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Biomedical subjects

G Lambert

Publications and source records attributed to G Lambert.

At least 19 recordsLinked to original sources
PubMed2006

Brain leptin resistance in human obesity revisited.

Leptin is a 16 kDa peptide predominantly produced by adipocytes. Leptin and its receptor are known to be involved in the regulation of energy balance. The data from animal studies as well as our own observations of leptin overflow from the brain suggest that the central nervous system is a site of leptin synthesis. Using simultaneous arterio-venous blood sampling we here confirm that leptin is released from the brain into the internal jugular vein, and that release is greater in overweight men and in females compared to lean men, 467.3 ng/min+/-160.4 and 1426 ng/min+/-769.3 vs 80.0 ng/min+/-29.3, respectively (P<0.05). Furthermore, we have examined the gene expression of leptin and its receptor isoforms by reverse transcription-polymerase chain reaction (RT-PCR) in human cadaver hypothalami across a broad range of adiposity. Leptin gene expression was detected in a number of donors; the presence of detectable leptin mRNA was related to the mode of death rather than BMI or gender. We have also demonstrated gene expression of the three leptin receptor isoforms in the human hypothalamus. No relation was observed between the levels of hypothalamic expression of the long signaling form of the leptin receptor and BMI. In summary, this study indicates that it is very difficult to explain human obesity on the basis of central nervous system "leptin resistance", in that leptin is released in the brain, and at a higher level in the obese, and brain leptin receptor gene expression is not impaired in obesity.

Adult↗
PubMed2006

A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer.

To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by oral paclitaxel (Taxol) 160 mg+CsA 700 mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol) 160 mg as 3-h infusion on day 15. The median (range) area under the plasma concentration-time curve of paclitaxel was 2.06 (1.15-3.47) microg h ml(-1) and 1.97 (0.58-3.22) microg h ml(-1) after oral administration of SMEOF#3 and Taxol, respectively, and 4.69 (3.90-6.09) microg h ml(-1) after intravenous Taxol. Oral SMEOF#3 resulted in a lower median T(max) of 2.0 (0.5-2.0) h than orally applied Taxol (T(max)=4.0 (0.8-6.1) h, P=0.02). The median apparent bioavailability of paclitaxel was 40 (19-83)% and 55 (9-70)% for the oral SMEOF#3 and oral Taxol formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower T(max) than orally applied Taxol, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel.

Administration, Oral↗
PubMed2006

Kinetics of prebeta1 HDL and alphaHDL in type II diabetic patients.

BACKGROUND: The aim of this study was to analyze the recycling of high density lipoprotein (HDL) in six type II diabetic patients compared with six control subjects by endogenous labelling of apolipoprotein A-I (Apo A-I) with stable isotope Apo A. MATERIALS AND METHODS: The -I-HDL kinetics were performed by infusion of (5.5.5-(2)H3)-leucine for 14 h. The prebeta1 and alphaHDL were separated by gel filtration fast protein liquid chromatrography system (FPLC). Kinetics of isotopic enrichment of Apo A-I were analyzed with a multi-compartmental model software (SAAM II, SAAM Institute, Seattle, WA). RESULTS: Plasma Apo A-I concentration was decreased in patients with type II diabetes as a result of a decrease in Apo A-I-alphaHDL (P < 0.05). Diabetic patients were also characterized by an increased relative contribution of Apo A-I in prebeta1 HDL (18.3 +/- 2.8% vs 11.9 +/- 3.7%, P < 0.01). The synthetic rate of prebeta1 HDL was slightly increased in diabetic patients compared with control (NS) and an increase of recycling rate of alpha to prebeta1 HDL was observed (11.67 +/- 3.14 d(-1) vs 7.09 +/- 4.51 d(-1), P < 0.05). The clearance rate of Apo A-I was higher in diabetic patients (P < 0.05 for Apo A-I-prebeta1 HDL and P < 0.005 for Apo A-I-alphaHDL). CONCLUSION: This study suggests that the usual increase in prebeta1 HDL in type II diabetic patients is mainly related to an increased conversion rate of alpha to prebeta1 HDL.

Adult↗
PubMed2005

Assembling the building blocks of cell theory.

Changes of scientific paradigms happen with the emergence of new theories, like the cell theory in the 19th century. These new conceptions are the result of a collective work occurring over decades or centuries. Scientists who participate in these important mutations are fully in tune with their time, even when they are considered precursors, and it is always difficult to judge how far they were right and how far they were wrong.

Animals↗
PubMed2005

[Colloid drug delivery systems: a response to therapeutic expectations arising from biotechnological advances?].

New and fascinating advances in biotechnology have open new perspectives since the use of monoclonal antibodies for therapeutic application, particularly cancer, has been approved. Over the last two decades, numerous research teams have demonstrated that the progression of cancer is often associated with an over-expression of one or several proteins, called tumor antigens. In order to target tumors specifically, researchers have tried to couple monoclonal antibodies with colloid vectors such as liposomes, nanoparticles, and emulsions containing cytotoxic compounds. Use of these conjugated vector-antibody systems for the treatment of cancer is designed to target cancerous cells while sparing healthy cells. We present here a discussion on the synergy between biotechnology and modern molecular pharmotechnology, opening new horizons for therapy.

Animals↗
PubMed2004

A generalized extension to the Hounsell-Wilkinson head scatter model.

Hounsell and Wilkinson (1997 Phys. Med. Biol. 42 1737-49) have demonstrated that the concept of a scatter-plane source can accurately describe head scatter in irregularly shaped fields produced by the MLC of an Elekta linear accelerator. In these linacs, the solid jaw is below the MLC set and plays no part on defining the view of the main source of head scatter, the flattening filter. A more complicated situation arises for linear accelerator head designs which incorporate a solid upper jaw pair with the MLC jaws further from the source. Application of the Hounsell and Wilkinson technique to these accelerator designs does not achieve the accuracy in the Elekta application. We present a generalized extension to Hounsell and Wilkinson's model and present results for typical treatment field shapes on a Siemens Primus linear accelerator.

Biophysical Phenomena↗
PubMed2004

An animal model of chronic placental insufficiency: relevance to neurodevelopmental disorders including schizophrenia.

Evidence now suggests that compromised prenatal brain development may increase the risk for the manifestation of neurological disorders such as schizophrenia. We present a guinea-pig model which mimics a condition of human pregnancy, namely, chronic placental insufficiency. Previously we reported that at term there are changes in the brains of these offspring which are relevant to changes in patients with schizophrenia. The aim of this study was to examine whether deficits in brain structure persist to adolescence and young adulthood (8-12 weeks) and have implications for behavioral function. Reduced uteroplacental blood flow was induced via unilateral ligation of the uterine artery at mid-gestation. The brain was examined in control and prenatally compromised (PC) animals 8 weeks after birth using morphometric and immunohistochemical markers. In a separate cohort of animals, prepulse inhibition (PPI) of the acoustic startle response was assessed at 4, 8 and 12 weeks of age. Brain neurochemistry was examined by determining the concentrations of dopamine and its metabolite, dihydroxyphenylacetic acid (DOPAC), at 12 weeks using high performance liquid chromatography. In PC animals compared with controls there was a reduction in brain weight, persistent enlargement of the lateral ventricles, a reduction in the volume of the basal ganglia and septal region and no evidence of gliosis. No differences were observed in concentration of catecholamines in any brain region examined. At 12, but not 4 or 8, weeks of age, PPI was reduced in PC animals compared with controls. The findings of reduced brain weight, ventriculomegaly, reduced basal ganglia volume and absence of astrogliosis in the PC guinea-pig brain at adolescence parallel some of the changes observed in patients with schizophrenia. The impairment of PPI is comparable to sensorimotor gating deficits observed in patients with schizophrenia. These results indicate that adverse prenatal conditions lead to long-term alterations in brain structure and function which resemble alterations seen in patients with schizophrenia and therefore support the early neurodevelopmental hypothesis of schizophrenia.

Animals↗
PubMed2003

Sympathetic nerve activity and neurotransmitter release in humans: translation from pathophysiology into clinical practice.

AIM: There has been a revolution in cardiovascular neuroscience in recent years with, in some cases, translation into clinical practice of the knowledge of pathophysiology gained through application of sympathetic nerve recording and catecholamine isotope dilution methodology. OBESITY-RELATED HYPERTENSION: An earlier hypothesis, based on findings in most models, was that weight gain in obesity is due in part to sympathetic nervous underactivity reducing thermogenesis. Microneurography and regional noradrenaline spillover measurements in human obesity have disproven this hypothesis, weakening the case for the use of beta3-adrenergic agonists to stimulate thermogenesis. Sympathetic nerve firing rates in post-ganglionic fibres directed to the skeletal muscle vasculature are increased, as is renal sympathetic tone, with a doubling of the spillover rate of noradrenaline from the kidneys. Given these findings, antiadrenergic antihypertensive drugs may be the preferred agents for obesity-related hypertension, but this has not been adequately tested. ESSENTIAL HYPERTENSION: Whether stress causes high blood pressure, previously hotly debated, has been under recent review by an Australian Government body, the Specialist Medical Review Council. Despite medicolegal implications, the ruling was that stress is one proven cause of hypertension. The judgment was reached after consideration of the epidemiological evidence, but in particular the described neural pathophysiology of essential hypertension: (a) persistent sympathetic nervous stimulation is commonly present, (b) suprabulbar projections of noradrenergic brainstem neurones are activated and (c) adrenaline is released as a cotransmitter in sympathetic nerves. These were taken to be biological markers of stress. CARDIAC FAILURE: At one time, the failing heart was thought to be sympathetically denervated. Longterm administration of inotropic adrenergic agonists, to provide the cardiac catecholamine stimulation thought to be lacking, increased mortality. Noradrenaline isotope dilution methodology subsequently demonstrated that the sympathetic outflow to the heart was preferentially activated, cardiac noradrenaline spillover being increased as much as 50-fold. The level of stimulation of the cardiac sympathetic nerves was the most powerful predictor of death. These observations provide the theoretical foundation for the very successful introduction of beta-adrenergic blockers for treatment of heart failure.

Autonomic Nervous System Diseases↗
PubMed2003

Therapeutic potentialities of EWS-Fli-1 mRNA-targeted vectorized antisense oligonucleotides.

We have used structured antisense oligonucleotides (AON), which are protected against extra and intracellular degradation by their internal structure. We have shown that if correctly designed this structure does not prevent them from hybridizing to the mRNA target. This concept allows reducing the number of thioate groups in the oligonucleotide and therefore the potential toxicity. Junction oncogenes are found in cancers such as certain leukemias, Ewing sarcoma, and thyroid papillary carcinomas. Ewing sarcoma is a cancer of children and young adults with bone metastasis. It is caused by a chromosomic translocation t(11;22) (q24;q12) creating a fusion gene between the genes EWS and Fli-1 giving rise to a chimeric protein which is an unnatural transcription factor. Immortalized NIH/3T3 cells transfected by the EWS-Fli-1 cDNA under the control of the LTR retroviral promoter--which do not undergo apoptosis and which became tumoral--were used for this study. As a model of Ewing sarcoma in nude mice, we have used permanently expressing human EWS-Fli-1 cells grafted to nude mice. The nanospheres or nanocapsules have been used to deliver two different AON: a phosphorothioate, and a structured chimeric AON, both targeted toward the junction area of EWS-Fli-1. Both types of AON-loaded nanoparticles inhibited the growth of the xenografted tumor after intratumoral injections into nude mice, whereas similar nanoparticles with control oligonucleotides had no effect. With AON in nanospheres, we have shown after 24 hours that the mRNA of EWS-Fli-1 was specifically down-regulated, confirming the antisense activity of the targeted AON.

Animals↗
PubMed2002

Sympathetic nervous activation following subarachnoid hemorrhage: Influence of intravenous clonidine.

BACKGROUND: Subarachnoid hemorrhage is often accompanied by systemic complications and cerebral vasospasm. Elevated levels of circulating catecholamines may be involved in the pathophysiology behind these events. The alpha-2-agonist clonidine inhibits sympathetic outflow by a central mechanism. Unrestricted sympathoexcitation may be detrimental and administration of clonidine may be beneficial in these patients. METHODS: Using isotope dilution methodology, norepinephrine kinetic determinations, comprising determination of arterial norepinephrine concentration and rates of norepinephrine spillover to and removal, or clearance, from plasma, were performed on three occasions during the first week after subarachnoid hemorrhage in 25 patients. Eleven of these patients received clonidine (continuous i.v. infusion 5.8 +/- 0.7 microg x kg(-1) x 24 h(-1)) and the remainder, standard therapy. Initial results were compared with 17 healthy age-matched subjects and eight patients suffering from severe traumatic brain injury without traumatic subarachnoid hemorrhage. RESULTS: Subarachnoid hemorrhage patients exhibited markedly elevated arterial plasma norepinephrine concentrations [3.74 +/- 0.48, P < 0.001 vs. healthy subjects (1.59 +/- 0.11 nmol/L) and P < 0.05 vs. head trauma patients (1.94 +/- 0.29 nmol/L)]. The rate of clearance of norepinephrine from plasma in the subarachnoid patients was also significantly greater than that observed in the healthy subjects (2.66 +/- 0.15 vs. 2.14 +/- 0.15 L/min, P < 0.05) and the head trauma patients (2.00 +/- 0.12 L/min, P < 0.05). Compared with both control groups, on admission the rate of spillover of norepinephrine to plasma following subarachnoid hemorrhage was markedly elevated (9.11 +/- 1.12, P < 0.001). Clonidine treatment (continuous i.v. infusion 5.8 +/- 0.7 microg x kg(-1) x 24 h(-1)) did not reduce the increased rate of spillover of norepinephrine to plasma following subarachnoid hemorrhage. CONCLUSION: Sympathetic nervous activity is markedly elevated following subarachnoid bleeding. Clonidine had no effect on the rate of norepinephrine spillover to, or clearance from, plasma in these patients. Clearly, further studies are required to elucidate the mechanisms responsible for generating sympathetic nervous activation following subarachnoid hemorrhage.

Adrenergic alpha-Agonists↗
PubMed2002

Neurohormonal influences on maintenance and reversal of two-kidney one-clip renal hypertension.

The factors involved in maintenance and reversal of mean arterial blood pressure (MAP) in the chronic two-kidney one-clip hypertensive rat (2K1C-RHR) are still debated. The reduction in MAP after reversal of 2K1C hypertension has been ascribed either to release of a renal medullary depressor hormone (RMDH) or suppression of the renin-angiotensin and/or sympathetic nervous system. We studied in conscious rats: (i) The effects of angiotensin II receptor blockade (ARB; candesartan), sympathetic blockade (propranolol and phentolamine) or a combination on MAP in 6-week long 2K1C-RHR; (ii) The effects of reversal of 2K1C hypertension by removal of the constricting clip (unclipping, UC) or nephrectomy (Nx) on MAP, plasma renin activity (PRA) and noradrenaline (NA) spillover rates. The results show that: (i) MAP in the 2K1C-RHR was almost normalized by ARB but not significantly affected by the sympathetic blockade. The combination was not more effective than ARB alone; (ii) UC and Nx reduced MAP in 2K1C to similar levels as ARB. No significant changes in PRA or catecholamines could be detected in UC and Nx groups. We conclude that hypertension in 2K1C-RHR is maintained by the renin-angiotensin system without much contribution from the sympathetic nervous system. Furthermore, we found no evidence that UC of our model of 2K1C was associated with a generalized decrease in sympathetic tone or substantial release of RMDH from the unclipped kidney. Thus, we conclude that in the present model of 2K1C, both maintenance and reversal of hypertension are controlled by the renin-angiotensin system.

Angiotensin II↗
PubMed2002

Risk behaviours and prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae genital infections among Montreal street youth.

We estimated the prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae genital tract infections among 302 Montreal street youth (223 boys) and identified associated risk factors. Study participants, 14-25 years old (average 20.9 years), meeting specific criteria for homelessness, were recruited in street youth agencies. Participation included a structured interview and provision of a urine specimen. Among sexually active youth, (n = 300) 30.0% had more than five heterosexual partners and 13.0% had at least one homosexual partner (last year), 10.7% had received money in exchange for sex (last six months) and 47.0% reported sexual relations resulting in pregnancy (lifetime). Among all youths, 82.1% had used at least one type of illicit drug, and 30.1% injected drugs at least once (last six months). The prevalence of C. trachomatis infection was 6.6% (95% CI 4.1-10.0%). Prevalence did not vary significantly by sex, age or any other variable, except history of pregnancy (10.4% among youth with history of pregnancy vs 3.6% among others, P = 0.02). No cases of N. gonorrhoeae infection were found.

Adolescent↗
PubMed2001

Impact of the renin-angiotensin system on cerebral perfusion following subarachnoid haemorrhage in the rat.

1. This study investigated the effects of blocking the AT1 angiotensin receptors with irbesartan, either peripherally or centrally, on systemic blood pressure, intracranial pressure and cerebral perfusion pressure following experimental subarachnoid haemorrhage (SAH) in urethane-anaesthetized rats. Sympathetic nervous activation was determined by measuring plasma noradrenaline levels. 2. In untreated animals, SAH induced a sustained increased in intracranial pressure from 2.1 +/- 0.3 to 16 +/- 2 mmHg (3 h, P < 0.001). Cerebral perfusion pressure was reduced by 20 % (P < 0.001), this reduction being maintained for 3 h. Sympathetic activation was evident in the high level of plasma noradrenaline measured 3 h post-SAH (751 +/- 104 vs. 405 +/- 33 pg ml(-1), P < 0.05). 3. Acute peripheral pretreatment with irbesartan (3 mg kg(-1), I.V.) prevented the rise in plasma noradrenaline and further aggravated the decrease in cerebral perfusion pressure by producing transient systemic hypotension (blood pressure was 85 +/- 6 mmHg at 2 h post-SAH vs. 100 +/- 3 mmHg, P < 0.01). 4. Intracisternal pretreatment with irbesartan (0.035 mg) did not prevent the rise in plasma noradrenaline post-SAH but enhanced the rise in intracranial pressure by 75 % compared with untreated animals. 5. This study demonstrates that peripheral endogenous angiotensin II interacts with the sympathetic nervous system in order to maintain an adequate cerebral perfusion following SAH. Endogenous angiotensin II in the brain seems to exert a protective effect by counteracting the elevation in intracranial pressure that occurs following experimental SAH.

Angiotensin II↗
PubMed2001

Noradrenaline synthesis, release and vesicular transport in the rat brain following subarachnoid haemorrhage.

The present study was designed to estimate the release of noradrenaline, and to evaluate the efficiency of noradrenaline vesicular transport, as indicated from measures of dihydroxyphenylglycol (DHPG), and synthesis in the medulla and hypothalamus following subarachnoid haemorrhage in rats. Subarachnoid haemorrhage was induced by the injection of homologous blood into the cisterna magna (n = 11). Sham operated animals served as controls (n = 11). Three days following subarachnoid haemorrhage, medulla and hypothalamus were dissected and placed in an in vitro superfusion system. Exposure to K(+) (50 mM) for 2 min served as a stimulus for the release of the neurotransmitter noradrenaline, its precursor (dihydroxyphenylalanine [DOPA]) and intraneuronal metabolite, DHPG. Basal noradrenaline overflow from both the medulla and hypothalamus were similar in the two groups of rats but basal DOPA overflow from the medulla was significantly reduced in the subarachnoid haemorrhage animals (0.97 +/- 0.15 vs. 1.97 +/- 0.38 pg/10 min/mg, p < 0.01). Administration of K(+) induced the release of noradrenaline, the response from the medulla in the subarachnoid haemorrhage group being attenuated (p < 0.01) compared with the sham operated animals (174% and 240%, respectively). K(+) induced a similar release of noradrenaline from the hypothalamus in both groups of rats (239% in sham animals and 283% in the subarachnoid haemorrhage group). The overflow of DHPG from both the hypothalamus and medulla was similar in both groups of animals. Our results suggest that the diminution in noradrenaline release from the medulla occurs as a result of a reduction in the rate of noradrenaline synthesis and release.

Animals↗
PubMed2001

Acute and chronic alterations in blood pressure variability following experimental subarachnoid haemorrhage.

This study examined the role of the renin-angiotensin and vasopressin systems on systolic blood pressure (SBP) variability following subarachnoid haemorrhage (SAH) in conscious rats. Animals received no treatment, the angiotensin II AT1 receptor antagonist, losartan, or the vascular vasopressin receptor antagonist, AVPX. SAH resulted in a transient sympathetic activation as estimated from the increase in the mid-frequency oscillations of SBP (3.2 +/- 0.8 mm Hg2, 3 hours after the injury vs. 1.3 +/- 0.3 mm Hg2 in control conditions, p < 0.01). On the second and fourth day following SAH, a marked elevation in the low-frequency component of SBP was observed (7.1 +/- 1.0 mm Hg2 on day 2 vs. 2.6 +/- 0.3 mm Hg2 in control conditions, p < 0.001 and 6.3 +/- 1.1 mm Hg2 on day 4 vs. 2.6 +/- 0.3 mm Hg2 in control conditions, p < 0.01). Pre-treatment with losartan prevented the acute rise in the mid-frequency oscillations in SBP and partially reduced the low-frequency component observed at 2 and 4 days. Administration of AVPX on the second and fourth day following SAH normalised the elevated low-frequency oscillations in SBP. This study indicates that the modifications in SBP variability observed in the early and delayed stage after subarachnoid haemorrhage involve angiotensin II. Vasopressin seems to be implicated in the delayed development of low-frequency fluctuations of SBP.

Animals↗