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Query: UNIPROT:P06889 (Mol)
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A randomized, placebo-controlled trial was designed to evaluate safety and immunogenicity of an anti-cytokine vaccine in high risk HIV-positive patients. This strategy was aimed to modulate the impaired cytokine regulation in AIDS. Twelve asymptomatic patients on antiretroviral therapy for at least 1 year and with CD4 cell counts between 100-300/mm3 were randomized to receive adjuvanted formol-inactivated interferon alpha-2a (IFN alpha) and continue the current antiretroviral treatment, whatever it was, or to receive the adjuvant alone and the current antiretroviral treatment. All patients received 4 i.m. injections monthly, followed by booster injections every 3 months. Clinical status, immunology and virology were monitored. Immune response to vaccination was evaluated in term of antibody detection (ELISA) and serum anti-IFN alpha neutralizing capacity. Only local discomfort and transient fever were reported. All vaccines except one showed increased levels of anti-IFN alpha Abs and developed serum IFN alpha neutralizing capacity. Viral load did not increase in vaccinees while it remained unchanged or even increased in placebo-treated patients. None of them showed HIV-related symptoms and all had their CD4 cell counts stabilized over 18 months, whereas 2 placebo-treated patients developed full-blow AIDS. In conclusion, anti-IFN alpha vaccine was safe and immunogenic. Stable clinical and immunological status over 18 months was observed in vaccinees coupled to increased serum IFN alpha neutralizing capacity.
Cell Mol Biol (Noisy-le-grand) 1995 May
PMID:Anti-alpha interferon immunization: safety and immunogenicity in asymptomatic HIV positive patients at high risk of disease progression. 758 Aug 31

Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among men. First line treatment is primarily aimed at blocking the synthesis and action of androgens. As primary endocrine treatment, androgen deprivation is usually achieved by orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in order to block the residual adrenal androgens. However, nearly all the patients will eventually relapse. Available or potential second line therapies include, among others, alternative endocrine manipulations and chemotherapy. Cytochrome P450-dependent enzymes are involved in the synthesis and/or degradation of many endogenous compounds, such as steroids and retinoic acid. Some of these enzymes represent suitable targets for the treatment of prostate cancer. In first line therapy, inhibitors of the P450-dependent 17,20-lyase may achieve a maximal androgen ablation with a single drug treatment. Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its side-effects, mainly gastric discomfort, limit its widespread use. A series of newly synthesized, more selective, steroidal 17,20-lyase inhibitors related to 17-(3-pyridyl)androsta-5,16-dien-3beta-ol, may open new perspectives in this field. In prostate cancer patients who relapse after surgical or medical castration, therapies aiming at suppressing the remaining adrenal androgen biosynthesis (ketoconazole) or producing a medical adrenalectomy (aminoglutethimide+hydrocortisone) have been used, but are becoming obsolete with the generalization of maximal androgen blockade in first line treatment. The role of inhibition of aromatase in prostate cancer therapy, which was postulated for aminoglutethimide, could not be confirmed by the use of more selective aromatase inhibitors, such as formestane. An alternative approach is represented by liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic acid (RA). In vitro, it enhances the antiproliferative and differentiation effects of RA in cell lines that express RA metabolism, such as F9 teratocarcinoma and MCF-7 breast carcinoma cells. In vivo, monotherapy with LIA increases RA plasma levels and, to a greater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the rat Dunning prostate cancer models, it inhibits the growth of androgen-independent as well as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the pattern of cytokeratins characteristic of increased differentiation were observed. Early clinical trials show that LIA, in second or third line therapy in metastatic prostate cancer, induces PSA responses in about 30% of unselected patients. In some patients regression of soft tissue metastasis ha been observed. In a subgroup of patients, an important relief of metastatic bone pain was also noted.
J Steroid Biochem Mol Biol 1996 Jan
PMID:P450-dependent enzymes as targets for prostate cancer therapy. 860 34

The widespread use and dramatic success of prosthetic joint implant surgery (arthroplasty) has greatly improved the quality of life for many individuals suffering from degenerative, arthritic, or injured joints. However, in a number of cases, recipients experience discomfort at the arthroplasty site that can signal biomechanical failure, or periprosthetic infection of the joint, or both. In fact, infection remains a devastating obstacle, preventing arthroplasty from being an almost perfect medical procedure. Existing tests for the diagnosis of infection in orthopedics are disappointing because of the relatively high frequency of false negative results. To overcome this shortcoming, and to reduce the number of infected revision arthroplasties, a methodology based on molecular biology has been established. The method allows the rapid, sensitive and accurate diagnosis of orthopedic infections, and should aid the clinician with treatment regimens, surgical decisions, and overall patient management in the growing arthroplasty population.
Mol Med Today 1998 May
PMID:Advances in the diagnosis of infection in prosthetic joint implants. 961

We and others have previously shown that the dopamine D4 exon III repeat (D4DR) and the serotonin-transporter promoter region (5-HTTLPR) polymorphisms are not only associated with adult personality traits1-7 but also with temperament in 2-week-old neonates.8 We now report the results of a second study of these infants and their temperament at 2 months using Rothbart's Infant Behavior Questionnaire (IBQ).9 There were significant negative correlations between neonatal orientation and motor organization as measured by the Neonatal Behavioral Assessment Scale (NBAS)10 at 2 weeks and negative emotionality, especially distress in daily situations, at 2 months of age. There were significant main effects for negative emotionality and distress when the infants were grouped by the D4DR and the 5-HTTLPR polymorphisms. Infants with long D4DR alleles had significantly lower scores on Negative Emotionality (F[1, 72] = 8.50, P = 0.005) and Distress to Limitations (F[1,72] = 4.93, P = 0.03) than infants with short D4DR alleles. In contrast, infants with the short homozygous (s/s) 5-HTTLPR genotype had higher scores on Negative Emotionality (F[1,72] = 3.88, P = 0.053) and Distress to Limitations (F[1,72] = 4.94, P = 0.029) than infants with the I/s or I/I genotypes. The strongest effects occurred in those infants with the s/s 5-HTTLPR polymorphism who also were lacking long D4DR alleles which in some studies has been linked to adult novelty seeking.1,6 These infants showed most negative emotionality and most distress to daily situations, temperament traits that are perhaps the underpinning of adult neuroticism.
Mol Psychiatry 1999 Jul
PMID:Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants. 1048 54

Compounds of the trace element vanadium have been shown to mimic insulin in in vitro and in vivo systems. These compounds have been found to exert anti-diabetic effects in rodent models of type 1 and type 2 diabetes mellitus as well as in a limited number of studies in human diabetic subjects. Thus, vanadium compounds have emerged as agents for potential use in diabetes therapy. However, treatment of diabetic animals with inorganic vanadium salts has also been associated with some toxic side-effects such as gastrointestinal discomfort and decreased body weight gain. In addition, vanadium salts have been reported to exert toxic effects on the liver and kidney. More recently, it was shown that organic vanadium compounds were much safer than inorganic vanadium salts and did not cause any gastrointestinal discomfort, hepatic or renal toxicity. This review briefly summarizes the anti-diabetic and toxic effects of vanadium compounds.
Mol Cell Biochem 2000 Mar
PMID:Anti-diabetic and toxic effects of vanadium compounds. 1083 8

The intake of food has physiological consequences via physical (e.g. distension) and chemical (e.g. glucose) stimulation of receptors in the viscera and, in the longer term, by changes in signals from adipose tissue (e.g. leptin), integrated by the CNS. These consequences are associated with the sensory properties of the food such that repeated exposure to a food generates a conditioned acceptance or rejection reflex with the physiological consequences of eating as the unconditioned stimulus (US) and the sensory characteristics of the food as the conditioned stimulus (CS). Such learnt preferences and aversions occur throughout the animal kingdom, from nematodes to human beings, with much of the research being carried out with insects, laboratory animals and farm animals. Preferences for and aversions to particular foods are manifested in non-random choices between two or more foods on offer but also influence the quantity eaten when only one food is available. These considerations have been developed into a theory of Minimal Total Discomfort which proposes that an animal experiments with the amount eaten per day, and its selection between different foods, until the total of the signals generated from excesses or deficiencies of food components is minimised. Changes in food composition and/or nutrient requirements can therefore be matched by appropriate changes in intake and selection.
Comp Biochem Physiol A Mol Integr Physiol 2001 Mar
PMID:Consequences of feeding for future feeding. 1124 38

Body cooling before exercise (i.e. pre-cooling) reduces physiological strain in humans during endurance exercise in temperate and warm environments, usually improving performance. This study examined the effectiveness of pre-cooling humans by ice-vest and cold (3 degrees C) air, with (LC) and without (LW) leg cooling, in reducing heat strain and improving endurance performance in the heat (35 degrees C, 60% RH). Nine habitually-active males completed three trials, involving pre-cooling (LC and LW) or no pre-cooling (CON: 34 degrees C air) before 35-min cycle exercise: 20 min at approximately 65% VO2peak then a 15-min work-performance trial. At exercise onset, mean core (Tc, from oesophagus and rectum) and skin temperatures, forearm blood flow (FBF), heart rate (HR), and ratings of exertion, body temperature and thermal discomfort were lower in LW and LC than CON (P<0.05). They remained lower at 20 min [e.g. Tc: CON 38.4+/-0.2 (+/-S.E.), LW 37.9+/-0.1, and LC 37.8+/-0.1 degrees C; HR: 177+/-3, 163+/-3 and 167+/-3 b.p.m.), except that FBF was equivalent (P=0.10) between CON (15.5+/-1.6) and LW (13.6+/-1.0 ml.100 ml tissue(-1) x min(-1)). Subsequent power output was higher in LW (2.95+/-0.24) and LC (2.91+/-0.25) than in CON (2.52+/-0.28 W kg(-1), P=0.00, N=8), yet final Tc remained lower. Pre-cooling by ice-vest and cold air effectively reduced physiological and psychophysical strain and improved endurance performance in the heat, irrespective of whether thighs were warmed or cooled.
Comp Biochem Physiol A Mol Integr Physiol 2001 Apr
PMID:Effect of pre-cooling, with and without thigh cooling, on strain and endurance exercise performance in the heat. 1128 11

Vagus nerve stimulation (VNS) has gained recognition as a treatment for refractory epilepsies where surgical treatment is not possible. While it appears that this treatment is effective in some patients, the mechanism of action is not clearly understood. The purpose of this study was to clarify findings of other positron emission tomography and single-photon emission tomography (SPET) investigations by measuring the acute effect of VNS on patients who have normal cerebral anatomy on magnetic resonance imaging and who have not previously been exposed to VNS. We investigated six subjects (two males and four females, mean age 29.5 years, range 21-39 years) with intractable epilepsy. One patient had primary generalised epilepsy causing generalised tonic-clonic seizures; the remaining five patients had localisation-related epilepsy causing complex partial seizures. SPET imaging was performed using 250 MBq of (99m)Tc-HMPAO and a four-scan paradigm - two with and two without stimulation. The stimulation began at VNS current levels of 0.25 mA and was increased according to the limit of patients' tolerance, usually defined by coughing or discomfort. The stimulating waveform was of continuous square wave pulses of 500 micro s duration at 30 Hz. Image analysis was by SPM99. Reduced perfusion during stimulation was observed in the ipsilateral brain stem, cingulate, amygdala and hippocampus and contralateral thalamus and cingulate. The study provides further evidence of the involvement of the limbic system in the action of vagal nerve stimulation.
Eur J Nucl Med Mol Imaging 2003 Feb
PMID:Investigation into the mechanisms of vagus nerve stimulation for the treatment of intractable epilepsy, using 99mTc-HMPAO SPET brain images. 1255 50

One of the curious but common consequences of opioid administration in the clinical setting is the induction, at sites uninvolved in the original presentation of discomfort, of pain itself. The induction of pain is also a reliable, measurable phenomenon in animals receiving continuous delivery of opioid. Such pain induction is associated with the expression of spinal dynorphin, a finding that is especially intriguing in light of dynorphin's ability to recapitulate many of the characteristics of chronic, neuropathic pain when administered intrathecally (i.e., into the spine). The effective treatment of chronic pain syndromes-and of tolerance to antinociceptive therapies-may thus rest on an understanding of the biological roles of dynorphin in neurotransmission.
Mol Interv 2001 Aug
PMID:Neuropathic pain: the paradox of dynorphin. 1499 49

A multicentre study was sponsored by the International Atomic Energy Agency (Vienna) to assess the safety and efficacy of trans-arterial rhenium-188 HDD conjugated lipiodol (radioconjugate) in the treatment of patients with inoperable hepatocellular carcinoma (HCC). The radioconjugate was prepared by using an HDD (4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) kit developed in Korea, and lipiodol. Over a period of 18 months, 70 patients received at least one treatment of radioconjugate. Some patients were re-treated if there was no evidence of disease progression. The level of radioconjugate administered was based on radiation-absorbed dose to critical normal organs, calculated following a "scout" dose of radioconjugate. The organs at greatest risk for radiation toxicity are the normal liver, the lung and the bone marrow. An Excel spreadsheet was used to determine maximum tolerated activity (MTA), defined as the amount of radioactivity calculated to deliver no more than 12 Gy to lungs, or 30 Gy to liver, or 1.5 Gy to bone marrow. These doses have been found to be safe in multiple trials using external beam therapy, but this has not been confirmed for systemically administered radiopharmaceuticals. Patients were followed for at least 12 weeks after therapy, until recovery from all toxicity. The clinical parameters evaluated included toxicity, response as determined by contrast-enhanced computed tomography, palliation of symptoms, overall survival, performance status (Karnofsky) and hepatic function (Child's classification). Liver function tests, serum alpha-fetoprotein (AFP) levels and complete blood counts were done at each follow-up visit. In the majority of patients, the scout dose studies indicated the radiation absorbed dose to normal liver to be the limiting factor to the treatment dose, while in a few patients dose to lung was the limiting factor. Radiation dose to bone marrow was negligible and was thus not a factor for the MTA calculations. Side-effects were minimal and usually presented as loss of appetite, right hypochondrial discomfort and low-grade fever, even at high levels of administered radioactivity. The symptoms resolved with simple supportive therapy within 3 days of onset. Liver function tests at 24 and 72 h showed no significant changes and complete blood counts at 1 week, 4 weeks and 12 weeks showed no changes (no bone marrow suppression). Sixteen patients were treated in the dose escalation phase of the study, when the activities administered started at 1.8 GBq (50 mCi) and rose to 7.7 GBq (206 mCi). In the efficacy phase of the study a further 54 patients were treated. Both groups of patients are included in this paper. The treatment activity of 188Re-lipiodol administered transarterially ranged from 1.8 to 9.8 GBq (50-265 mCi), with a mean activity of 4.6 GBq (124 mCi). Survival at 3 months was 90%, and at 6 months, 60%; 19% survived for 1 year. Mean survival after treatment in the total treated group of 70 patients was 9.5 months, with a range of 1-18 months. The results of this multicentre study show that 188Re-lipiodol is a safe and cost-effective method to treat primary HCC via the transarterial route. In terms of efficacy, it is potentially a new therapeutic approach for further evaluation by treatment of larger numbers of patients.
Eur J Nucl Med Mol Imaging 2004 Feb
PMID:Preliminary results of transarterial rhenium-188 HDD lipiodol in the treatment of inoperable primary hepatocellular carcinoma. 1512 8


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