Scurvy in an Adolescent: A Case Report.

Scurvy is a rare condition characterized by a deficiency in dietary vitamin C. Historically a disease taught in the context of long ocean voyages with limited vitamin intake, it is now rare in developed nations. The classical physical exam findings include gingival bleeding, perifollicular hemorrhages, and corkscrew hairs. We discuss the case of a 15-year-old female with scurvy whose initial presentation suggested more common diagnoses seen in the emergency department setting. Her course was complicated by a prior history of anorexia nervosa and a restrictive diet that lacked necessary vitamins. Once the patient's dietary habits were identified, a detailed physical exam revealed the characteristic findings. She was subsequently discharged with oral vitamin C supplements and was scheduled for outpatient follow-up to monitor symptoms.

An inhibitor of RORγ for chronic pulmonary obstructive disease treatment.

The role of RORγ as a transcription factor for Th17 cell differentiation and thereby regulation of IL-17 levels is well known. Increased RORγ expression along with IL-17A levels was observed in animal models, immune cells and BAL fluid of COPD patients. Increased IL-17A levels in severe COPD patients are positively correlated with decreased lung functions and increased severity symptoms and emphysema, supporting an urgency to develop novel therapies modulating IL-17 or RORγ for COPD treatment. We identified a potent RORγ inhibitor, PCCR-1 using hit to lead identification followed by extensive lead optimization by structure-activity relationship. PCCR-1 resulted in RORγ inhibition with a high degree of specificity in a biochemical assay, with > 300-fold selectivity over other isoforms of ROR. Our data suggest promising potency for IL-17A inhibition in human and canine PBMCs and mouse splenocytes with no significant impact on Th1 and Th2 cytokines. In vivo, PCCR-1 exhibited significant efficacy in the acute CS model with dose-dependent inhibition of the PD biomarkers that correlated well with the drug concentration in lung and BAL fluid, demonstrating an acceptable safety profile. This inhibitor effectively inhibited IL-17A release in whole blood and BALf samples from COPD patients. Overall, we identified a selective inhibitor of RORγ to pursue further development of novel scaffolds for COPD treatment.

Unintentional Opioid Ingestions Presenting to a Pediatric Emergency Department.

OBJECTIVES: The purpose of this study was to describe unintentional opioid exposures in young children, including demographics, medical interventions, and clinical outcomes. METHODS: This was a retrospective, cross-sectional study of children 0 to 6 years of age with possible opioid exposure over a 3-year period (July 2010 to June 2013). Data collected included sex, age, specific drug, whether they were referred to the emergency department (ED) by the Regional Poison Control Center, presence of symptoms, therapeutic interventions, ED disposition, and clinical outcomes for admitted patients. RESULTS: Median age of patients included in the study was 2 years, and 64% of these children were male. The most common drug of exposure was buprenorphine/naloxone. Of the 429 charts screened, 140 patients were reported to be symptomatic and referred to the ED, of which 113 patients actually presented to the ED. An additional 122 patients presented to the ED without Regional Poison Control Center referral. Of the total 235 patients presenting to ED, 76 (32%) received a therapeutic intervention. Of 231 total opioid exposures, 31 exposures were administered naloxone. Three children underwent endotracheal intubation. Sixty-five patients were hospitalized, with a median length of stay of 1 day. Although there were no fatalities, 1 child suffered severe morbidity (anoxic brain injury). CONCLUSIONS: While opioid exposures in young children are a common and potentially life-threatening problem, most children remain asymptomatic. The majority of patients are able to be discharged from the ED after observation, and of those who are admitted, most have favorable outcomes and brief hospital stays. A small number of these patients require considerable medical interventions.

A cross sectional study of outcomes of muscle pedicle grafting in neck of femur fractures and avascular necrosis of femoral head.

Avascular necrosis (AVN) of the femoral head is a progressive disease that generally affects patients in the second through fifth decades of life; if left untreated, it leads to complete deterioration of the hip joint. Treatments range from simple decompression of the femoral head, to muscle pedicle bone grafting of the involved area, or by using a vascularized fibular graft with varying degree of success. If the disease have progresses further causing secondary arthritis, Total Hip Arthroplasty may be necessary. We present a study of management of 60 young patients aged less than 50 years having either early stage AVN (stage I and II A/B of Ficat & Arlet classification) or Neck of the femur fractures, treated with quadratus femoris muscle pedicle bone grafting & cancellous screws. With aim To evaluate the results of the above modality in the management of AVN of the hip & neck femur fractures and to study the radiological & functional outcome of the procedure in young patients.

Discovery of 5-(2-chloro-4'-(1H-imidazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-tetrazole as potent and orally efficacious S-nitrosoglutathione reductase (GSNOR) inhibitors for the potential treatment of COPD.

Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure-activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: <15 nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD.

Alleviating CYP and hERG liabilities by structure optimization of dihydrofuran-fused tricyclic benzo[d]imidazole series - Potent, selective and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-2.

In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106 mg/kg).

Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1.

This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3 mg/kg in guinea pig.

Tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives as microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors: SAR and in vivo efficacy in hyperalgesia pain model.

A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F=33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model.

Design and synthesis of novel xanthine derivatives as potent and selective A2B adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases.

Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A2B adenosine receptor (A2BAdoR). Selective antagonists have been shown to attenuate airway reactivity and improve inflammatory conditions in pre-clinical studies. Hence, the identification of novel, potent and selective A2BAdoR antagonist may be beneficial for the potential treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). Towards this effort, we explored several prop-2-ynylated C8-aryl or heteroaryl substitutions on xanthine chemotype and found that 1-prop-2-ynyl-1H-pyrazol-4-yl moiety was better tolerated at the C8 position. Compound 59, exhibited binding affinity (Ki) of 62 nM but was non-selective for A2BAdoR over other AdoRs. Incorporation of substituted phenyl on the terminal acetylene increased the binding affinity (Ki) significantly to <10 nM. Various substitutions on terminal phenyl group and different alkyl substitutions on N-1 and N-3 were explored to improve the potency, selectivity for A2BAdoR and the solubility. In general, compounds with meta-substituted phenyl provided better selectivity for A2BAdoR compared to that of para-substituted analogs. Substitutions such as basic amines like pyrrolidine, piperidine, piperazine or cycloalkyls with polar group were tried on terminal acetylene, keeping in mind the poor solubility of xanthine analogs in general. However, these substitutions led to a decrease in affinity compared to compound 59. Subsequent SAR optimization resulted in identification of compound 46 with high human A2BAdoR affinity (Ki = 13 nM), selectivity against other AdoR subtypes and with good pharmacokinetic properties. It was found to be a potent functional A2BAdoR antagonist with a Ki of 8 nM in cAMP assay in hA2B-HEK293 cells and an IC50 of 107 nM in IL6 assay in NIH-3T3 cells. Docking study was performed to rationalize the observed affinity data. Structure-activity relationship (SAR) studies also led to identification of compound 36 as a potent A2BAdoR antagonist with Ki of 1.8 nM in cAMP assay and good aqueous solubility of 529 µM at neutral pH. Compound 46 was further tested for in vivo efficacy and found to be efficacious in ovalbumin-induced allergic asthma model in mice.

A2B adenosine receptor antagonists: Design, synthesis and biological evaluation of novel xanthine derivatives.

A2BAdoR is a low affinity adenosine receptor that functions by Gs mediated elevation of cAMP and subsequent downstream signaling. The receptor has been implicated in lung inflammatory disorders like COPD and asthma. Several potent and selective A2BAdoR antagonists have been reported in literature, however most of the compounds suffer from poor pharmacokinetic profile. Therefore, with the aim to identify novel, potent and selective A2BAdoR antagonists with improved pharmacokinetic properties, we first explored more constrained form of MRS-1754 (4). To improve the metabolic stability, several linker modifications were attempted as replacement of amide linker along with different phenyl or other heteroaryls between C8 position of xanthine head group and terminal phenyl ring. SAR optimization resulted in identification of two novel A2BAdoR antagonists, 8-{1-[5-Oxo-1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-xanthine (31) and 8-(1-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-xanthine (65), with high binding affinity (Ki = 1 and 1.5 nM, respectively) and selectivity for A2BAdoR with very good functional potency of 0.9 nM and 4 nM, respectively. Compound 31 and 65 also displayed good pharmacokinetic properties in mice with 27% and 65% oral bioavailability respectively. When evaluated in in vivo mice model of asthma, compound 65 also inhibited airway inflammation and airway reactivity in ovalbumin induced allergic asthma at 3 mpk dose.

A radiographic survey of agenesis of the third molar: A panoramic study.

PURPOSE: It is a well-known fact that nature tries to eliminate what is not in use. Because of this, the number of certain teeth which are no longer necessary for function are either getting increasingly impacted or are not developing at all. This is especially the case where third molars are concerned. Furthermore, the presence or absence of the third molar is significant to all branches of dentistry and in particular, forensic dentistry. OBJECTIVES: The objectives of this study is to assess (1) The prevalence of third molar agenesis in population of age group 18-25 years. (2) The genderwise difference of third molar agenesis. (3) The difference between maxilla and mandible. MATERIALS AND METHODS: Dental patients, who are advised or referred for orthopantomograph, visited to the Department of Oral Medicine and Radiology were included in the study. The study population comprised 300 patients. STATISTICAL ANALYSIS: The data obtained was tabulated and subjected to statistical analysis. SPSS version 17 software was used for the analysis of the data. The Chi-square test was used for the same. RESULTS: The incidence of agenesis of the third molar is significantly higher for tooth number 18 (P < 0.001). Overall, it is significantly higher among females compared to the males (P < 0.001) in our study population. CONCLUSION: (1) The present study reports 46.7% agenesis of the third molar. (2) The frequency of third molar agenesis was found significantly greater in the females. (3) Third molar agenesis showed a greater predilection in maxilla compared to mandible.

Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise?

Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel is expressed abundantly on the C fibers that innervate almost entire respiratory tract starting from oral cavity and oropharynx, conducting airways in the trachea, bronchi, terminal bronchioles, respiratory bronchioles and upto alveolar ducts and alveoli. Functional presence of TRPA1 on non-neuronal cells got recognized recently. TRPA1 plays a well-recognized role of "chemosensor", detecting presence of exogenous irritants and endogenous pro-inflammatory mediators that are implicated in airway inflammation and sensory symptoms like chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cystic fibrosis. TRPA1 can remain activated chronically due to elevated levels and continued presence of such endogenous ligands and pro-inflammatory mediators. Several selective TRPA1 antagonists have been tested in animal models of respiratory disease and their performance is very promising. Although there is no TRPA1 antagonist in advanced clinical trials or approved on market yet to treat respiratory diseases, however, limited but promising evidences available so far indicate likelihood that targeting TRPA1 may present a new therapy in treatment of respiratory diseases in near future. This review will focus on in vitro, animal and human evidences that strengthen the proposed role of TRPA1 in modulation of specific airway sensory responses and also on preclinical and clinical progress of selected TRPA1 antagonists.

Discovery of 2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitor.

The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d {2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide} exhibited excellent mPGES-1 enzyme (IC50: 8nM), cell (A549 IC50: 16.24nM) and human whole blood potency (IC50: 249.9nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7mg/kg, respectively.

Treatment of Oral Leukoplakia with Diode Laser: a Pilot Study on Indian Subjects.

BACKGROUND: To evaluate the safety, convenience and effectiveness of 940nm diode laser for treatment of homogenous leukoplakia. MATERIALS AND METHODS: Ten patients having homogenous leukoplakia which were diagnosed clinically were selected from an Indian dental educational institution for the study. Toludine blue staining was applied locally over the lesion. The area where there was increased uptake of stain was excised using a 940 nm EZLASE TM diode laser (BIOLASE-USA). RESULTS: Although various treatment modalities have been tried and the search continues for novel treatment modalities for complete removal of homogenous leukoplakia, from results of our preliminary pilot study it is clear that the use of 940 nm diode laser as a treatment modality for homogenous leukoplakia is a good substitute. Healing was perfect without any complication within a duration of 1 month. Pain intensity was also mild and absolutely zero on the VAS scale after 1 month follow up. CONCLUSIONS: 940 nm diode lasers are safe and can be effectively used as a treatment modality of homogenous leukoplakia, without any complication and without compromising health and oral function of patients. Considering recurrence factor, long term follow up for patients is a must.

Transient receptor potential ankyrin 1 receptor activation in vitro and in vivo by pro-tussive agents: GRC 17536 as a promising anti-tussive therapeutic.

Cough is a protective reflex action that helps clear the respiratory tract which is continuously exposed to airborne environmental irritants. However, chronic cough presents itself as a disease in its own right and despite its global occurrence; the molecular mechanisms responsible for cough are not completely understood. Transient receptor potential ankyrin1 (TRPA1) is robustly expressed in the neuronal as well as non-neuronal cells of the respiratory tract and is a sensor of a wide range of environmental irritants. It is fast getting acceptance as a key biological sensor of a variety of pro-tussive agents often implicated in miscellaneous chronic cough conditions. In the present study, we demonstrate in vitro direct functional activation of TRPA1 receptor by citric acid which is routinely used to evoke cough in preclinical and clinical studies. We also show for the first time that a potent and selective TRPA1 antagonist GRC 17536 inhibits citric acid induced cellular Ca(+2) influx in TRPA1 expressing cells and the citric acid induced cough response in guinea pigs. Hence our data provides a mechanistic link between TRPA1 receptor activation in vitro and cough response induced in vivo by citric acid. Furthermore, we also show evidence for TRPA1 activation in vitro by the TLR4, TLR7 and TLR8 ligands which are implicated in bacterial/respiratory virus pathogenesis often resulting in chronic cough. In conclusion, this study highlights the potential utility of TRPA1 antagonist such as GRC 17536 in the treatment of miscellaneous chronic cough conditions arising due to diverse causes but commonly driven via TRPA1.

Pemphigus vulgaris--a report of three cases.

Pemphigus vulgaris (PV) is a potentially life-threatening illness that manifests in the mouth and on skin. In a majority of patients it affects the oral mucosa and is sometimes difficult to diagnose when only mucosal involvement is present. In an attempt to highlight the proper treatment plan of this potentially fatal disorder, the authors document a report of three cases. These patients were prescribed conventional steroids which brought about partial relief but early recurrence with discontinuation of the drug. Subsequent management of these patients with azathioprine along with corticosteroids improved the outcome of the disease with longer remission periods. In this case series, the steroid sparing effect of azathioprine was achieved successfully and hence needs to be considered as a primary drug in management of PV.

Nasal myiasis with orbital and palatal complications.

A 15-year-old girl presented with a chief complaint of bleeding from her nose. She had noticed worms emerging from her right nostril. She had a continuous dull ache on the right side of her nose, spreading over the maxillary sinus area, and on the infra-orbital margin on the same side. She complained of difficulty breathing through her right nostril and a foul smell, which was associated with orbital oedema. Intra-oral examination revealed erythema of the soft palate on the same side, which was tender on palpation. Her condition was diagnosed as nasal myiasis with orbital and palatal extension. Nasal myiasis was treated by surgical removal of the maggots and with Ivermectin and local application of turpentine. The symptoms resolved and the dangers of orbital complications and penetration into the intracranial cavity were averted. The serious short-term complications of nasal myiasis were prevented by prompt treatment.

Differential toxicity of sulfur mustard administered through percutaneous, subcutaneous, and oral routes.

Sulfur mustard (SM), chemically 2,2'-dichloro diethyl sulphide, is an incapacitating and extremely toxic chemical warfare agent. It causes serious blisters on contact with human skin. While screening various antidotes against its toxicity, we observed that SM was more toxic through percutaneous (p.c.) route compared to oral (p.o.) and subcutaneous (s.c.) routes. The LD(50) of SM in female mice was found to be 5.7, 8.1 and 23.0 mg/kg through p.c., p.o., and s.c. routes, respectively. The body weight of the animals was monitored and it was found that percentage body weight loss was more in the p.c. route. There was significant DNA fragmentation in liver in all the three routes evaluated at 19.3 mg/kg dose of SM. The depletion of hepatic GSH content was found to be more in the p.c. route of exposure compared to s.c. route. There was significant reduction in WBC count in all the three routes of exposure. Histopathological evaluation of lung, liver, and spleen also showed that the damage was more in the p.c. route and severity of lesions was dependent on the dose of exposure. The most affected organ was liver by all the three routes. LD(50) was also determined in male rats and it was found to be 2.4, 2.4, and 3.4 mg/kg through p.c., p.o. and s.c. routes respectively. Since skin contains maximum number of metabolically active and rapidly dividing cells, differential metabolism of SM cannot be ruled out. Probably, this is the first report of a chemical showing more toxicity through p.c. route compared to s.c. route.