NC differentiation. Our data shows that nadl1.1 is required for alcama rescue of NC differentiation in edn1(-/-) mutants and that Alcama interacts with Nadl1.1 during chondrogenesis. Collectively our results support a model by which Alcama on the endoderm interacts with Nadl1.1 on NC to mediate Edn1 signaling and NC differentiation during chondrogenesis.

Primary measurement of total ultrasonic power with improved accuracy in rf voltage measurement.

Out of the various existing ultrasonic power measurement techniques, the radiation force balance method using microbalance is most widely used in low power (below 1 W) regime. The major source of uncertainty associated with this technique is the error in ac voltage measurement applied to the transducer for the generation of ultrasonic waves. The sources that deteriorate the ac voltage measurement accuracy include cable length and impedance mismatch. We introduce a new differential peak to peak measurement approach to reduce the ac voltage measurement error. The method holds the average peak amplitude of each polarity. Ultralow offset difference amplifier is used to measure peak to peak voltage. The method is insensitive to the variations in the dc offset of the source. The functionality of this method has been tested and compared with the conventional rf voltage measurement method. The output of this proposed technique is dc, which can be measured with an error of less than 0.1%.

Ultrastructural basis of enhanced antitumor cytotoxicity of cord blood-derived CTLs: a comparative analysis with peripheral blood and bone marrow.

Umbilical cord blood cells (UCBC) are a rich source of immature immune effector and accessory cells, including dendritic cells. UCBC-derived cytotoxic T lymphocytes (CTLs) generated against human breast cancer or neuroblastoma have shown an increased tumor-specific cytotoxicity compared to peripheral blood (PB)-derived CTLs. The precise mechanism of this increased cytotoxicity is not known. Since dendritic cells (DCs) play a central role in the immunostimulation, we compared the ultrastructure and antigen presenting nature of DCs from UCBC, PB and bone marrow (BM) at various stages of maturation using scanning and transmission electron microscopy as well as fluorescent microscopy to elucidate the mechanism underlying the increased cytotoxicity of UCBC-derived CTLs. DCs were examined for their immunophenotype nuclear morphology, dendritic processes and cytoplasmic endosomal vesicles after 0, 3, 7 and 10 days in culture with antigen priming on day 6. Results showed that there were smaller and more vesicles in UCB-DCs compared to DCs from the other two sources, while the endosomal vesicles in PB-DCs were heterogenous in size. The antigen processing ability of the UCB-DCs showed an increase in antigen-positive endosomes compared to PB-DCs as determined by the fluorescent microscopy. Thus, our results provided the comparative analyses of DCs from cord blood, peripheral blood and bone marrow, and suggested that UCBC-DCs might have better antigen presenting ability leading to increased CTL-mediated antitumor cytotoxicity.

TRC4186, a novel AGE-breaker, improves diabetic cardiomyopathy and nephropathy in Ob-ZSF1 model of type 2 diabetes.

Advanced glycation end products (AGEs) contribute significantly to diabetic complications, both macro- and microvascular. TRC4186 is an AGE-breaker that has been evaluated in vitro and in vivo and shown to reduce AGE burden. The aim of this study was to determine the effect of TRC4186 on diabetic cardiomyopathy and nephropathy in obese Zucker spontaneously hypertensive fatty rats (Ob-ZSF1), an animal model of diabetes with progressive cardiac and renal dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC4186, 9 or 27 mg/kg twice daily intraperitoneally or vehicle control and monitored telemetrically throughout the study. Cardiac function was assessed terminally by Millar catheter. Markers of cardiac and renal dysfunction were measured and changes evaluated histopathologically. TRC4186 at 27 mg/kg prevented rise in blood pressure (BP) and also improved cardiac output (CO) secondary to better diastolic relaxation as well as systolic emptying in association with the reduction in afterload. At 9 mg/kg, CO was improved by compensatory increase in pre-load however afterload reduction was not adequate to allow efficient systolic emptying. Brain natriuretic peptide (BNP) and interleukin-6 (IL-6) expression was reduced with treatment. Deterioration in renal function was retarded as evident from albumin to creatinine ratio and renal histopathology. TRC4186, an AGE-breaker, clearly preserved cardiac function and reduced the severity of renal dysfunction in Ob-ZSF1, an animal model with persistent severe hyperglycemia leading to diabetic heart failure and renal failure.

Enhanced transcription of complement and coagulation genes in the absence of adaptive immunity.

A recessive nonsense mutation in the zebrafish recombination activating gene 1 (rag1) gene results in defective V(D)J recombination; however, animals homozygous for this mutation (rag1(-/-)) are reportedly viable and fertile in standard, nonsterile aquarium conditions but display increased mortality after intraperitoneal injection with mycobacteria. Based on their survival in nonsterile environments, we hypothesized that the rag1(-/-) zebrafish may possess an "enhanced" innate immune response to compensate for the lack of an adaptive immune system. To test this hypothesis, microarray analyses were used to compare the expression profiles of the intestines and hematopoietic kidneys of rag1 deficient zebrafish to the expression profiles of control (heterozygous) siblings. The expression levels of 12 genes were significantly altered in the rag1(-/-) kidney including the up regulation of a putative interferon stimulated gene, and the down regulation of genes encoding fatty acid binding protein 10, keratin 5 and multiple heat shock proteins. The expression levels of 87 genes were shown to be significantly altered in the rag1(-/-) intestine; the majority of these differences reflect increased expression of innate immune genes, including those of the coagulation and complement pathways. Subsequent analyses of orthologous coagulation and complement genes in Rag1(-/-) mice indicate increased transcription of the complement C4 gene in the Rag1(-/-) intestine.

Overexpression of PPK-1, the Caenorhabditis elegans Type I PIP kinase, inhibits growth cone collapse in the developing nervous system and causes axonal degeneration in adults.

Growth cones are dynamic membrane structures that migrate to target tissue by rearranging their cytoskeleton in response to environmental cues. The lipid phosphatidylinositol (4,5) bisphosphate (PIP(2)) resides on the plasma membrane of all eukaryotic cells and is thought to be required for actin cytoskeleton rearrangements. Thus PIP(2) is likely to play a role during neuron development, but this has never been tested in vivo. In this study, we have characterized the PIP(2) synthesizing enzyme Type I PIP kinase (ppk-1) in Caenorhabditis elegans. PPK-1 is strongly expressed in the nervous system, and can localize to the plasma membrane. We show that PPK-1 purified from C. elegans can generate PIP(2)in vitro and that overexpression of the kinase causes an increase in PIP(2) levels in vivo. In developing neurons, PPK-1 overexpression leads to growth cones that become stalled, produce ectopic membrane projections, and branched axons. Once neurons are established, PPK-1 overexpression results in progressive membrane overgrowth and degeneration during adulthood. These data suggest that overexpression of the Type I PIP kinase inhibits growth cone collapse, and that regulation of PIP(2) levels in established neurons may be important to maintain structural integrity and prevent neuronal degeneration.