Chlorpromazine-induced cutaneous pigmentation--effect of replacement with clozapine.
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Antipsychotic Agents↗
Biomedical subjects
S Lal
Publications and source records attributed to S Lal.
Cost of mass annual single dose diethylcarbamazine distribution for the large scale control of lymphatic filariasis.
Economic analysis of the revised strategy to control lymphatic filariasis with mass annual single dose diethylcarbamazine (DEC) at 6 mg/kg body weight launched in one of the districts of Tamil Nadu in 1996 was carried out. This exploratory study, proposed for five years in 13 districts under 7 states on a pilot scale through the Department of Public Health is an additional input of the existing National Filaria Control Programme in India. A retrospective costing exercise was undertaken systematically from the provider's perspective following the completion of the first round of drug distribution. The major activities and cost components were identified and itemized cost menu was prepared to estimate the direct (financial) and indirect (opportunity) cost related to the implementation of the Programme. The total financial cost of this Programme to cover 22.7 lakh population in the district was Rs. 22.05 lakhs. The opportunity cost of labour and capital investment was calculated to be Rs. 7.98 lakhs. The total per capita cost was Rs. 1.32, with Rs. 0.97 and Rs. 0.35 as financial and opportunity cost respectively. Based on these estimates, the implementation cost of the Programme at Primary Health Centre (PHC) level was calculated and projected for five years. The additional financial cost for the existing health care system is estimated to be Rs. 27,800 per PHC every year. DEC tablets (50 mg) was the major cost component and sensitivity analysis showed that the cost of the Programme could be minimized by 20 per cent by switching over to 100 mg tablets. The analysis indicates that this Programme is a low-cost option and the results are discussed in view of its operational feasibility and epidemiological impact.
Adolescent↗
Impact assessment of IEC campaign during anti-malaria month, June 1998 through KABP study.
To assess the IEC Campaign during anti malaria month (June, 98), a base line KABP study through pre-assessment and post-assessment was conducted in the State of Gujarat (four districts namely Ahmedabad, Dang, Panchmahal and Baroda). The study was carried out based on questionnaire (open and closed) developed by NAMP in the randomly selected population. A rapid assessment of the current level of KABP among a sample of population before and after the observance of anti-malaria month. The results of the KABP study revealed that there is definite impact (between 2.18 to 30%) and change in the KABP of the local people, where intensive and continuous I.E.C. activities are being undertaken. In order to achieve the desired change in knowledge, attitude, behaviour and practice of the respondents, it requires continuous I.E.C. campaign throughout the year. The attitude, behaviour and practice in the hard core areas need special efforts, where maximum efforts are required to bring a change in. It should be taken more intensively in the problematic and hardcore areas on priority basis.
Attitude to Health↗
Anthropophily of Anophelines in Duars of West Bengal and other regions of India.
Attempts have been made to identify the source of blood meals of twenty three anopheline species from various areas of high malaria endemicity in India. Anopheles minimus, Anopheles fluviatilis and Anopheles dirus showed a high propensity for human blood in North-Eastern parts of the country while Anopheles sundicus was found to be anthropophilic in Andaman & Nicobar Islands. Anopheles culicifacies, Anopheles maculatus and Anopheles philippinensis were found primarily zoophilic in north-eastern areas. High anthropophily has been closely related to sporozoite infection in anophelines specially in Anopheles minimus and is of great epidemiological significance.
Animals↗
Analysis of 14 CAG repeat-containing genes in schizophrenia.
Recently, it has been suggested that trinucleotide repeat-containing genes may be involved in the etiology of schizophrenia. This study was aimed at investigating putative associations between allelic variants or expansions of CAG repeat-containing genes (CAGrCG) and schizophrenia or its variability with respect to responsiveness to conventional neuroleptics. CAG repeat allelic variants of 14 expressed sequences were compared among three groups of subjects: neuroleptic-responder (R; n = 43) and neuroleptic-nonresponder (NR; n = 63) schizophrenic patients, and a control group (C; n = 122). No CAG expansions, in the range of those observed in neurodegenerative diseases, were identified in these 14 expressed sequences. The sizes of CAG repeat for the hGT1 gene were marginally different among the three groups of subjects (Kruskal-Wallis H (2, 456) = 10.48, Bonferroni corrected P = 0.047). Comparisons among the different groups indicated that neuroleptic responders have shorter alleles compared to controls (Mann-Whitney adjusted Z = -3.23, P = 0.0012). NR patients were not different from controls. These preliminary results suggest that the hGT1 gene, or a gene in its vicinity, may be involved in the etiology of schizophrenia or in modifying the disease phenotype with regard to outcome and/or neuroleptic responsiveness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:694-699, 1999.
Adolescent↗
Lack of association between the hSKCa3 channel gene CAG polymorphism and schizophrenia.
Genetic anticipation, a phenomenon characterized by increased severity of symptoms and earlier age at onset of a disease in successive generations, is believed to be present in schizophrenia. In several neurodegenerative diseases showing anticipation, the mutation causing the disease is an expanded trinucleotide repeat. Therefore, genes containing trinucleotide repeats prone to expansion have become a suitable family of candidate genes in schizophrenia. A human calcium-activated potassium channel gene (hSKCa3), possibly mapping to chromosome 22q11-13, a region previously linked to schizophrenia, was recently described. This gene contains two contiguous expressed CAG repeat stretches. Recently, long allelic variants of one of these CAG repeats were found to be overrepresented in schizophrenic patients compared to normal controls. In this study we attempted to replicate this result and to study the relationship between the length of this CAG repeat on the one hand and the severity and age at onset of the disease on the other hand. No association with the disease or correlation with the severity of schizophrenia was identified. In addition, hSKCa3 was mapped to chromosome 1. Our results do not support the involvement of this particular CAG repeat-containing gene in schizophrenia.
Adult↗
Neural correlates of eye tracking deficits in first-degree relatives of schizophrenic patients: a positron emission tomography study.
BACKGROUND: Schizophrenia is thought to arise from the interaction of genetically mediated and environmentally triggered abnormalities in brain function. Reduced frontal activation, reported in schizophrenic patients, may be one expression of genetic risk. The present study investigated whether frontal activation in relatives of schizophrenic patients would be related to eye tracking deficits (ETD), which are considered a behavioral marker of risk for schizophrenia. METHODS: Subjects were first-degree relatives of schizophrenic patients (n = 17) and controls (n = 11). Relatives were divided into those with normal and abnormal pursuit based on qualitative ratings. Subjects were scanned using positron emission tomography and the H(2)15O bolus subtraction technique while performing smooth pursuit and fixation. Brain areas more active in pursuit than fixation were identified in the 3 groups. Correlations were used to investigate the relationship between activation of pursuit regions and pursuit gain in the relatives. RESULTS: Controls significantly activated frontal eye fields (FEFs) and posterior areas, including the motion processing area, V5, and cuneus. The 2 groups of relatives activated the same posterior regions as controls, but differed from each other in activation of FEFs. Relatives with normal tracking activated right dorsal FEFs while relatives with ETD did not. Individual subtractions revealed that 90% of controls and 100% of the relatives with normal tracking activated FEFs during pursuit compared with 42% of relatives with ETD (P = .009). Pursuit gain was significantly and selectively associated with percent activation of right dorsal FEFs (r = 0.74). CONCLUSIONS: Subtle frontal dysfunction seems to be a pathophysiological substrate of ETD in relatives of schizophrenic patients, and may be one aspect of genetically mediated differences in brain function relevant to schizophrenia.
Eye Movements↗
Immunohistochemical localization of calmodulin-dependent cyclic phosphodiesterase in the human brain.
The amplification of cyclic nucleotide 'second messenger' signals within neurons is controlled by phosphodiesterases which are responsible for their degradation. Calmodulin-dependent phosphodiesterase (CaMPDE) is an abundant enzyme in brain which carries out this function. For the first time, we have localized CaMPDE in the normal human brain at various ages, using a mononoclonal antibody designated A6. This antibody was generated using standard techniques, purified, and applied to tissue sections. Autopsy specimens of human brain with no neuropathological abnormalities were selected representing a range of pre- and postnatal ages. Sections of various brain regions were evaluated for immunoreactivity, graded as nil, equivocal, or definite. We demonstrated definite CaMPDE immunohistochemical staining in neocortex, especially in neurons in layers 2 and 5. There was definite neuronal immunoreactivity in the hippocampus, and in the subiculum. The striatum had definite patchy neuronal staining. Definite terminal staining in the globus pallidus externa and substantia nigra pars reticulata outlined resident neurons, interpreted as axonal terminal staining. Cerebellar Purkinje cells showed definite immunoreactivity. In the developing brain, definite immunohistochemical staining was seen in the cerebellar external granular layer. The expression of CaMPDE in specific subsets of neurons suggests they may correlate with cells having dopaminergic innervation and/or high levels of neuronal integration.
3',5'-Cyclic-AMP Phosphodiesterases↗
Polyglutamine-containing proteins in schizophrenia.
Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamine-expanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab 1C2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia.
Age of Onset↗
The AG dinucleotide terminating introns is important but not always required for pre-mRNA splicing in the maize endosperm
Previous RNA analysis of lesions within the 15 intron-containing Sh2 (shrunken2) gene of maize (Zea mays) revealed that the majority of these mutants affect RNA splicing. Here we decipher further two of these mutants, sh2-i (shrunken2 intermediate phenotype) and sh2-7460. Each harbors a G-to-A transition in the terminal nucleotide of an intron, hence destroying the invariant AG found at the terminus of virtually all nuclear introns. Consequences of the mutations, however, differ dramatically. In sh2-i the mutant site is recognized as an authentic splice site in approximately 10% of the primary transcripts processed in the maize endosperm. The other transcripts exhibited exon skipping and lacked exon 3. A G-to-A transition in the terminus of an intron was also found in the mutant sh2-7460, in this case intron 12. The lesion activates a cryptic acceptor site downstream 22 bp within exon 13. In addition, approximately 50% of sh2-7460 transcripts contain intron 2 and 3 sequences.
Journal Article↗
A splice site mutant of maize activates cryptic splice sites, elicits intron inclusion and exon exclusion, and permits branch point elucidation.
DNA sequence analysis of the bt2-7503 mutant allele of the maize brittle-2 gene revealed a point mutation in the 5' terminal sequence of intron 3 changing GT to AT. This lesion completely abolishes use of this splice site, activates two cryptic splice sites, and alters the splicing pattern from extant splice sites. One activated donor site, located nine nt 5' to the normal splice donor site, begins with the dinucleotide GC. While non-consensus, this sequence still permits both trans-esterification reactions of pre-mRNA splicing. A second cryptic site located 23 nt 5' to the normal splice site and beginning with GA, undergoes the first trans-esterification reaction leading to lariat formation, but lacks the ability to participate in the second reaction. Accumulation of this splicing intermediate and use of an innovative reverse transcriptase-polymerase chain reaction technique (J. Vogel, R.H. Wolfgang, T. Borner [1997] Nucleic Acids Res 25: 2030-2031) led to the identification of 3' intron sequences needed for lariat formation. In most splicing reactions, neither cryptic site is recognized. Most mature transcripts include intron 3, while the second most frequent class lacks exon 3. Traditionally, the former class of transcripts is taken as evidence for the intron definition of splicing, while the latter class has given credence to the exon definition of splicing.
Alternative Splicing↗
Metformin reduces systemic methylglyoxal levels in type 2 diabetes.
Methylglyoxal (MG) is a reactive alpha-dicarbonyl that is thought to contribute to diabetic complications either as a direct toxin or as a precursor for advanced glycation end products. It is produced primarily from triose phosphates and is detoxified to D-lactate (DL) by the glyoxalase pathway. Because guanidino compounds can block dicarbonyl groups, we have investigated the effects of the diamino biguanide compound metformin and of hyperglycemia on MG and its detoxification products in type 2 diabetes. MG and DL were measured by high-performance liquid chromatography in plasma from 57 subjects with type 2 diabetes. Of these subjects, 27 were treated with diet, sulfonylureas, or insulin (nonmetformin), and 30 were treated with metformin; 28 normal control subjects were also studied. Glycemic control was determined by HbA1c. MG was significantly elevated in diabetic subjects versus the normal control subjects (189.3 +/- 38.7 vs. 123.0 +/- 37 nmol/l, P = 0.0001). MG levels were significantly reduced by high-dosage (1,500-2,500 mg/day) metformin (158.4 +/- 44.2 nmol/l) compared with nonmetformin (189.3 +/- 38.7 nmol/l, P = 0.03) or low-dosage (< or = 1,000 mg/day) metformin (210.98 +/- 51.0 nmol/l, P = 0.001), even though the groups had similar glycemic control. Conversely, DL levels were significantly elevated in both the low- and high-dosage metformin groups relative to the nonmetformin group (13.8 +/- 7.7 and 13.4 +/- 4.6 vs. 10.4 +/- 3.9 micromol/l, P = 0.03 and 0.06, respectively). MG correlated with rising HbA1c levels (R = 0.4, P = 0.03, slope = 13.2) in the nonmetformin subjects but showed no increase with worsening glycemic control in the high-dosage metformin group (R = 0.0004, P = 0.99, slope = 0.02). In conclusion, MG is elevated in diabetes and relates to glycemic control. Metformin reduces MG in a dose-dependent fashion and minimizes the effect of worsening glycemic control on MG levels. To the extent that elevated MG levels lead to their development, metformin treatment may protect against diabetic complications by mechanisms independent of its antihyperglycemic effect.
Adult↗
T102C polymorphism in the 5HT2A gene and schizophrenia: relation to phenotype and drug response variability.
Although genes play a major role in the etiology of schizophrenia, no major genes involved in this disease have been identified. However, several genes with small effect have been reported, though inconsistently, to increase the risk for schizophrenia. Recently, the 5HT2A 2 allele (T102C polymorphism) was reported to be over-represented in patients with schizophrenia. Other reports have found an excess of allele 2(C) only in schizophrenic patients who are resistant to clozapine, not in those who respond to clozapine. In this study, the 5HT2A receptor allele 2 frequencies were compared between 2 groups of patients with schizophrenia (39 responders and 63 nonresponders) based on long-term outcome and response to typical neuroleptics. A control group of 90 healthy volunteers screened for mental disorders was also included. Genotype 2/2 tended to be more frequent in patients with schizophrenia with poor long-term outcome and poor response to typical neuroleptics (Bonferroni corrected p = 0.09). This difference was significant in men (Bonferroni corrected p = 0.054) but not in women. In addition, the age at first contact with psychiatric care was significantly younger in the patients with schizophrenia with genotype 2/2 than in patients with genotype 1/1. These result suggest that the 5HT2A-receptor gene may play a role in a subset of schizophrenia characterized by poor long-term outcome and poor response to neuroleptics.
Adult↗
Novel protein inhibitor of calmodulin-dependent cyclic nucleotide phosphodiesterase from glioblastoma multiforme.
Previous investigations from our laboratory have demonstrated a significant reduction in the catalytic function of the 60 kDa and 63 kDa isozymes of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) when comparing human cerebral tissue that was free of tumor and glioblastoma multiforme (GBM) and gliosarcoma [Lal S., Raju R. V. S., Macaulay R. B. J., and Sharma R. K. (1996) Can. J. Neurol. Sci., 23, 245-250]. The results suggested the possibility of an endogenously produced inhibitor of CaMPDE expressed in these tumors. Further investigation has initially characterized the presence of a heat-labile, protein inhibitor of both the 60 kDa and 63 kDa isozymes of CaMPDE. Sephacryl S-200 gel filtration column chromatography indicated that the inhibitor has an apparent molecular weight of 22 kDa and experimental evidence demonstrates that this inhibitor protein may act independently of calmodulin, and is therefore a novel CaMPDE inhibitor. Previous work on non-CNS tumors has shown high levels of CaMPDE activity and absence of an inhibitor. This suggests that a different mechanism may exist for the proliferation of these subsets of tumors.
3',5'-Cyclic-AMP Phosphodiesterases↗
Premature degenerative shoulder changes in spinal cord injury patients.
Shoulder pain and the resultant dysfunction is an expected problem in individuals with spinal cord injury. But there is a remarkable lack of information about the natural history, diagnosis, prevention and long term outcomes. Degenerative changes may develop prematurely in their shoulders, due to overuse and altered mechanical stresses, with or without symptoms was the hypothesis of this prospective study. Information from this study is expected to assist in identification of high risk SCI individuals, and ultimately in development of preventive strategies. The shoulders of 53 spinal cord injury patients from the onset of injury until 15 years duration were subjected to clinical and radiological examination at the Rehabilitation Institute of Chicago. Thirty-eight out of 53 (72%) patients demonstrated radiological evidence of degenerative changes, but only six (11%) complained of pain in the shoulders. This study demonstrated a correlation between individuals with higher level of wheelchair activity (72%), higher age (92% above and 8% less than 30 years) and female gender (89% females versus 65% males) more prone to develop degenerative changes in the shoulders. Acromioclavicular joint was predominantly affected. Detailed radiological findings, etiopathological factors and long term recommendations are discussed. The need for further studies and consistent management strategies are stressed.
Adult↗
Disseminated intravascular coagulation complicating polyarteritis nodosa in alpha-1-antitrypsin deficiency.
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Aged↗
Predicting high blood pressure in pregnancy: a multivariate approach.
OBJECTIVE: To identify predictors of pregnancy-induced hypertension and pre-eclampsia in 212 nulliparous women before 20 weeks' gestation and at approximately 28 weeks' gestation. STUDY DESIGN: A randomized, prospective study in a teaching hospital. We performed standardized measurements of systolic and diastolic arterial blood pressures, body mass index, urinary calcium:creatinine ratio and components of the renin-angiotensin system, including platelet angiotensin II binding site density. Attending clinicians were blinded to the results. Outcome was assessed by one observer at the end of pregnancy. Discriminant function analysis was used to identify significant predictors. RESULTS: Fifty-five women had transient, presumed 'white-coat', systolic hypertension at the time of first pregnancy visit; they were twice as likely to develop pregnancy-induced hypertension and pre-eclampsia and five times more likely to deliver prematurely. Body mass index, platelet angiotensin II binding site density and urinary calcium:creatinine ratio measured before 20 weeks gestation were also significant predictors. At 28 weeks of pregnancy, measurements of the blood pressure were significant predictors (reflecting the near clinical expression of the disease), together with the plasma angiotensinogen concentration. CONCLUSIONS: A single systolic blood pressure reading of 140 mmHg or more before 20 weeks' gestation indicates a higher than normal risk of pregnancy-induced hypertension and pre-eclampsia and premature delivery. Discriminator biochemical variables were also identified at this time, which might allow the more rational use of prophylactic measures.
Adult↗
Development of an improved cloning vector and transformation system in Amycolatopsis mediterranei (Nocardia mediterranei).
A versatile plasmid cloning vector pRL60 carrying kanamycin/neomycin resistance (km/neo), erythromycin resistance (ermE) and alpha-amylase (alpha-amy) marker genes that replicates in various Amycolatopsis mediterranei strains and Escherichia coli has been constructed. This cloning vector has been derived from a hybrid plasmid pRL50, which was developed by cloning ermE from pIJ4026 into a pRL1 derivative pULAM2. While cloning ermE into the BamHI site of pULAM2, only a hybrid plasmid pRL50 with an additional copy of pULAM2 was selected. Thus pRL50 (18.7 kb) contained two copies each of the km/neo, alpha-amy, and one copy of ermE. When pRL50 was transformed into A. mediterranei DSM 40773 through electroporation and selected under erythromycin resistance, the plasmid underwent a spontaneous deletion of 8.5 kb fragment resulting in the formation of plasmid pRL60. pRL60 (10.2 kb) is a shuttle vector between A. mediterranei and E. coli with three marker genes: km/neo, ermE and alpha-amy. ermE is expressed in A. mediterranei thus allowing good selection of transformants. The alpha-amy gene of pRL60 is also expressed in A. mediterranei DSM 40773 and its activity can be easily detected on starch containing medium after iodine staining. Most critical parameters evaluated for electrotransformation using pRL60 in A. mediterranei were growth phase, electrical field strength, pulse length, pretreatment of mycelia with lysozyme and use of salt free water. At optimized parameters, a transformation efficiency of 4.0 x 10(4) transformants/microg DNA was reproducibly achieved for A. mediterranei DSM 40773. pRL60 could also be transformed into A. mediterranei DSM 43304, DSM 46095, MTCC-17 and in mutants F1/24 and T-195, (derived from an industrial strain of A. mediterranei N813). The alpha-amy of pRL60 conferred an amylolytic phenotype to all these strains. With the development of pRL60 and a reproducible transformation protocol, the application of recombinant DNA techniques to these industrial microorganisms has now become feasible.
Actinobacteria↗