Design, parallel synthesis of Biginelli 1,4-dihydropyrimidines using PTSA as a catalyst, evaluation of anticancer activity and structure activity relationships via 3D QSAR studies.

Biginelli 1,4-dihydropyrimidines are extensively screened for their potential anticancer activity in the last decade. In this context, a series of Biginelli 1,4-dihydropyrimidines were designed and synthesised using PTSA as an efficient catalyst. The synthesised 1,4-dihydropyrimidines were screened for their anticancer activity against MCF-7 breast cancer cells by measuring cytotoxicity. The compounds exhibited activity ranging from weak to significant in terms of percentage cytotoxicity which is proportional to the anticancer activity. Amongst the screened compounds, compounds 4, 6 and 8 exhibited potential anticancer activity. Furthermore, CoMSIA studies were performed to derive the structure activity relationships in a 3D grid space by plotting experimental vs predicted cytotoxic activities. We have an opinion that, this developed model helps us in future to develop more potential 1,4-dihydropyrimidines for their cytotoxicity or anticancer activity.

Kappa-on-Heavy (KoH) bodies are a distinct class of fully-human antibody-like therapeutic agents with antigen-binding properties.

We describe a Kappa-on-Heavy (KoH) mouse that produces a class of highly diverse, fully human, antibody-like agents. This mouse was made by replacing the germline variable sequences of both the Ig heavy-chain (IgH) and Ig kappa (IgK) loci with the human IgK germline variable sequences, producing antibody-like molecules with an antigen binding site made up of 2 kappa variable domains. These molecules, named KoH bodies, structurally mimic naturally existing Bence-Jones light-chain dimers in their variable domains and remain wild-type in their antibody constant domains. Unlike artificially diversified, nonimmunoglobulin alternative scaffolds (e.g., DARPins), KoH bodies consist of a configuration of normal Ig scaffolds that undergo natural diversification in B cells. Monoclonal KoH bodies have properties similar to those of conventional antibodies but exhibit an enhanced ability to bind small molecules such as the endogenous cardiotonic steroid marinobufagenin (MBG) and nicotine. A comparison of crystal structures of MBG bound to a KoH Fab versus a conventional Fab showed that the KoH body has a much deeper binding pocket, allowing MBG to be held 4 Å further down into the combining site between the 2 variable domains.

An electrical probe of the phonon mean-free path spectrum.

Most studies of the mean-free path accumulation function (MFPAF) rely on optical techniques to probe heat transfer at length scales on the order of the phonon mean-free path. In this paper, we propose and implement a purely electrical probe of the MFPAF that relies on photo-lithographically defined heater-thermometer separation to set the length scale. An important advantage of the proposed technique is its insensitivity to the thermal interfacial impedance and its compatibility with a large array of temperature-controlled chambers that lack optical ports. Detailed analysis of the experimental data based on the enhanced Fourier law (EFL) demonstrates that heat-carrying phonons in gallium arsenide have a much wider mean-free path spectrum than originally thought.

Rare presentation of bronchiectasis with multiple bronchial stones.

The incidence of bronchiectasis has declined markedly in developed countries with improvement in health care, antibiotics, vaccines and control of tuberculosis (<0.6/1000 persons), but is still high in developing countries. Early complete resection of affected lung segment remains the mainstay of treatment as it causes maximum improvement in symptoms, minimum deterioration of lung function and prevents disease progression. Surgery is indicated in unsuccessful medical treatment and complications of bronchiectasis e.g. haemoptysis, lung abscess, lung masses and pneumothorax. Bronchiectasis with multiple broncholithiasis is a very rare presentation and very few cases have been reported in literature so far. This article presents here, the symptoms and signs, operative and perioperative management and literature review of a case of bronchiectasis with multiple bronchial stones.

Measurement of the high-temperature Seebeck coefficient of thin films by means of an epitaxially regrown thermometric reference material.

The Seebeck coefficient of a typical thermoelectric material, silicon-doped InGaAs lattice-matched to InP, is measured over a temperature range from 300 K to 550 K. By depositing and patterning a thermometric reference bar of silicon-doped InP adjacent to a bar of the material under test, temperature differences are measured directly. This is in contrast to conventional two-thermocouple techniques that subtract two large temperatures to yield a small temperature difference, a procedure prone to errors. The proposed technique retains the simple instrumentation of two-thermocouple techniques while eliminating the critical dependence of the latter on good thermal contact. The repeatability of the proposed technique is demonstrated to be ±2.6% over three temperature sweeps, while the repeatability of two-thermocouple measurements is about ±5%. The improved repeatability is significant for reliable reporting of the ZT figure of merit, which is proportional to the square of the Seebeck coefficient. The accuracy of the proposed technique depends on the accuracy with which the high-temperature Seebeck coefficient of the reference material may be computed or measured. In this work, the Seebeck coefficient of the reference material, n+ InP, is computed by rigorous solution of the Boltzmann transport equation. The accuracy and repeatability of the proposed technique can be systematically improved by scaling, and the method is easily extensible to other material systems currently being investigated for high thermoelectric energy conversion efficiency.

A "2-omega" technique for measuring anisotropy of thermal conductivity.

A popular method of measuring the thermal conductivity of thin films and substrates, the "3-omega" method, is modified to yield a new technique for measuring the anisotropy in thermal transport in bulk materials. The validity of the proposed technique is established by measuring the thermal conductivity of strontium titanate, which is expected to be isotropic because of its cubic unit cell. The technique is then applied to rutile TiO(2). The analysis of experimental results on (100) and (001) TiO(2) reveals that the anisotropy is a function of the crystalline quality, as quantified by the effective thermal conductivity obtained through conventional "3-omega" measurements. The advantages of the proposed technique are similar to those of the standard "3-omega" method, namely the simplicity of sample preparation and measurement, and negligible errors due to radiation because of the small volume of material being heated. For anisotropy determination, the proposed technique has the additional advantage that a single sample is sufficient to determine both components of the thermal conductivity, namely the values in and perpendicular to the plane of cleavage. This is significant for materials in which there is a large variation in the crystalline quality from sample to sample. For such materials, it is unreliable to use two different samples, one for measuring the thermal conductivity in each direction. Experimental data are analyzed using a 3D Fourier-series based method developed in this work. The proposed method determines each component of the thermal conductivity with an estimated accuracy of about 10%.

Semimetal/semiconductor nanocomposites for thermoelectrics.

In this work, we present research on semimetal-semiconductor nanocomposites grown by molecular beam epitaxy (MBE) for thermoelectric applications. We study several different III-V semiconductors embedded with semimetallic rare earth-group V (RE-V) compounds, but focus is given here to ErSb:In(x)Ga(1−x)Sb as a promising p-type thermoelectric material. Nanostructures of RE-V compounds are formed and embedded within the III-V semiconductor matrix. By co-doping the nanocomposites with the appropriate dopants, both n-type and p-type materials have been made for thermoelectric applications. The thermoelectric properties have been engineered for enhanced thermoelectric device performance. Segmented thermoelectric power generator modules using 50 µ m thick Er-containing nanocomposites have been fabricated and measured. Research on different rare earth elements for thermoelectrics is discussed.

Radiotherapy-related axillary artery occlusive disease: percutaneous transluminal angioplasty and stenting. Two case reports and review of the literature.

Radiotherapy-related axillary artery occlusive disease is a relatively rare condition. This complication is usually encountered in patients with breast carcinoma treated by radiotherapy and might be frequently concealed by the presence of lymphoedema. We discuss this rare complication of radiotherapy treatment for breast cancer and present two cases and their successful treatment by a modified percutaneous transluminal angioplasty and stenting technique. A review of literature on the subject is also presented.

A population-based study of immunohistochemical detection of p53 alteration in bladder cancer.

The molecular pathology of bladder cancer has been the subject of considerable interest and mutation of the p53 gene, which has been associated with more invasive bladder cancer, has been widely studied. Further, there is evidence that p53 inactivation (either mutation or protein dysregulation), independent of stage, may be predictive of bladder cancer progression. In an effort to avoid possible biases associated with selection of more advanced cases, we examined p53 inactivation in a population-based study of bladder cancer in New Hampshire, using both mutation and immunohistochemical methods. We found the overall prevalence of mutation to be approximately 10%, while immunohistochemical analysis suggests that approximately 66% of the tumours have dysregulated p53 at the protein level. There was a significant association of mutation with persistent p53 staining, but there remained a marked number of tumours discordant for mutation and aberrant p53 immunohistochemistry. Based upon immunohistochemical staining alone, intensity rather than extent of p53 staining was more strongly related to tumour invasiveness. Additionally, all tumours with a mutation in exon 8 stained intensely. Taken together, this suggests that intense staining represents a distinct phenotype of dysfunctional protein. Our data indicate that population-based approaches to somatic alteration of p53 in bladder cancer are crucial to understanding the relationship of p53 changes to aetiology and the outcome of this disease, and further suggest that the pattern of immunohistochemical staining may represent distinct, discernible phenotypes. British Journal of Cancer (2004) 90, 1572-1576. doi:10.1038/sj.bjc.6601748 www.bjcancer.com Published online 6 April 2004

Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer.

The short arm of chromosome 3 is thought to harbor a novel oncogenic locus that is important in the genesis of lung cancer. The region at 3p21 is believed to contain a distinct locus that is sensitive to loss from the action of tobacco smoke carcinogens and has been reported to be specifically targeted for deletion in lung cancer. To investigate whether 3p21 alteration in lung cancer is associated with carcinogen exposure, PCR-based analysis was performed to detect loss of heterozygosity (LOH) on chromosome 3 at 3p21 in non-small cell lung carcinoma (NSCLC). We also measured instability at the BAT-26 locus, because the mismatch DNA repair gene, hMLH1, is found at 3p21. LOH at 3p21 was analyzed for association with the clinical features of NSCLC, p53 mutation status, polynuclear aromatic hydrocarbon-DNA adduct levels (measured using 32P-postlabeling) and carcinogen exposure information including cigarette smoking and asbestos exposure. Of 219 lung cancers, 150 cases (68.5%) were informative at the D3S1478 locus, and 44.2% of squamous cell carcinoma cases and 30.2% of adenocarcinoma cases showed 3p21 LOH. None of the cancers showed BAT-26 instability. The prevalence of 3p21 LOH was higher in both current and former smokers compared with never smokers and was higher in p53 mutated cases. Among squamous cell carcinoma cases, there was a strong association of increased 3p21 LOH with increasing polynuclear aromatic hydrocarbon-DNA adducts levels (P = 0.03), as well as an increased prevalence LOH with earlier age of smoking initiation (P = 0.02). Our results confirm that 3p21 LOH is strongly associated with measures of biologically effective dose of exposure to tobacco carcinogens. Our results also suggest that alterations of hMLH1 are not related to any of the reported associations, because there was no evidence of microsatellite instability. Finally, LOH in 3p21 may be an early molecular event in NSCLC, because it is significantly associated with a tendency to start smoking at a young age.

Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells.

Polymorphisms in several DNA repair genes have recently been identified, but little is known about their phenotypic significance. To determine whether variation in DNA repair genes is related to host DNA damage, we studied the association between polymorphisms in XRCC1 (codon 399) and ERCC2 (codon 751) and two markers of DNA damage, sister chromatid exchange (SCE) frequencies (n = 76) and polyphenol DNA adducts (n = 61). SCE frequencies were determined using a modified fluorescence-Giemsa method and polyphenol DNA adducts were determined using a P1-enhanced (32)P-post-labeling procedure. XRCC1 and ERCC2 genotypes were identified using PCR-RFLP. Mean SCE frequencies among current smokers who were homozygous carriers of the 399Gln allele in XRCC1 were greater than those in 399Arg/Arg current smokers. We also observed a possible gene-dosage effect for XRCC1 399Gln and detectable DNA adducts, and significantly more adducts among older subjects who were carriers of the 399Gln allele than in younger subjects with the 399Arg/Arg genotype. The polymorphism in ERCC2 was unrelated to SCE frequency or DNA adduct level. Our results suggest that carriers of the polymorphic XRCC1 399Gln allele may be at greater risk for tobacco- and age-related DNA damage.

Effectiveness of ampicillin and combination of penicillin and chloramphenicol in the treatment of pneumonias: randomized controlled trial.

OBJECTIVE: To assess the effectiveness of ampicillin and a combination of benzyl penicillin and chloramphenicol in the treatment of pneumonias. DESIGN: Randomized controlled trial. SETTING: Tertiary care hospital. SUBJECTS: Patients 5 months to 4 years old with pneumonias of < 2 weeks duration. Exclusion criteria included acute bronchiolitis, allergy to penicillin, postmeasles pneumonia or prior administration of trial antibiotics in full dose for more than 2 days. INTERVENTION: Patients were randomized to receive either ampicillin (100 mg/kg/day) or combination of benzyl penicillin (100,000 units/kg/day) and chloramphenicol (100 mg/kg/day). The outcome measure was cure rate. RESULTS: There were 52 and 49 patients in the ampicillin and the combination groups, respectively. There was no significant difference in the baseline characteristics between groups except, nasal flare and cyanosis which were less in benzyl penicillin plus chloramphenicol group. There was also no difference either in the primary outcome, cure rate or secondary outcomes (days for cure, duration of tachypnea, fever and grunt) in the two. CONCLUSION: Considering the potential toxicity of chloramphenicol and the number of injections and doses to be given for the combination, ampicillin as a single drug could be preferred for the treatment of pneumonias, in this part of the country.

Value of antibiotic therapy in tuberculin-positive children with parenchymal lung lesions.

BACKGROUND: A tuberculin-positive child with radiological evidence of a parenchymal lung lesion is likely to be treated for tuberculosis by a physician. However, non-tuberculous microbial infections may also cause parenchymal lung lesions. We tried to distinguish tuberculous from non-tuberculous lung lesions by administering a course of antibiotics. METHODS: Three hundred and five tuberculin-positive children with parenchymal lung lesions due to pneumonia, bronchiectasis (cylindrical and reversible) and minor fissure opacification were studied at the Tuberculosis Clinic, Institute of Child Health, Madras. Those with more serious forms of tuberculosis like miliary, cavitary and segmental lesions and with grade III and IV undernutrition were excluded. Three weeks of oral antibiotic therapy, with erythromycin (30 mg/kg/day) and chloramphenicol (50 mg/kg/day) for the first two weeks followed by co-trimoxazole (trimethoprim 6 mg/kg/day and sulphamethoxazole 25 mg/kg/day) for the third week, was given. Chest X-rays were taken before and after antibiotic therapy. RESULTS: Sixty per cent of the children with pneumonia, 57% with bronchiectasis and 62% with minor fissure opacification showed complete radiological clearance. CONCLUSION: In tuberculin-positive children with parenchymal lung lesions radiological clearance was seen in 60% after three weeks of antibiotic therapy indicating that the parenchymal lung lesions were caused by non-tuberculous organisms. Hence a course of antibiotic therapy in these children may have diagnostic value as well as considerable financial, social and therapeutic implications.

Flexible fibreoptic bronchoscopy in 582 children--value of route, sedation and local anesthetic.

The value of route, sedation and local anesthetic was studied in 582 children aged 50 days to 12 years who were subjected to flexible fibreoptic bronchoscopy (FFBS) at the Institutes of Child Health, Madras, during January 1989 to July 1993. Pentax 3.5 mm and Olympus 4.9 mm bronchoscopes were used. Bronchoscopy was performed with sedation and/or local anesthetic through nasal/oral route after premedication with atropine. It was successfully carried out through nasal route in 97.4% and only in 40% through oral route. As nasal route proved advantageous, the oral route was abandoned.

Missed opportunities for immunization in children under 2 years attending an urban teaching hospital.

A cross-sectional survey was done to assess the missed opportunity for immunization (MOI) in children under two years of age attending Medical Outpatient, Newborn Follow-up Service and Immunization Clinic of Institute of Child Health and to evaluate interventions. Baseline survey phase-I was done and two interventions: (i) education and awareness of immunization among health personnel; and (ii) attaching immunization slip to the outpatient form were done. After each intervention phase-II and phase-III surveys were carried out. The data from the different phases were analyzed for the effect of interventions. The total number of children surveyed were 634; 423 from Medical Outpatients, 108 from Newborn Follow-up Service and 103 from immunization Clinic. MOI was 35.5%, 23.1% and 9.7% in the above health facilities, respectively. After intervention I, the MOI was 24.5% and 12.2% in Medical Outpatient and Newborn Follow-up Service and none in Immunization Clinic. After intervention-II there was an improvement in immunization of 18.4%, 30.4% and 16.0% in the three health facilities mentioned above. MOI was avoided because the medical officers advised immunization in the above children. The difference in the MOI among Medical Outpatient and Immunization Clinic between baseline, phase-I and phase-II were significant (p < 0.001). It is concluded that MOI can be brought down by creating awareness periodically and that attaching an immunization schedule to the outpatient forms is an effective method of reducing MOI.

PIP: In November 1991, a baseline survey was conducted to examine missed opportunities for immunization (MOI) in 634 children aged under 2 years attending the outpatient clinic, newborn follow-up service, and the immunization clinic of the Institute of Child Health in Madras, India. The proportion of MOIs stood at 35.5% in the outpatient clinic, 23.1% in the newborn follow-up service, and 9.7% in the immunization clinic. Shortly after the baseline survey, clinicians received education and increased awareness of immunization. This intervention was evaluated in January 1992. The proportion of MOIs after the first intervention was 24.5% for the outpatient clinic, 12.2% for the newborn follow-up service, and 0 in the immunization clinic. In May 1992, clinicians were instructed to attach an immunization slip to the outpatient form. This intervention was evaluated in June 1992. After the second intervention, the proportion of MOIs was 18.4% in the outpatient clinic, 8% in the newborn follow-up service, and 0 in the immunization clinic. In the outpatient department, MOIs decreased significantly between the baseline and the two interventions (p = 0.003). They did not fall significantly between the two interventions, however. In the immunization clinic, the MOIs also declined significantly between the baseline and the two interventions (p = 0.001). Throughout the study period, the immunization clinic had a lower MOI rate than the outpatient clinic (p 0.001). These findings indicate that periodic sessions creating awareness about immunization (e.g., once every 2-3 months) for health personnel in hospitals and attaching immunization data details to the outpatient forms of the health facility effectively reduces MOIs.

Etiological agents of acute poliomyelitis in south India.

This study was done to identify the specific etiological agents that cause acute poliomyelitis (APM). All the children newly diagnosed clinically as APM at the Institute of Child Health, Madras, during the period May 1988 to May 1989 were recruited. Stool specimen collection, transportation and identification of viruses by culture were done by standard procedures. The total number of children recruited was 312. Specimens were contaminated/insufficient in 10. Analysis was done for 302 cases. Polio virus type II was identified in 25.5% children, type I in 18.5%, type III in 15.9%, multiple polioviruses in 6.3% and non-polio enteroviruses (NPEV) in 20.2% cases. No virus was identified in 13.6%. Among the APM cases clinically diagnosed, the proportion of NPEV has increased considerably from 5% in 1984 to 20.2% in 1988-89. The age distribution was not significantly different between polio viruses and NPEV. The distribution of polio viruses and NPEV did not differ significantly in relation to immunization status, source of water supply, method of excreta disposal and the clinical types. For surveillance and control/eradication program of poliomyelitis, laboratory confirmation is essential.

Evaluation of CSF variables as a diagnostic test for bacterial meningitis.

Specific aetiological diagnosis of bacterial meningitis (BM) in developing countries is often difficult. Frequently, differentiating BM from viral and TB meningitis is not easy. A study was carried out with the easily and quickly performed CSF morphological and biochemical changes as a diagnostic test against the gold standard of CSF culture and/or the latex agglutination test (LAT). Children between 2 months and 11 years of age, suspected to have acute meningitis, were prospectively recruited. CSF cell count and morphology, Gram stain, culture, and protein and sugar estimations were carried out as per standard procedures. The laboratory personnel were blind to the clinical details and the findings of each other. Diagnosis based on gold standard was possible in 55 out of 114 cases. With CSF polymorphs > 60 per cent and sugar < 50 per cent of blood level as constants, various levels of total cells and protein were considered for their diagnostic properties. The protein level was not useful. We found the best cut-off level of cell count for diagnosis of BM to be 300/mm3, based on the receiver operating characteristics curve, the point of maximum accuracy. These findings were validated by comparing the clinical features, CSF changes and outcome characteristics of non-confirmed cases with the above criteria with the confirmed cases; these were found to be the same except for age.(ABSTRACT TRUNCATED AT 250 WORDS)