Anatomic basis of Arnold's ear-cough reflex

A clinical survey of 500 patients revealed 4.2% incidence of Arnold's ear-cough reflex. The reflex was bilateral in 2.8% of the patients. It was also elicitable from the anterior meatal wall in 2% of the patients, thus questioning the classically taught distribution of Arnold's nerve. Arnold's nerve also mediates the auriculo-palatal, auriculo-lacrimal, auriculo-cardiac and the ear-vomiting reflexes; but these are less apparent and not so commonly encountered.     

Changes in some metabolic parameters in patients of nasal obstruction

In twenty seven patients of partial nasal obstruction 0₂ uptake and CO₂ output were measured by Noyon’s Diaferometer. Respiratory exchange ratio and resting metabolic rate were calculated. The results were compared with normal healthy persons. The findings suggest that increased respiratory efforts by patients of nasal obstruction lead to increased metabolic activity and there is shift in the energy substrate of metabolism.     

Unexpected detection of simian SA11-human reassortant strains of rotavirus G3P[8] genotype from diarrhea epidemic among tribal children of Western India

This investigation is in continuation with the earlier studies on diarrhea epidemic due to rotavirus, that occurred at Jawhar western India, among tribal children during Dec 2000-Jan 2001 published by National Institute of Virology, Pune. Three rotavirus strains were isolated in cell culture from fecal specimens of affected children. Monoclonal antibody ELISA and RT-PCR typed the isolates as G3P [8]. Two isolates agglutinated guinea pig erythrocytes thereby indicating their animal origin. Antiserum against simian G3, SA11 neutralized both the isolates largely than antiserum against human G3 (YO). Nucleotide sequencing of VP7 gene, nested PCR product of three isolates, and two original fecal specimens showed 100% identity with both simian G3, SA11 prototype and ROSVP7, SA11 strains whereas, lower identity (82%) with human G3 (YO) strain. Partial sequence analysis of the VP4 gene of fecal specimen FS-006964 & isolate I-006964 showed 99% identity with G1P[8] strain, while 80% identity with simian G3P[2], SA11 strain. Thus, the strains appeared to be reassortants between human and simian origin. Serological studies further supported the identity of the causative agent as simian G3, SA11 like strains. Neutralizing antibody titers at very low level against simian G3, SA11 as well as human G3 (YO) strains among the population at Jawhar suggested an overall lack of immunity against the virus. Seroconversion against simian G3, SA11 was shown by six out of seven child patients. Thus, simian G3, SA11 like strains are claimed for the first time as etiological agents of diarrhea in humans.     

Chemical variability in the essential oil components of Achillea millefolium agg. from different Himalayan habitats (India)

Essential oil diversity was studied in wild Achillea millefolium from two different high altitude Himalayan habitats (1600 m, 2850 m) and their cultivated populations under uniform environmental conditions at lower altitudes of Jammu (300 m). The populations proved to represent two different ecotypes: the 1,8-cineole type and the borneol type with appreciable differences in the contents of oils and mono- and sesquiterpenes. Populations from all these habitats showed considerable overlap in various constituents and the major components were characterized as beta-pinene (10.6 % - 17.7 %), 1,8-cineole (3.0 % - 15.1 %), borneol (0.2 % - 12.1 %), and beta-caryophyllene (8.5 % - 16.2 %). No variation in morphology and chromosome number was observed under comparable environmental conditions from different habitats. Preliminary investigation indicates the existence of different ecotypes from the Himalayan habitats.     

Periodontal health status among permanent residents of low, optimum and high fluoride areas in kolar district, India

Purpose: To assess and compare the periodontal health status among permanent residents of low, optimum and high fluoride areas in Kolar District, India. Materials and Methods: A house-to-house survey was conducted in a population consisting of 925 permanent residents aged 35 to 44 years in three villages having different levels of fluoride concentrations in the drinking water. The fluoride concentrations in selected villages were 0.48 ppm (low), 1.03 ppm (optimum) and 3.21 ppm (high). The ion selective electrode method was used to estimate the fluoride concentration in the drinking water. Periodontal status was assessed using the Community Periodontal Index (CPI) and loss of attachment (LOA). Results were analysed using the chi-square test and logistic regression. The chi-square test was used to find the group differences and logistic regression to find association between the variables. Results: The overall prevalence of periodontitis was 72.9%; specifically, prevalences were 95.4%, 76.3% and 45.7% in low, optimum and high fluoride areas, respectively. The number of sextants with shallow or deep pockets decreased (shallow pockets: 525, 438, 217; deep pockets: 183, 81, 34) from low to high fluoride areas (odds ratio: 71.3). The low fluoride area had a 7.9-fold higher risk of periodontitis than the optimum fluoride area and a 30-fold higher risk than the high fluoride area, which was highly significant (χ2 = 53.5, P < 0.0001 and χ2 = 192.8, P < 0.001, respectively). Conclusions: The severity of periodontal disease is inversely associated with the fluoride concentrations in drinking water. This relation can provide an approach to fluoride treatments to reduce the prevalence or incidence of this disease.     

CpG oligodeoxynucleotide 2006 and miltefosine, a potential combination for treatment of experimental visceral leishmaniasis

In view of the severe immunosuppression in visceral leishmaniasis (VL), a rational approach to effectively combat the parasitic scourge would be to enhance the immune status of the host. Use of CpG oligodeoxynucleotide (CpG-ODN) against leishmaniasis has previously been reported, especially as an immunomodulator and adjuvant with various immunogens. In the present study, experiments were carried out with BALB/c mice and hamsters infected with Leishmania donovani. Immunostimulating class B bacterial CpG-ODN namely, ODN-2006, was administered at various doses by the intraperitoneal (i.p.) route. The dose of CpG-ODN-2006 (1 nM/single dose) showing the most antileishmanial activity was given as free and liposomal forms with different doses of miltefosine, namely, 5 and 10 mg/kg of body weight, for 5 days in mice and hamsters, respectively. Among the various groups, mice coadministered liposomal CpG-ODN and miltefosine (5 mg/kg) showed the best inhibitory effect (97% parasite inhibition) compared with free CpG-ODN plus miltefosine and miltefosine, free CpG-ODN, and liposomal CpG-ODN given separately. Similar responses were observed in the case of hamsters, where the combination of liposomal CpG-ODN with miltefosine (10 mg/kg) gave 96% parasite inhibition. Promising antileishmanial efficacy was observed in animals treated with liposomal CpG-ODN and miltefosine.     

A concise and sequential synthesis of the nitroimidazooxazole based drug,Delamanid and related compounds

A concise, protection-group free and sequential route has been developed for the synthesis of the nitroimidazole based FDA-approved multi-drug resistant anti-tuberculosis drug, Delamanid and anti-leishmanial lead candidate VL-2098. The synthesis required chiral epoxides (11 and 17) as key intermediates. The chiral epoxide 11 was synthesised by sequential reaction cascades viz., allylation, selective N-arylation, Mitsunobu etherification, Sharpless asymmetric dihydroxylation and epoxidation, which do not require any special/dry reaction conditions. The steps involved towards the synthesis of epoxide also worked nicely in gram scales. After the synthesis of epoxide 11, the synthesis of Delamanid was achieved by reaction with 2-bromo-4-nitroimidazole 12 with an overall yield of 27%. Similarly, anti-leishmanial lead candidate VL-2098 was also synthesized in an overall yield of 36%.

A concise, protection-group free and sequential route has been developed for the synthesis of the nitroimidazole based FDA-approved multi-drug resistant anti-tuberculosis drug, Delamanid and anti-leishmanial lead candidate VL-2098.

Imidazoles are present in a wide variety of biologically relevant molecules exhibiting diverse pharmaceutical properties. Specifically, nitroimidazole containing compounds are active therapeutic agents against a wide variety of protozoan, bacterial (anaerobic) and leishmanial infections of humans and animals.¹ The notable examples of drugs are fexindazole,² metronidazole,³ benznidazole,⁴ tinidazole,⁵etc. Nitroimidazole was also well explored in the area of tuberculosis (TB) drug discovery (the structure of nitroimidazole containing drugs and lead compounds shown in Fig. 1).^6–9 CGI-17341 (I, developed by Ciba-Geigy, India) represents one of the very earliest outcomes but was not continued because of mutagenicity.⁶ Continued efforts to overcome the mutagenic liability led to the discovery of Delamanid (II, OPC-67683, a blockbuster against multi-drug resistant-TB, approved in 2014 by the EU)⁷ and Pretomanid^8a (III, PA-824, against multi-drug-resistant-MTB, approved in 2019 by the USFDA).¹⁰ Our involvement in the area of the TB drug discovery program and nitroimidazole chemistry^8b,c motivated us to develop a new concise and improved strategy towards the synthesis of Delamanid. The first synthesis of Delamanid was done by Tsubouchi et al. in 2004 (Otsuka Pharmaceutical Ltd. WO2004033463A1) which involved 16 steps (details shown in Fig. S1 of ESI^†).^11,12 The synthesis involves protection–deprotection strategy and made the process lengthy. Later on, in 2011, Otsuka had developed another concise route for Delamanid with improved yield (upper half of Fig. 2, details shown in Fig. S2 of ESI^†). This method involved the Sharpless epoxidation of 2-methyl allylalcohol followed by ring opening with 4-bromophenol. Then coupling with 4(4-trifluoromethoxy phenyl)piperidine fragment under palladium catalyzed conditions, which in turn was synthesized in 2–5 steps.¹³ Considering the importance of Delamanid, It could be better if more concise route was developed. In this regard, here we devised a route which involves sequential addition of fragments which not only avoid protection and deprotection but also provides the advantages of avoidance of dry conditions and costly intermediates. The lower half of Fig. 2 represents the strategy of the present method used for the synthesis of Delamanid, which involve the sequential coupling with following cascade viz., allylation, selective N-arylation, Mitsunobu ether formation, Sharpless dihydroxylation, epoxidation, ring opening and cyclization using inexpensive and easily available starting materials.Open in a separate windowFig. 1Nitroimidazole containing drugs and leads.Open in a separate windowFig. 2Previous and current approaches.The present synthesis started with 2-methylallyl chloride as first starting material and its selection is because of following reasons (i) as protecting group, (ii) inexpensive (33$ per 100 mL, Sigma) in comparison to 2-methylallyl alcohol (766$ per 100 mL, Sigma) which is used in earlier reported method and (iii) provide double bond functionality to generate epoxide via Sharpless dihydroxylation approach, which operates under open atmosphere conditions and avoids the anhydrous and dry environment as required for Sharpless epoxidation, used in the previous reported methods.^7,11b,12