First-in-Human Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of NTM-1633, a Novel Mixture of Monoclonal Antibodies against Botulinum Toxin E.

Botulism is a rare, life-threatening paralytic disease caused by botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given postexposure and challenging to produce and administer. NTM-1633 is an equimolar mixture of 3 human IgG monoclonal antibodies, E1, E2, and E3, targeting BoNT serotype E (BoNT/E). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1633. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1633 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1633; 6 placebo), and no deaths were reported. An unrelated serious adverse event was reported in a placebo subject. Adverse events in the NTM-1633 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1633 has a favorable PK profile with a half-life >10 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1633 also demonstrated low immunogenicity. NTM-1633 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile supports further development as a treatment for BoNT/E intoxication and postexposure prophylaxis.

Development of an indoor air purification system to improve ventilation and air quality.

Novel types of an air purification system for improving indoor air quality (IAQ) and ventilation by reducing carbon dioxide (CO2) concentration were assessed in office buildings in India. This study provides an evaluation of a control system that reduces toxic gases in indoor spaces using the synthesized filter media. The reduction potential of CO2 levels of the control system, for different air handling unit (AHU) capacities, were compared. Experimental studies and in-situ evaluation has been done using the air purification system. Ventilation rates and CO2 concentration are monitored before and after the installation of the purification system. The results of the investigation indicated CO2 concentrations were reduced by more than 40% with the purification system. Fresh air intake to maintain the desired ventilation rates has been reduced to more than 50%, further reduce heat load. Ventilation flow rates were achieved with this air purification system. This system has the potential aspiration in controlling the CO2 levels in mechanically ventilated buildings. CO2 concentrations were brought down to permissible limits and maintained further without introducing fresh air into the system. Based on the results, assessment of the air purification system is a crucial and wide range of applicability in indoor environments to reduce cooling costs.

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B.

Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments, including an equine antitoxin and human immune globulin, are given postexposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life of >20 days for the 0.330-mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent antidrug antibody responses in the low and middle dosing groups and none at the highest dose. NTM-1632 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under identifier NCT02779140.).

Clinical and Radiological Review of a Semi-Constrained Cervical Disc Replacement with a Ceramic-Ceramic Articulation with a Minimum Seven Years Follow-Up.

PURPOSE OF THE STUDY Artificial cervical disc replacement (CDR) has emerged as a viable treatment alternative to fusion for the management of symptomatic compressive radiculopathy and potentially for cervical myelopathy. The aim of our study was to evaluate the clinical and radiological outcomes of patients treated with a second generation semi-constrained CDR with a ceramicceramic articulation. MATERIAL AND METHODS A prospective cohort study of all patients undergoing a cervical disc replacement for cervical disc pathology, during the period from April 2007 to April 2011 using a ceramic-ceramic disc replacement comprised the study group. 52 patients were available for final clinical and radiological follow-up. Both, clinical and radiological evaluation were performed at each clinical visit at 6 weeks, 6 months, 12 months, 2 years, 5 years and 7 years. RESULTS There were a total of 52 patients, with 44 single level cases and 8 two level cases. The NDI improved significantly (p < 0.05) from a mean preoperative score of 56 % to a score of 20% at final follow-up. The mean preoperative mobility at the index level unit was 12.2 ± 4.5°, this decreased to 7.9 ± 3.2° at six weeks, but slightly increased to 12.9 ± 2.9° at final follow-up (gain not significant). Heterotrophic ossification (HO) was noted in 13 (25%) patients. CONCLUSIONS Cervical disc replacement with a ceramic-ceramic bearing surface is a viable option in the treatment of variety of cervical pathologies. This ceramic-ceramic interface may eliminate the potential problems of metallosis and poly-wear but further longer-term results should be studied. Key words: Cervical spine; disc replacement; ceramic articulation; neck disability; heterotrophic ossification.

Impact of urban heat island on meteorology and air quality at microenvironments.

This study analyzes the air pollution characteristics and their relation to meteorological conditions in Chennai, India. Meteorological conditions were the primary factor determining variations in daily average pollutant concentrations. The influence of urban infrastructure on meteorology is an important prediction on air quality. Understanding of the seasonal and diurnal secondary pollutant concentrations as a function of local meteorological conditions is necessary for urban air quality management. Micro-scale models for analyzing the surface layer interactions with the surrounding environment have recently gained attention. An attempt has been made to understand the effect of meteorology on air quality. This comprehensive study aims to assess the influence of local meteorology on urban air quality. The correlation was established between the change in meteorological parameters and mixing height on air quality at selected locations in a tropical urban environment. Results indicated the significant impact of land use patterns on the dispersion of air quality at study locations. Seasonal variations of ambient air temperatures at study locations were found to be more than 3°C in summer. Average mixing height variation among the study locations was observed to be more than 200 meters in summer. Results indicated the importance of wind velocity on the mixing height at study locations. The average concentrations of air quality parameters showed significant variation among the study locations. The maximum ozone (O3) concentration was recorded at the Central Business District (CBD) during the afternoon, i.e., around 38.3 ppb, whereas it was 26.8 and 14.6 ppb at the Residential Area (RA) and Urban Baseline (UBL), respectively. A strong correlation was observed between ambient temperature and O3 concentration during summer. In the winter, the average O3 concentration in all three-study locations increased to 45.3 ppb, 45.8 ppb, and 58.5 ppb at UBL, RA, and CBD sites, respectively. The study reveals the impact of microenvironments on air quality. Implications: An attempt has been made to study the seasonal and diurnal variation of air quality levels in selected study regions with land cover change. This article focuses mainly on the surface temperature intensity variations with respect to the percentage of land use pattern change in Chennai city, India, and the subsequent effect on meteorology of dispersion conditions and air quality parameters has been studied. The relationship between local meteorology and air quality has been established.

Using antifibrinolytics in the peripartum period - concern for a hypercoagulable effect?

INTRODUCTION: Although antifibrinolytic agents are used to prevent and treat hemorrhage, there are concerns about a potential increased risk for peripartum venous thromboembolism. We sought to determine the impact of tranexamic acid and ɛ-aminocaproic acid on in vitro clotting properties in pregnancy. METHODS: Blood samples were obtained from healthy pregnant, obese, and preeclamptic pregnant women (n = 10 in each group) prior to delivery as well as from healthy non-pregnant controls (n = 10). Maximum clot firmness (MCF) and clotting time (CT) were measured using rotation thromboelastometry in the presence of tranexamic acid (3, 30, or 300 µg/mL) or ɛ-aminocaproic acid (30, 300, or 3000 µg/mL). ANOVA and regression analyses were performed. RESULTS: Mean whole blood MCF was significantly higher in healthy pregnant vs. non-pregnant women (66.5 vs. 57.5 mm, p < 0.001). Among healthy pregnant women, there was no significant difference between mean MCF (whole blood alone, and with increasing tranexamic acid doses = 66.5, 66.1, 66.4, 66.3 mm, respectively; p = 0.25) or mean CT (409, 412, 420, 424 sec; p = 0.30) after addition of tranexamic acid. Similar results were found using ɛ-aminocaproic acid. Preeclamptic women had a higher mean MCF after the addition of ɛ-aminocaproic acid and tranexamic acid (p = 0.05 and p = 0.04, respectively) compared to whole blood alone. CONCLUSIONS: Pregnancy is a hypercoagulable state, as reflected by an increased MCF compared to non-pregnant women. Addition of antifibrinolytic therapy in vitro does not appear to increase MCF or CT for non-pregnant, pregnant, and obese women. Whether antifibrinolytics are safe in preeclampsia may require further study.

Obesity and recurrent intervertebral disc prolapse after lumbar microdiscectomy.

INTRODUCTION: The primary aim of this study was to investigate the relationship between obesity and recurrent intervertebral disc prolapse (IDP) following lumbar microdiscectomy. METHODS: A retrospective review of case notes from 2008 to 2012 was conducted for all patients who underwent single level lumbar microdiscectomy performed by a single surgeon. All patients were followed up at two weeks and six weeks following surgery, and given an open appointment for a further six months. RESULTS: A total of 283 patients were available for analysis: 190 (67%) were in the non-obese group and 93 (32.9%) in the obese group. There was no statistical difference in postoperative infection, dural tear or length of stay between the non-obese and obese groups. Recurrent symptomatic IDP was seen in 27 patients (9.5%) confirmed by magnetic resonance imaging. Nineteen (10.0%) were in the non-obese group and eight (8.6%) in the obese group (p>0.8). CONCLUSIONS: In our study, obesity was not a predictor of recurrent IDP following lumbar microdiscectomy. Our literature review confirmed that this study reports the largest series to date analysing the relationship between obesity and recurrent IDP following lumbar microdiscectomy in the British population.

Fine needle aspiration cytology--a reliable diagnostic tool in the diagnosis of thyroid gland enlargements.

To evaluate the accuracy and efficacy of fine needle aspiration cytology (FNAC) in the diagnosis of Thyroid gland enlargements. A retrospective analysis was done at Department of Pathology, Government Medical College and General Hospital, Anantapur, Andhra Pradesh, India. One hundred and fifty cases were included in this study. However in 10 cases aspirate was unsatisfactory and in 20 cases surgery was not performed and these cases were excluded from study. A total of 120 cases included in the final study. Detailed history, physical examination, routine investigations and other details of 120 patients were collected. FNAC with minimum two passes were performed in each case. Staining done with Haematoxylin and Eosin stain and Papanicolaou stains. FNAC smears and histopathology slides were reviewed. Among 120 cases 100 (83.66%) were reported cytologically as benign and 20 (16.66%) were malignant. But histologically 98 (81.66%) were benign and 22 (18.33%) were malignant. Commonest benign lesion of thyroid in both cytology and histology was nodular colloid goiter. Follicular adenoma was the second commonest one. Among malignant conditions papillary carcinoma was the commonest one in our FNAC samples, follicular carcinoma was the commonest in our histopathology samples. Four cases of false positive and 6 cases of false negative were observed. Sampling errors were mainly responsible for these false negative diagnoses. FNAC showed an accuracy of 96.6%, sensitivity 75%, specificity 95.83%, positive predicative value (PPV) 81.81% and negative predicative value (NPV) of 93.81%. Our results were similar to other international studies and suggest that FNAC is more specific and sensitive in detecting thyroid malignancy. Therefore its useas a reliable diagnostic test cannot be over emphasized. FNAC is an accurate and reliable diagnostic tool to evaluate the cause of Thyroid gland enlargements provided strict adherence to adequacy criteria are maintained.

A contemporary scientific support on role of ancient ayurvedic diet and concepts in diabetes mellitus (madhumeha).

Diabetes Mellitus (Madhumeha) is a well-known clinical syndrome since antiquity. First time the role of Diet in the prevention, etiology and treatment of Diabetes was mentioned in Ayurveda under the heading of Prameha and Madumeha. Caraka Samhita, Susruta Samhita and other Ayurvedic classics have appropriate descriptions on the role of diet, habits and life style in Prameha and Madhumeha, which is akin to Diabetes. Recent modern (contemporary) Researches and statistics support these descriptions. Aim of this article is to alarm people regarding role of diet and lifestyle in Diabetes through Ayurvedic approach and contemporary scientific correlation with support of clinical and statistical data.

Contribution of kautilya arthasashtra towards dravyaguna, rasasastra and bhaishajyakalpana branches of ayurvedic medicine.

It is believed Kautilya, whose name was Vishnugupta and is popular as Chanakya (The son of Chanaka) wrote Arthasastra. This article is mainly based on Kautilya's Arthasastra, translated by R. Shamasastry. In the preface of 1(st) to 5(th) edition of this text, the translator Dr. R. Shamasastry tried to clarify the uncertainty regarding the name of the author and the time of the text. Kamandaka and Dandi quotation support the time of this treatise somewhere between 321 and 300 B.C. These quotations also support the authorship of Vishnugupta. According to Kadambari, the author of Arthasastra was Kautilya and according to Manu and Dharmasastras, Chanakya had written this Arthasastra. Though there are some controversies regarding the name of the author and time of this text, translator R. Shamasastry tried his level best in providing proper support for naming this text as Kautilya'sArthasastra as the original available manuscript contains the name of Kautilya at the end of each of the hundred and fifty chapters of the work. Still there is controversy regarding the exact time of this text. If views of many scholars is considered, time of the text can be placed between 3(rd) century B.C. to 3(rd) century A.D. This translated original text contains 15 books (Basic discussions of the text), 150 chapters, 180 sections and 6000 Slokas (Thirty two syllables are considered as one Sloka).

Completion rates of anterior and posterior continuous curvilinear capsulorrhexis in pediatric cataract surgery for surgery performed by trainee surgeons with the use of a low-cost viscoelastic.

CONTEXT: Pediatric cataract surgery is traditionally done with the aid of high-molecular-weight viscoelastics which are expensive. It needs to be determined if low-cost substitutes are just as successful. AIMS: The study aims to determine the success rates for anterior and posterior capsulorrhexis and intraocular lens (IOL) implantation in the bag for pediatric cataract surgery performed with the aid of a low-molecular-weight viscoelastic. SETTINGS AND DESIGN: Nonrandomized observational study. MATERIALS AND METHODS: Children less than 6 years of age who underwent cataract surgery with IOL implantation in the period May 2008-May 2009 were included. The surgeries were done by pediatric ophthalmology fellows. A standard procedure of anterior capsulorrhexis, lens aspiration with primary posterior capsulorrhexis, anterior vitrectomy, and IOL implantation was followed. Three parameters were studied: successful completion of anterior and posterior capsulorrhexis and IOL implantation in the bag. RESULTS: 33 eyes of 28 children were studied. The success rate for completion was 66.7% and 88.2 % for anterior and posterior capsulorrhexis, respectively. IOL implantation in the bag was successful in 87.9%. CONCLUSIONS: 2% hydroxypropylmethylcellulose is a viable low-cost alternative to more expensive options similar to high-molecular-weight viscoelastics. This is of great relevance to hospitals in developing countries.

Cervical dilation as a predictor of pregnancy outcome following emergency cerclage.

OBJECTIVE: To determine whether cervical dilation at the time of physical examination indicated cerclage placement can predicts latency and gestational age at delivery. METHODS: A retrospective cohort study of all women who underwent physical examination indicated cerclage placement from 1996 to 2011 at Duke University Hospital (DUH) was performed. Physical examination indicated cerclage was defined as cerclage placement after 16 weeks in women with a cervical length of less than 2.5 cm and/or cervical dilation greater than or equal to 1 cm at time of procedure. Subjects were divided into two groups depending on cervical dilation at time of procedure (2 cm, <2 cm) for comparison. A multivariate linear regression model for the outcome gestational age of delivery was constructed, controlling for confounding variables. RESULTS: A total of 110 women with complete data were available for analysis. Median gestational age at cerclage placement was similar between the two groups (20.3 vs. 20.3 weeks, p = 0.8). Women with cervical dilatation ≥ 2 cm dilation delivered at an earlier median gestational age than women with cervical dilation <2 cm (27.0 vs. 35.6 weeks, p < 0.001). Cervical dilation at the time of cerclage placement independently predicted gestational age at delivery while controlling for use of intracervical Foley balloon catheter for membrane reduction, cerclage suture type, history of prior preterm birth, race, insurance status, and tobacco use. CONCLUSIONS: Women who receive a rescue cerclage are more likely to deliver at an earlier gestational age when cervical dilation is ≥ 2 cm at the time of procedure.

Religiosity is an important part of coping with grief in pregnancy after a traumatic second trimester loss.

Women (n = 15) who were pregnant after a traumatic late pregnancy loss (termination because of fetal death or serious anomalies) completed psychometric screening tests and scales, including the Perinatal Grief Scale (PGS), the Impact of Event Scale (IES), the Duke Depression Inventory (DDI), the Generalized Anxiety Disorder-7 (GAD), and the Hoge Scale for Intrinsic Religiosity (IR). Despite a mean elapsed time since the prior loss of 27 (range, 7-47) months, half (7/15, 47%) of the combined groups had high levels of grief on the PGS. Multiple positive scores on psychometric tests were frequent: Sixty percent (9/15) had high scores on the PGS Active Grief subscale or on the IES. Forty percent (6/15) had a high score on the DDI, and 17% (3/15) on the GAD. IR scores significantly and negatively correlated with scores on the Despair subscale of the PGS. The results from this pilot study suggest that high levels of grief and PTS symptoms are significant problems for pregnant women who have suffered late loss of a wanted pregnancy. Religiosity may play an important part in maternal coping during these stressful pregnancies.

Clinicopathological analysis of ovarian tumors--a study on five years samples.

Ovarian neoplasms have become increasingly important not only because of the large variety of neoplastic entities but more because they have gradually increased the mortality rate due to female genital cancers. A total of 120 cases of ovarian tumors were studied at the Department of Pathology, Konaseema Institute of Medical Sciences, Amalapuram, India, during the period of March 2005 to March 2010, to find out frequency of different histological patterns of ovarian tumors at Konaseema Region. Among 120 cases, majority 86 (71.6%) were benign, but alarming number 30 (25.0%) were malignant, remaining 4 cases were borderline. The commonest histological pattern observed in the study was epithelial tumors (61.6%). The commonest benign tumor was serous cyst adenoma, while; the commonest malignant tumors were granulosa cell tumor and endometrial carcinoma. Epithelial tumors were commonest variety of ovarian tumors followed by germ cell tumors. A relatively high number of malignancies were observed in this study.

Pregnancy outcomes associated with viral hepatitis.

The aim of this study was to examine the contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to pregnancy-related complications including gestational diabetes mellitus (GDM), preterm birth (PTB), intrauterine growth restriction (IUGR), pre-eclampsia, antepartum haemorrhage and cholestasis. The Nationwide Inpatient Sample was queried for all pregnancy-related discharges, pregnancy complications and viral hepatitis from 1995 to 2005. Logistic regression was used to examine the association between HBV, HCV, HBV + HCV and pregnancy-related complications including GDM, PTB, IUGR, pre-eclampsia, antepartum haemorrhage, cholestasis and caesarean delivery. Model covariates included maternal age, race, insurance status, substance use and medical complications including liver complication, hypertension, HIV, anaemia, thrombocytopenia and sexually transmitted infections. Of 297 664 pregnant women data available for analysis, 1446 had a coded diagnosis of HBV, HCV or both. High-risk behaviours, such as smoking, alcohol and substance use were higher in women with either HBV or HCV. Women with HBV had an increased risk for PTB (aOR 1.65, CI [1.3, 2.0]) but a decreased risk for caesarean delivery (aOR 0.686, CI [0.53, 0.88]). Individuals with HCV had an increased risk for GDM (aOR 1.6, CI [1.0, 2.6]). Individuals with both HBV and HCV co-infection had an increased risk for antepartum haemorrhage (aOR 2.82, CI [1.1, 7.2]). There was no association of viral hepatitis with IUGR or pre-eclampsia. Women with hepatitis have an increased risk for complications during pregnancy. Research to determine the efficacy and cost-effectiveness of counselling patients about potential risks for adverse outcomes is warranted.

Bleeding per vaginam is associated with funisitis in women with preterm prelabour rupture of the fetal membranes.

OBJECTIVE: To evaluate the risk of funisitis among women with preterm prelabour rupture of the membranes (PPROM) and subsequent bleeding per vaginam. DESIGN: Prospective cohort study. SETTING: A University Hospital in the USA. POPULATION: A total of 157 women with PPROM, divided into those with bleeding per vaginam during the hospital admission (n = 46) and those without bleeding per vaginam (n = 111). METHODS: Pathologist blinded to bleeding status assessed placental pathology for funisitis. MAIN OUTCOME MEASURES: Funisitis. RESULTS: Women with bleeding per vaginam were more likely to have funisitis (67.4% versus 36%, P < 0.001) compared with those without bleeding. Logistic regression demonstrated that bleeding per vaginam predicted funisitis after controlling for gestational age at admission, latency period and gestational age at delivery. CONCLUSIONS: Among women with PPROM, those with bleeding per vaginam are more likely to have funisitis than those without bleeding per vaginam.

Triacontanol and jasmonic acid differentially modulate the lipid organization as evidenced by the fluorescent probe behavior and 31P nuclear magnetic resonance shifts in model membranes.

Fluorescence resonance energy transfer (FRET), time-resolved fluorescence and anisotropy decays were determined in large unilamellar vesicles (LUVs) of egg phosphatidylcholine with the FRET pair N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dipalmitoyl-sn-glycero-3-phospho-ethanolamine as donor and lissamine rhodamine B 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine as acceptor, using 2-ps pulses from a Ti:sapphire laser on LUVs with incorporated plant growth regulators: triacontanol (TRIA) and jasmonic acid (JA). FRET efficiency, energy transfer rate, rotation correlation time, microviscosity, and diffusion coefficient of lateral diffusion of lipids were calculated from these results. It was observed that TRIA and JA differentially modulated all parameters studied. The effect of JA in such modulations was always partially reversed by TRIA. Also, the generalized polarization of laurdan fluorescence indicated that JA enhances the degree of hydration in lipid bilayers to a larger extent than does TRIA. Solid-state (31)P magic-angle spinning nuclear magnetic resonance spectra of LUVs showed two chemical shifts, at 0.009 and -11.988 ppm, at low temperatures (20 degrees C), while at increasing temperatures (20-60 degrees C) only one (at -11.988 ppm) was prominent and the other (0.009 ppm) gradually became obscure. However, LUVs with TRIA exhibited only one of the shifts at 0.353 ppm even at lower temperatures and JA did not affect the chemical shifts.