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Biomedical subjects

J Abraham

Publications and source records attributed to J Abraham.

At least 19 recordsLinked to original sources
PubMed2006

Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120.

The number of older adults with HIV-1 disease is increasing but little is known about how age influences behavioral deficits associated with HIV-1 infection. The purpose of this study was to determine in a murine model if aging influenced sickness behavior following central injection of HIV-1 gp120. In initial studies, behavioral deficits induced by acute and repeated intracerebroventricular (ICV) injection of gp120 were greater in aged mice than in adults. Furthermore, repeated ICV injection of gp120 increased hippocampal levels of IL-1 beta and IL-6 mRNA in aged mice but not in adults. To determine if IL-6, which is elevated in aged brain, affects expression of the gp120-binding target, CCR5, microglia (BV-2 cell line) were incubated with increasing concentrations of IL-6. Cell surface expression of CCR5 was increased by IL-6 in a dose-dependent manner. Additionally, IL-6 increased gp120-dependent chemotaxis. These results suggest that aging increases the sensitivity of mice to behavioral deficits caused by ICV gp120, perhaps by increasing expression of CCR5 and augmenting production of cytokines.

Aging↗
PubMed2006

Pilot study of preoperative combined modality treatment for locally advanced operable oesophageal carcinoma: toxicities and long-term outcome.

AIMS: Paclitaxel, a radiosensitiser, has significant activity in oesophageal cancer. We aimed to conduct a feasibility study of preoperative chemoradiation using paclitaxel, cisplatin and 5-fluorouracil (5-FU). MATERIALS AND METHODS: Sixteen eligible patients were enrolled. Infusional 5-FU, paclitaxel and cisplatin were given for 6 weeks before and concurrent with radiation. Conformal radiotherapy was delivered in two phases (45 Gy in 25 fractions). RESULTS: A total of 62.5% of the patients experienced Grade 3-4 toxicities, 50% required admission; one patient died during the neo-adjuvant phase. Twelve (75%) patients had oesophagectomy, and two (12.5%) died after surgery. Pathological complete remission (PCR) and minimal residual disease were observed in 25% (95% CI 0.5-49.5%) and 18% (95% CI 0-38%) of patients, respectively, who underwent surgery. The median survival was 39.7 months (95% CI 15, not reached); 1-, 2-, 3-, and 4-year survivals were 75% (95% CI 56.5-99.5), 56.3% (36.5-86.7), 50% (30.6-81.6), and 50% (30.6-81.6), respectively. CONCLUSION: Paclitaxel, cisplatin and 5-FU (TCF)-chemoradiation is an active regimen; the current dose schedule tested is associated with unacceptable toxicity, and cannot be recommended for routine clinical use.

Adenocarcinoma↗
PubMed2005

A case study of elemental and structural composition of dental calculus during several stages of maturation using SRXRF.

This work presents a study of elemental composition and preponderant structure of human dental calculus, as they mature in the mouth for a period of 1 year. The synchrotron radiation X-ray fluorescence technique using a white beam was employed as an analytical method. The set of samples were extracted from different dental elements of the same subject, who did not require any other clinical care. By means of analyzing the Ca/P molar ratio an estimation of the main crystallographic structure was attained, by simple comparison with stoichiometric values of the several crystalline structures that compose the calculus. The results showed a slowly progressive transformation of the initial crystalline structures (brushite) into more stable structures (hydroxyapatite), passing through octacalcium phosphate and whitlockite. The concentrations of mayor components (Ca and P) as a function of time followed a sigmoid curve. The analysis of trace element concentrations versus time indicated a null or small correlation of concentration values with the kinetics of the crystallization process.

Crystallography, X-Ray↗
PubMed2005

Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system.

Acute cognitive impairment (i.e., delirium) is common in elderly emergency department patients and frequently results from infections that are unrelated to the central nervous system. Since activation of the peripheral innate immune system induces brain microglia to produce inflammatory cytokines that are responsible for behavioral deficits, we investigated if aging exacerbated neuroinflammation and sickness behavior after peripheral injection of lipopolysaccharide (LPS). Microarray analysis revealed a transcriptional profile indicating the presence of primed or activated microglia and increased inflammation in the aged brain. Furthermore, aged mice had a unique gene expression profile in the brain after an intraperitoneal injection of LPS, and the LPS-induced elevation in the brain inflammatory cytokines and oxidative stress was both exaggerated and prolonged compared with adults. Aged mice were anorectic longer and lost more weight than adults after peripheral LPS administration. Moreover, reductions in both locomotor and social behavior remained 24 h later in aged mice, when adults had fully recovered, and the exaggerated neuroinflammatory response in aged mice was not reliably paralleled by increased circulating cytokines in the periphery. Taken together, these data establish that activation of the peripheral innate immune system leads to exacerbated neuroinflammation in the aged as compared with adult mice. This dysregulated link between the peripheral and central innate immune system is likely to be involved in the severe behavioral deficits that frequently occur in older adults with systemic infections.

Aging↗
PubMed2004

Effect of early weaning, split-weaning and nursery feeding programmes on the growth of Landrace x Desi pigs.

An experiment using 164 crossbred pigs born to 20 first-parity sows was conducted to evaluate the growth performance of piglets in four weaning management regimens: T1, conventional weaning at 56 days; T2, early weaning at 28 days; T3, split-weaning of the heavier half of the litter at day 28, the remaining half being weaned at 56 days; and T4, split-weaning of the lighter half of the litter at 28 days, with the animals kept on a special nutrient diet up to 56 days, and the heavier half being weaned at 56 days. Split-weaning of the lighter half in combination with feeding a special nutrient diet resulted in an increase of average daily gain of 21% from day 28 to day 140 compared to conventional weaning and of 36% compared to early weaning at day 28. Compared to the control (T1), the average weights of piglets at the 140th day in groups T4 and T3 were 19.6% and 6.16%, respectively, higher, whereas that of the T2 was 8% lower. It is concluded that feeding a special nutrient diet to lighter pigs is beneficial in overcoming the post-weaning lag and enables maximal weight gain.

Animal Feed↗
PubMed2001

Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833.

PURPOSE: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion. PATIENTS AND METHODS: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833. RESULTS: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma. CONCLUSION: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Post-translational modification of p53 protein in response to ionizing radiation analyzed by mass spectrometry.

The p53 tumor suppressor protein promotes cell cycle arrest or apoptosis in response to DNA damage and other forms of stress. p53 protein functions as a transcription factor by binding to specific DNA sequences and regulating the transcription of target genes. This activity of p53 is reported to be regulated by phosphorylation and acetylation occuring at various sites on the molecule. Here, we have used a direct and non-radioactive approach involving mass spectrometric analysis of p53 protein to identify sites that are covalently modified in vivo, either constitutively or in response to ionizing radiation. Following partial purification by immuno-affinity chromatography and enzymatic in-gel digestion, the resulting p53 peptides were analyzed by MALDI-TOF and nanoelectrospray mass spectrometry. Mass spectrometry analyses identified four sites at the N terminus that were phosphorylated in response to irradiation, a single constitutive phosphorylation site at serine 315 and several acetylation sites.

Amino Acid Sequence↗
PubMed1999

Phosphorylation of p53 protein in response to ionizing radiation occurs at multiple sites in both normal and DNA-PK deficient cells.

The tumour suppressor gene product, p53, is involved in mediating cellular responses to DNA damage including growth arrest and/or apoptosis. The mechanism by which p53 protein senses the presence of damaged DNA is not understood. The possibility that p53 may be post-translationally modified by enzymes that are activated in response to DNA damage including DNA-dependent protein kinase (DNA-PK), poly(ADP-ribose) polymerase and stress activated protein kinase has received considerable attention. Recent studies have indicated that DNA-PK is not required for the transactivation or apoptosis-promoting activities of p53 protein. However, the possibility that other functions of p53 may be dependent on phosphorylation by DNA-PK has not been explored. Here we describe a series of experiments that compares the expression, function and phosphorylation status of p53 protein in normal and DNA-PK-deficient scid cells. While several novel p53 phosphoforms are generated in response to DNA damage in normal cells, the same phosphoforms are observed in scid cells.

Animals↗
PubMed1999

Harmonising and competing for medicines regulation: how healthy are the European Union's systems of drug approval?

Europeanised procedures of marketing authorisation for medicines are becoming increasingly important within EU Member States relative to national licensing systems. Since 1 January 1998 parallel national applications for drug approvals in EU Member States have disappeared and it is only possible to market a new drug in more than one Member State via Europeanised procedures. Yet the implications of these Euro-procedures for public health remain little researched or debated. This paper discusses the health and safety implications of three key features of such Europeanisation, namely, the harmonisation of drug safety standards, the competition between the national regulatory agencies of Member States for application fees from industry and the industrial capture of regulators within the regulatory process. Drawing on 42 interviews in Brussels, Germany, Sweden, the Netherlands and the UK, the perspectives of European regulators, industrial scientists and regulatory affairs managers on these matters are analysed. While most industry sources believe that the new Euro-procedures will not harm public health, at least half of the regulators were concerned that European harmonisation of safety standards and competition between national agencies to accelerate approval times in order to attract industry fees pose a threat to public health and safety. National regulatory agencies find themselves in an internal EU market competing for regulatory fees from industry. This marketisation of regulation puts pressure on regulators to 'sell themselves' as the fastest in reviewing and approving drugs. Swedish regulators displayed the greatest anxieties about these matters. Unfortunately, we found it impossible to verify these regulators' worries or industry's optimism because of the secrecy that attends these Euro-procedures. Thus, a situation obtains in which a significant number of regulators are warning that the EU medicines licensing systems, which are being put in place, might well compromise safety, yet these systems are deficient in their capacity to accommodate independent scrutiny, upon which informed policy changes could be based.

Consumer Product Safety↗
PubMed1999

Respiratory tract inflammation during the induction of chronic bronchitis in rats: role of C-fibres.

The hypothesis that chronic stimulation of C-fibres by inhaled irritants contributes to the inflammatory changes that occur during the development of chronic bronchitis was tested. The effect of neonatal capsaicin pretreatment on the development of respiratory tract inflammation was examined in a rat model of chronic bronchitis induced by SO2 exposure. Adult capsaicin- and vehicle-treated rats were exposed to SO2 (250 parts per million (ppm) 5 h x day(-1)) for one day, 2 weeks or 4 weeks. Nasal (NL), airway (AL) and bronchoalveolar (BAL) lavages were performed and the number and types of cells in the lavage fluids measured. SO2-induced changes in ventilation were also measured on day 1 of SO2 exposure and in the 3rd and 5th week of exposure. In the vehicle-treated rats, neutrophils became elevated in NL after just one day of SO2 exposure, in AL after 2 weeks, and in the BAL after 4 weeks. In comparison to vehicle animals, more neutrophils were recovered in the AL of capsaicin-treated rats after one day of SO2 (p=0.012), and in the BAL after 2 or 4 weeks (p=0.004 and p=0.01, respectively). On day 1, SO2 caused a transient increase in tidal volume and a sustained decrease in frequency that was not different in capsaicin- and vehicle-treated rats. With continued exposure, these ventilatory responses to SO2 were attenuated in both groups of rats. These data support the hypothesis that the presence of C-fibres limits or delays the inflammation that occurs during the development of chronic bronchitis induced by SO2 exposure. The protective effect of C-fibres is not the result of ventilatory responses to stimulation of these afferents.

Animals↗
PubMed1999

Ultrasound imaging of apoptosis: high-resolution non-invasive monitoring of programmed cell death in vitro, in situ and in vivo.

A new non-invasive method for monitoring apoptosis has been developed using high frequency (40 MHz) ultrasound imaging. Conventional ultrasound backscatter imaging techniques were used to observe apoptosis occurring in response to anticancer agents in cells in vitro, in tissues ex vivo and in live animals. The mechanism behind this ultrasonic detection was identified experimentally to be the subcellular nuclear changes, condensation followed by fragmentation, that cells undergo during apoptosis. These changes dramatically increase the high frequency ultrasound scattering efficiency of apoptotic cells over normal cells (25- to 50-fold change in intensity). The result is that areas of tissue undergoing apoptosis become much brighter in comparison to surrounding viable tissues. The results provide a framework for the possibility of using high frequency ultrasound imaging in the future to non-invasively monitor the effects of chemotherapeutic agents and other anticancer treatments in experimental animal systems and in patients.

Animals↗
PubMed1999

Complacent and conflicting scientific expertise in British and American drug regulation: clinical risk assessment of triazolam.

This paper presents a case study in the production and interpretation of regulatory science, focusing on the conflicting British and American clinical risk assessments of triazolam (Halcion) - the most controversial sleeping pill in the world. The regulation of triazolam is shown to be more permissive in the USA than in the UK. Six principal socio-political factors are put forward to explain this; differential regulatory trust; regulators' socio-technical data selections; medico-scientific disciplinary influences; organizational and professional interests; conflicts of interest of expert advisers; and the growth of the neo-liberal regulatory state. The risk assessments of both the British and American regulatory agencies are shown to be complacent relative to technical standards which the agencies themselves later accepted. It is suggested that, when the interests of pharmaceutical manufacturers and patients diverge, regulatory assessments are crucially affected by whether regulators are predisposed to award the benefit of the scientific doubts to the manufacturers or patients, and by the balance of such predispositions both within and between regulatory institutions of scientific expertise. The triazolam case indicates that the amount of trust placed in the pharmaceutical industry by the British American regulatory systems may hamper detection of flaws in manufacturers' medical data in a timely manner and, as a consequence, compromise patients' interests. Some policy implications for drug regulation are sketched.

Clinical Medicine↗
PubMed1999

Neurosciences - A neurosurgeon's perspective.

The advancements in the field of science in the past fifty years have highlighted the need to integrate all fields of human endeavours and have emphasised interdependency of various disciplines. The separation of humanities, therefore, from neurosciences is a preposterous practical joke on all thinking men. With the human genome project on the anvil, biotechnology is making significant headway holding out promise for organ regeneration. Macro evolution is over, but micro-evolution continues in the brain. Neural Darwinism thus, continues to evolve as long as individual remains conscious and has memory. In the milieu of widely varying internal physiological mechanisms and external stimuli, an alternative theory to preprogrammed directionalism is proposed by three mechanisms namely developmental variation and selection, experiential selections and reentrant signalling. Reentrant signalling reorients and correlates the external inputs leading to psychic development preceding the development of consciousness. The cholinergic and aminergic neuro-modelling systems are well suited to serve as value systems. The main achievement of consciousness is to bring together the many categorizations involved in perceptions into a SCENE. Another part of evolution involved capacity of reentrant signalling to be guided by a value system where it is provided with a lot of choices. With 10(13) neurons and 10(16) connections, freedom of choice may manifest into a 'Buddha' or a 'Hitler'. As part of the evolutionary process, it was interesting how capacity to categorize the need to worship by referring to environment outside evolved into a search within our minds. As the next stage of evolution, neuroscience may, thus, serve as the next gateway to understanding the mind and soul.

Buddhism↗