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N Hussain

Publications and source records attributed to N Hussain.

At least 19 recordsLinked to original sources
PubMed2005

Using a mammalian cell cycle simulation to interpret differential kinase inhibition in anti-tumour pharmaceutical development.

Systems biology needs to show practical relevance to commercial biological challenges such as those of pharmaceutical development. The aim of this work is to design and validate some applications in anti-cancer therapeutic development. The test system was a group of novel cyclin-dependent kinase (CDK) inhibitors synthesised by Cyclacel Ltd. The measured in vitro IC50s of each compound were used as input data to a proprietary cell cycle model developed by Physiomics plc. The model was able to predict over three orders of magnitude the cytotoxicity of each compound without model adaptation to specific cancer cell types. This pattern matched the experimentally determined data. One class of compounds was predicted to cause an increase of the cell cycle length with a non-linear dose-response curve. Further work will use apoptosis and DNA replication simulations to look at overall cell effects.

Animals↗
PubMed2005

Mood disorder with psychotic features, schizoaffective disorder, and schizophrenia with mood features: trouble at the borders.

Psychiatry has long struggled with the problem of how to understand the relationship between psychotic symptoms and mood symptoms. In the past, these debates were over conceptualizations of categories based on syndromal definitions of mental illnesses. Ample data now exists that provide insight into the biologic basis for syndromal distinctions. We examine the syndromes of mood disorder with psychotic features, schizoaffective disorder, and schizophrenia with mood features, reviewing their classification, clinical features, course, and treatment. We provide evidence that, clinically, mood disorders and schizophrenia do not separate neatly. We will also review data arising from studies in brain imaging, molecular neurobiology, and genetics. Evidence is accumulating that overlap across diagnostic boundaries for both pathologic and etiologic factors exist, along with disorder-specific factors. The nosology that will carve the reality of psychotic illness at the joints awaits further advances in genetics and neurobiology. Or, alternatively, carving out categories may turn out to be less useful for some purposes than considering dimensions.

Diagnosis, Differential↗
PubMed2004

Glutamatergic regulation of long-term grafts of fetal lateral ganglionic eminence in a rat model of Huntington's disease.

Transplanting fetal striatal tissue is currently considered to be an important alternative strategy in the treatment of Huntington's disease. Although grafted striatal tissue differentiates and shows certain structural and neurochemical features of the normal striatum and receives host afferents, it is not clear whether host-derived afferent inputs can modulate the activity of neurotransmitter receptors and their signaling in the graft. An intricate interaction between dopaminergic and glutamatergic systems is pivotal for striatal function. In the present study, the modulation of D(2) receptors in the graft by host-derived glutamatergic afferents via NMDA receptors was investigated using haloperidol-induced c-Fos expression. The results indicate that haloperidol induces c-Fos in a large number of neurons in the P-zones of the graft and this induction is significantly suppressed by pretreatment with the NMDA receptor antagonist, MK-801. Therefore, the NMDA receptor-mediated modulation of D(2) receptor function seen in the normal striatum is established in the striatostriatal grafts.

Animals↗
PubMed2003

Admissions with atrial fibrillation in a multiracial population in Kuala Lumpur, Malaysia.

BACKGROUND: There are established differences in cardiovascular disease in different racial groups. Worldwide, the literature regarding the clinical epidemiology of atrial fibrillation in non-white populations is scarce. OBJECTIVES: To document the prevalence of atrial fibrillation (AF) in the multiracial population of Malaysia, and to describe the clinical features and management of these patients. SETTING: Busy city centre general hospital in Kuala Lumpur, Malaysia, over a 1-month period. SUBJECTS: One-thousand four hundred and thirty-five acute medical admissions, of whom 40 patients (2.8%) had AF. RESULTS: Of 1435 acute medical admissions to Kuala Lumpur General Hospital over the 4-week study period, 40 had AF (21 male, 19 female; mean age 65 years). Of these, 18 were Malay, 16 Chinese and six Indian. Nineteen patients had previously known AF (seven with paroxysmal AF) and 21 were newly diagnosed cases. The principal associated medical conditions were ischaemic heart disease (42.5%), hypertension (40%) and heart failure (40%). Dyspnoea was the commonest presentation, whilst stroke was the cause of presentation in only two patients. Investigations were under-utilised, with chest X-ray and echocardiography in only 62.5% of patients and thyroid function checked in 15%. Only 16% of those with previously diagnosed AF were on warfarin, with a further three on aspirin. Anticoagulant therapy was started in 13.5% of patients previously not on warfarin, and aspirin in 8%. Records of contraindications to warfarin were unreliable, being identified in only 25%. For those with known AF, 58% were on digoxin. For new onset AF, digoxin was again the most common rate-limiting treatment, initiated in 38%, whilst five patients with new onset AF were commenced on amiodarone. DC cardioversion was not used in any of the patients with new onset AF. CONCLUSION: Amongst acute medical admissions to a single centre in Malaysia the prevalence of AF was 2.8%. Consistent with previous similar surveys in mainly western (caucasian) populations, standard investigations in this Malaysian cohort were also inadequate and there was underuse of anticoagulation, medication for ventricular rate control and cardioversion to sinus rhythm.

Adrenergic beta-Antagonists↗
PubMed2003

Translation and cultural adaptation of health questionnaires.

BACKGROUND: Health research in Pakistan often requires questionnaires in English language developed in the West to be translated into the local language. Many of the factors measured by these questionnaires are complex and apply to a different culture. Simple translations may lead to problems of validity and reliability in the Pakistani setting. This paper describes the strategies adopted for the translation and cross-cultural adaptation of the Self-Reporting Questionnaire (SRQ), a screening questionnaire for mental health developed by the World Health Organisation. METHODS: A general protocol was developed for translation of questionnaires into Urdu, describing each step in the translation procedure. Key informant interviews were carried out to obtain better cultural understanding of difficult concepts. The translation was tested and disputed items discussed in a focus group in a structured manner. RESULTS: Modifications were made to the questionnaire in light of the target population's culture and language. CONCLUSION: Simple translations are often insufficient for complex questionnaires. Key informant interviews and focus groups are useful to address conceptual and construct issues in such questionnaires.

Cross-Cultural Comparison↗
PubMed2003

Differences in clinical presentation of pulmonary tuberculosis in association with age.

OBJECTIVE: To study the differences in presentation of pulmonary tuberculosis in young adult and elderly patients. DESIGN: A prospective study was conducted between December 1999 to May 2000, which included all the patients presenting with pulmonary tuberculosis at the Department of Thoracic Medicine, Jinnah Postgraduate Medical Centre (JPMC), Karachi. PATIENTS AND METHODS: There were 67 young adult (mean age 30.63 yrs) and 36 elderly patients (mean age 65.92 yrs) with pulmonary tuberculosis. The difference in presentation of two groups were analyzed for statistical difference. Chi-square test was used for testing difference of percentage. The students t-test was used for testing difference of mean. The P<0.05 level of significance was adopted. RESULTS: The elderly patients were more likely to have dyspnoea (73% vs 23.9% P<0.001) and non-specific symptoms (62.2% vs 17.9% P<0.001) but less haemoptysis (21.6% vs 46.3% P<0.01). The chest radiograph in elderly patients more commonly had extensive bilateral infiltration (32.4% vs 14.9% P<0.03) and lower zone infiltration (37.8% vs 3% P<0.001). CONCLUSION: The result of our study suggests that elderly patients with pulmonary tuberculosis were more likely to present with dyspnoea, non-specific symptoms and atypical radiographic appearance.

Adult↗
PubMed2002

Muscarinic, adenosine A(2) and histamine H(3) receptor modulation of haloperidol-induced c-fos expression in the striatum and nucleus accumbens.

It is generally believed that haloperidol exerts its motor side effects and therapeutic effects mainly by antagonizing dopamine D(2) receptors in the striatum and the nucleus accumbens, respectively. Several neurotransmitters/modulators, including glutamate, acetylcholine, adenosine and histamine, affect dopaminergic activity in these centers. We have recently shown that N-methyl-D-aspartate receptor-mediated modulation of haloperidol-induced c-fos expression differs in functionally specific regions of the striatum and the nucleus accumbens. In the present study, the entire striatum and the nucleus accumbens were comprehensively examined for the pattern of modulation of haloperidol-induced c-fos expression by adenosine A(2), histamine H(3) and muscarinic receptor antagonists. Blockade of muscarinic and H(3) receptors resulted in a profound suppression of haloperidol-induced c-fos expression in the dorsolateral part of the striatum. In addition, the H(3) receptor antagonist suppressed the effects of haloperidol in the ventrolateral aspect of the striatum and the rostral parts of the medial striatum. Muscarinic receptor antagonists suppressed haloperidol-induced c-fos expression throughout the shell and in the mid-level of the core of the nucleus accumbens while A(2) and H(3) receptor antagonists did not.We found that the muscarinic and H(3) receptor antagonists suppress the induction of c-fos by haloperidol in the dorsolateral aspect of the striatum, an area implicated in the development of extrapyramidal motor symptoms following chronic haloperidol treatment. By contrast, haloperidol-induced c-fos expression in the nucleus accumbens, an area implicated in the therapeutic effects of haloperidol, was suppressed by the muscarinic receptor antagonist, but not by the H(3) receptor antagonist. Therefore we conclude that H(3) receptor modulation may provide a useful therapeutic target in future efforts to minimize neuroleptic-induced motor side effects.

Animals↗
PubMed2002

Lowering anti-dsDNA antibodies--what's new?

Antibodies to dsDNA are specific to SLE and are pathogenic, both due to their ability to deposit in tissues through a variety of mechanisms, and to their ability, when present in immune complexes, to activate inflammatory cells. The relationship of serum anti-dsDNA antibody levels to disease activity is a complex one and the factors that determine whether or not such antibodies will be pathogenic in an individual SLE patient are incompletely understood. Although anti-dsDNA antibodies can be made by naïve B cells and B cells belonging to the B1 and marginal zone subsets, pathogenic anti-dsDNA antibodies have the hallmarks of germinal center development and exposure to T cell help, including accumulation of somatic mutations and class switching to the IgG isotype. Epitope spreading may result in aquisition of cross-reactivities with multiple target organ antigens and aquisition of a memory phenotype will allow these B cells to acquire antigen presentation functions that amplify the autoreactive response. In the early stages of disease, or after remission induction protocols, autoreactive B cells may be susceptible to treatments that target T cell costimulation or that deplete or tolerize naïve and mature B cells. Therapeutic approaches targeting innate immune responses or regulatory T cells are starting to be tested in pre-clinical models. In later disease stages, memory and plasma cell accumulation may render patients more resistant to this type of therapeutic approach. Deposition of anti-dsDNA antibodies in target tissues can stimulate an inflammatory cascade that leads to tissue damage. A number of murine models have now been developed that show that interruption of this cascade can prevent or reverse such damage. This type of approach may be beneficial for individuals with established disease. As we learn more about the specific defects that cause SLE, it may become possible to individualize therapy based on patient specific biologic markers.

Animals↗
PubMed2001

Transcytosis of nanoparticle and dendrimer delivery systems: evolving vistas.

The translocation of particulate matter across the gastrointestinal tract is now a well documented phenomenon offering new potential for the delivery of drugs with poor dissolution profiles and labile chemistries via encapsulation in biodegradable nanoparticles. The last few years have seen an acceleration in the number of publications describing the varying facets of this approach and the multidisciplinary nature of this field. This review delineates data from this rather fragmented area and from cognate fields to provide a physicochemical viewpoint of the importance of surface chemistries of oral drug delivery vehicles and their interactions in and with gut contents prior to uptake. The role of lymphoid and non-lymphoid tissues is examined, and the role of bioadhesion is discussed. The exciting potential of molecular encapsulation of drugs via dendrimers and star branched molecules is discussed in the context of nanotechnological applications for the oral route. Evolving vistas include a better understanding of the plasticity of the intestinal epithelium and M-cell induction as well as the influence of disease states on particulate uptake. In this review we address a number of issues deemed vital to an understanding of the subject including (i) some background knowledge on particulate uptake (the subject of several reviews), (ii) factors affecting uptake such as diameter and surface charge and character, (iii) the dynamic nature of particle interactions in the gut, (iv) the dynamic nature of the processes of capture, adhesion, uptake, transcytosis and translocation, and (v) the influence of surface ligands.

Administration, Oral↗
PubMed2001

Fluorometric method for the simultaneous quantitation of differently-sized nanoparticles in rodent tissue.

The oral absorption and systemic translocation of particulate matter via the gastrointestinal tract has been shown by a number of laboratories using a wide variety of particles in different animal species. While there is debate on the magnitude of particle intestinal translocation, which is encumbered by the differing experimental protocols, particularly the method of quantitation of absorbed material, few have sought to examine the pharmacokinetic aspects of particle absorption. We describe in this communication the development of a simple and a rapid fluorometric assay of quantifying tissue-laden fluorescent nanoparticles that is able to isolate, detect and quantify the presence of two or more particle populations differing both in their size and fluorescent label. Six types of polystyrene nanoparticles incorporating different fluorescent markers were spiked in whole livers. The fluorophores were extracted using our previously developed method of freeze-drying the tissue and using chloroform as the extractive solvent. Only two types of particle populations, orange-labelled 40 nm and Fluoroscein-emitting 500 nm nanoparticles, were sufficiently recoverable and provided a high signal-to-noise ratio for further work. The amount of tissue and type of biological tissue type also impacted on the nanoparticle recovery and detection, reflecting, perhaps, the quenching effects of interacting tissue-derived molecules. In addition, the results also indicate that the use of nanoparticles incorporating fluorescent dyes that have emission over 500 nm overcome the tissue interfering autofluorescence for low doses of nanoparticles. The use of this fluorometric method has several advantages compared with other modes of quantitation in that it is rapid, non-radioactive and the marker is non-leaching. More importantly, it allows the simultaneous detection of multiple fluorophores such that two or more different fluorescent particle populations can be detected in the same sample. This may enable the uncharted area of pharmacokinetic parameters, such as the impedance, augmentation or site of gut uptake of differently sized particles to be studied.

Animals↗