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.

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.

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.

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.

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.

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.

Potency of oral polio vaccine stored at distribution centers in Madras.

This study was done with the objective to measure, monitor, and document the potency of oral polio vaccine and the storage conditions in the city of Madras for a period of one year from May 88. The Corporation of Madras which takes care of indenting and supplying the vaccine has 87 centers for storage and distribution. We took 12 samples a month from these centers by stratified random sampling technique adopting proportionate sampling. The samples were coded and sent to the laboratory. The investigator noted the storage conditions in a specially designed data card. Results were notified to the managers concerned. 122 samples were tested out of which 28 (23%) showed loss of potency (less than log 10(5.84]. The loss of potency is statistically significant in centers not having dial thermometer and where inappropriate carrier was used for transport of vaccine. It was least in Maternity and Child Health Centers probably due to the orientation of the personnel. The frequency of loss of potency was more in the beginning of the study and decreased as the study progressed. Monitoring of storage conditions and potency of vaccine along with periodic training and reorientation of health personnel are stressed.

Influence of maternal nutritional status on mode of delivery and asphyxia neonatorum.

To assess the influence of maternal malnutrition on the mode of delivery and asphyxia neonatorum, a cross sectional survey of 615 women in the age group of 20-28 yrs at the time of delivery was done. Women with chronic ailments and complicated pregnancies were excluded. The mothers were then classified into three groups based on Weight Height Product Index (WHPI) namely well nourished (WN), moderately malnourished (MMN) and severely malnourished (SMN). The proportion of asphyxiated babies among the three groups did not differ (P greater than 0.05). Abnormal deliveries like caesarean section were more common among SMN group compared to WN group ((P less than 0.01). No such difference was made out between MMN and WN groups (P greater than 0.05).

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.

Reasons for partial/non-immunization with oral polio vaccine/triple antigen among children under five years.

To identify the reasons for non-immunization/postponing immunization, parents of 615 poliomyelitis (APM) children and 908 children attending the Outpatient Department (OPD) for other ailments were interviewed. A total of 165 (26.9%), 185 (30.1%) and 264 (43%) among APM and 645 (71%), 183 (20.2%) and 80 (8.8%) among OPD children were immunized, partially immunized and unimmunized, respectively. Forty two per cent and 21% among parents of APM and OPD children, respectively in the unimmunized group were unaware of the need for immunization. The other reasons are minor illnesses, lack of interest, fear of side reaction, non-availability of vaccine or vaccinator. The decision to withhold immunization was mostly by parents when the child had some minor illnesses, mostly respiratory infections. It is recommended to educate the health personnel-clinicians and para-clinical workers by seminar and training and the public through mass media and group contact on the need for and completion of the immunizations.

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.

Bacterial meningitis: diagnosis by latex agglutination test and clinical features.

To know the usefulness of Latex Agglutination Test (LAT) for the diagnosis of bacterial meningitis (BM), it was performed in all the 114 consecutive samples of CSF with polymorphs from 114 prospectively recruited children aged 2 months to 11 years. Definite diagnosis of BM based on culture and/or LAT was evident in 55. Among the 46 LAT positive, culture was positive in 3 only. Major organisms identified by LAT were H. influenzae B (HiB) in 28 and S. pneumoniae (SP) in 15. Ninety per cent of HiB and 67% of SP bacterial meningitis were under one year of age. Fever > 7 days prior to admission was not uncommon (38%) and 26% had received prior antibiotics. Meningeal signs were present in 64%. CSF cells were < 500/mm3 in 24% and sugar was > 50% of blood level in 23%. There was no significant difference in the immediate outcome between HiB and SP meningitis. The case fatality was 22% and was significantly high in cases who had altered level of consciousness on admission (p = 0.02). It is concluded that LAT is very useful for rapid diagnosis of BM.

Risk factors for persistent diarrhea among children under 2 years of age. Case control study.

A case control study was done at the Institute of Child Health, Madras, among prospectively recruited children aged 1-23 months to identify the risk factors for persistent diarrhea. Cases were children with diarrhea persisting for > 14 days. Controls were children with acute diarrhea who had recovered within 7 days. Two controls for each case, matched for age were recruited. The total number of cases and controls recruited were 170 and 340. Fifteen risk factors for association with persistent diarrhea were studied. When the factors were adjusted for covariables by logistic regression, only 6 factors were found to be significant, namely, malnutrition (OR 2.9; 95% CI 1.9-4.5), dysenteric stools (OR 2.4; 95% CI 1.3-4.3), indiscriminate use of antimicrobials (OR 2.4; 95% CI 1.6-3.9), associated illnesses (OR 2.1; 95% CI 1.5-3.1), stools > 10/day (OR 1.8; 95% CI 1.2-2.8) and persistence of dehydration (OR 1.4; 95% CI 1.2-1.7). However, when invasive diarrhea was excluded, weight loss during study period became a significant factor. It is concluded that all children with acute diarrhea should be investigated for associated illnesses and treated adequately, indiscriminate use of antimicrobials should be avoided and nutritional support should be provided.

Intramuscular injection as a provoking factor for paralysis in acute poliomyelitis. A case control study.

In order to identify the role of intramuscular injection (IM) as a provoking factor for poliomyelitis, a case control study as done at the Institute of Child Health, Madras from May 1988 to May 1989. The case was defined as acute poliomyelitis if he had acute asymmetric flaccid paralysis of lower motor neurone type without objective sensory disturbance following a short episode of fever. Controls were taken from children attending outpatient department for fever. Two controls matched for aged and sex were recruited for each case. Recruitment, data collection and clinical examination were done by a single pediatrician. IM injection received within 30 days prior to onset of paralysis or illness was considered to be the risk factor. The total number of cases and controls recruited were 257 and 515, respectively. Among cases, 172 (66.9%) out of 257 and among controls 252 (48.9%) out of 515, received IM injection within one month earlier to onset of paralysis or illness. The overall risk of paralysis, estimated for IM injection, was increased [odds ratio (OR) 2.1 (95% CI, 1.5-3.0)]. The maximum risk for paralysis was observed to be 2 weeks preceding the illness; the ORs for < 7 days was 2.2 (95% CI, 1.6-3.2) and for 7-13 days 3.2 (95% CI, 1.8 to 5.8). The risk of paralysis associated with IM injection was similar for unimmunized and immunized cases (OR 2.4 and 2.2). Multiple injections were not associated with a higher risk of developing paralysis.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Prevalence of placentally transmitted antibodies for measles in infants 3 to 11 months old in an urban slum community.

Upto 35% of infants aged between 6 and 11 months are infected with measles in India with its associated high morbidity and mortality. The objective of the study is to know the waning pattern of placentally transmitted antibodies (PTA) for measles so that the age at which children are likely to become susceptible to measles infection could be identified. A cross-sectional serological survey of children aged 3 to 11 months in one of the Integrated Child Development Service (ICDS) area in Madras city slums was done. Venous blood from 376 children was collected and was tested for Hemagglutination Inhibition (HI) antibodies by standard microtitration technique. Titre greater than or equal to 1:8 has been considered as protective. The proportion of children with immune level and the Geometric Mean Titre (GMT), declined to the least by 5 months which denotes that most of the infants become susceptible to measles infection from as early as 5 months of age. There is no significant difference in the waning pattern between different age groups, sex and nutritional status. A community study for effectiveness of measles vaccine at 6-8 months of age is needed to know the feasibility of immunization earlier than 9 months of age.

Age for measles immunization seroconversion after measles vaccination at 6-8 months of age--a randomized controlled trial.

The objective of the study was to compare the effectiveness of measles vaccine by seroconversion in vaccinated children with non-vaccinated children of 6 to 8 months age group in a city slum community so as to study the feasibility of advancing the age of immunization. Live attenuated lyophilized Schwartz strain of measles vaccine was used. Hemagglutination inhibition (HI) antibody was estimated. Seroconversion was defined as either the conversion of negative to positive or a two fold rise in titre. One hundred and thirty two children completed the study. There was no difference in the age, sex and nutritional status between vaccinated and non-vaccinated groups (p greater than 0.7). The seroconversion rate in the vaccinated group was 65% and in the non-vaccinated group was 26%. The age, sex and nutritional status did not significantly affect the seroconversion. Our data suggest that immunization with measles vaccine may be effective as early as 6 months of age. Immunization at 6 months may be needed at least for children in densely populated areas like cities and towns.

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%.

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.