Bioavailability of long-chain omega-3 polyunsaturated fatty acid enriched luncheon meats

(Nutr Diet 2005;62:130–137) Objective: To determine the acute and chronic effects of low doses of long chain (LC) n‐3 polyunsaturated fatty acids (PUFA) on plasma LC n‐3 PUFA levels. Design: In the acute study, six healthy omnivores, avoiding fish meals on the day prior to the study, provided a fasting blood sample initially and post prandially at four hours. In the chronic study, 12 healthy subjects provided a fasting blood sample at baseline and three weeks after daily consumption of the test food. Main outcome measures: Plasma non‐esterified fatty acid and phospholipid LC n‐3 PUFA composition. Statistical analysis: Differences in plasma non‐esterified fatty acids and phospholipid LC n‐3 PUFA. A pre‐ and post‐consumption of the test food were assessed using paired t‐tests (spss ). Results: The acute study demonstrated that a low dose of LC n‐3 PUFA (25% eicosapentaenoic acid and 75% docosahexaenoic acid) significantly increased eicosapentaenoic acid levels in plasma of human subjects postprandially from 0.30% to 0.42% of total non‐esterified fatty acids, a per cent change of 39% (P < 0.05). The chronic study demonstrated a significant increase in total n‐3 phospholipids from zero weeks (5.48% of total fatty acids) to three weeks (7.92% of total fatty acids), representing a per cent increase of 44% (P = 0.006). The n‐6 to n‐3 ratio of LC PUFA phospholipids demonstrated a significant reduction from 5.1 at zero weeks to 4.07 at three weeks, representing a reduction of 20% (P = 0.006). Conclusions: These findings demonstrate the bioavailability of LC n‐3 PUFA consumed as a low‐fat omega‐3‐enriched luncheon meat.     

Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex.

Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance to the discriminative stimulus effects of LSD.     

Altered gene expression during rat Wolffian duct development following di(n-butyl) phthalate exposure.

Di(n-butyl) phthalate (DBP) is a common plasticizer and solvent that disrupts androgen-dependent male reproductive development in rats. In utero exposure to 500 mg/kg/day DBP on gestation days (GD) 12 to 21 decreases androgen biosynthetic enzymes, resulting in decreased fetal testicular testosterone levels. One consequence of prenatal DBP exposure is malformed epididymides in adult rats. Reduced fetal testosterone levels may be responsible for the malformation, since testosterone is required for Wolffian duct stabilization and their development into epididymides. Currently, little is understood about the molecular mechanisms of Wolffian duct differentiation. The objective of this study was to identify changes in gene expression associated with altered morphology of the proximal Wolffian duct following in utero exposure to DBP. Pregnant Crl:CD(R) (SD) rats were gavaged with corn oil vehicle or 500 mg/kg/day DBP from GD 12 to GD 19 or 21. There were only small morphological differences between control and DBP-exposed Wolffian ducts on GD 19. On GD 21, 89% of male fetuses in the DBP dose group showed marked underdevelopment of Wolffian ducts, characterized by decreased coiling. RNA was isolated from Wolffian ducts on GD 19 and 21. Together with empirical information, cDNA microarrays were used to help identify candidate genes that could be associated with the morphological changes observed on GD 21. These candidate genes were analyzed by real-time RT-PCR. Changes in mRNA expression were observed in genes within the insulin-like growth factor (IGF) pathway, the matrix metalloproteinase (MMP) family, the extracellular matrix, and in other developmentally conserved signaling pathways. On GD 19, immunolocalization of IGF-1 receptor protein demonstrated an increase in cytoplasmic expression in the mesenchymal and epithelial cells. There was also a variable decrease in androgen receptor protein in ductal epithelial cells on GD 19. This study provides insight into the effects of antiandrogens on the molecular mechanisms involved in Wolffian duct development. The altered morphology and changes in gene expression following DBP exposure are suggestive of altered paracrine interactions between ductal epithelial cells and the surrounding mesenchyme during Wolffian duct differentiation due to lowered testosterone production.     

Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Role of the superior colliculus in the motor effects of cannabinoids and dopamine

We studied the cellular distribution of CB1 cannabinoid receptors in the superior colliculus of the rat using an antibody raised against the N-terminal of the receptor. The effect of unilateral cannabinoid receptor stimulation in the intermediate layers of the superior colliculus on rotational behavior in rats was also explored. The antibody against CB1 receptors outlined the crossed descending system of the superior colliculus (predorsal bundle output system) as well as the collicular commisure. The potent cannabinoid agonist CP55,940 (5 microgram/0.25 microliter) induced strong contralateral turning when microinjected unilaterally into the lateral intermediate layers of the superior colliculus. The levels of turning obtained with the intracollicular administration of the cannabinoid were comparable to the highest levels obtained with dopamine agonists in the basal ganglia. The D(2) dopamine agonist quinpirole or the D(1) dopamine agonist SKF82958 reversed this contralateral rotation but failed to affect motor behavior on their own. A new motor pathway for cannabinoids is discussed.     

A possible role for nerve growth factor in the augmentation of sodium channels in models of chronic pain

Inflammation induces an upregulation of sodium channels in sensory neurons. This most likely occurs as a result of the retrograde transport of cytochemical mediators released during the inflammatory response. The purpose of this study was to determine the effect of the subcutaneous administration of one such mediator, nerve growth factor (NGF), on the production of sodium channels in neurons of the rat dorsal root ganglion. For this, hindpaw withdrawal from either a thermal or mechanical stimulus was measured in rats at selected intervals for up to 2 weeks following injections of NGF. Sodium channel augmentation was then examined in dorsal root ganglia using site-specific, anti-sodium channel antibodies. Both thermal and mechanical allodynia was observed between 3 and 12 h post-injection. The hyperalgesic response returned to baseline by approximately 24 h post-injection. Sodium channel labeling was found to increase dramatically in the small neurons of the associated dorsal root ganglia beginning at 23 h, reached maximum intensity by 1 week, and persisted for up to 3 months post-injection. Pre-blocking NGF with anti-NGF prevented the NGF-induced decrease in paw withdrawal latencies and significantly reduced the intensity of sodium channel labeling. The results indicate that NGF is an important mediator both in the development of acute hyperalgesia and in the stimulation of sodium channel production in dorsal root ganglia during inflammation.     

Antibiotic resistance in clinical isolates of Pseudomonas aeruginosa in Jamaica.

OBJECTIVE: To assess antibiotic resistance in clinical isolates of Pseudomonas aeruginosa in Jamaica, and to obtain baseline information on the presence of this important pathogen. METHODS: A total of 51 isolates of Pseudomonas aeruginosa, obtained from 162 clinical specimens from major hospitals and laboratories in seven parishes in Jamaica, were analyzed between May and August 2002. Isolates were tested against 18 different antibiotics by a disk diffusion method. RESULTS: Organisms were cultured from wound swabs (56%), high vaginal swabs (10.5%) and ear swabs (42.5%). Overall, the highest percentage rates of resistance were found for cefaclor (100% of all isolates), nalidixic acid (82.4%), kanamycin (76.5%), and trimethoprim/sulfamethoxazole (56.9%). Resistance rates were 25.5% or lower for tobramycin, gentamicin and polymyxin B, cefotaxime, ciprofloxacin and norfloxacin, piperacillin, carbapenems and amikacin. Forty-one isolates showed intermediate sensitivity to most of the antipseudomonal antibiotics, and the remaining 10 isolates were resistant to eight or more antibiotics. The multiresistant isolates, most of which were hospital isolates, were all resistant to tetracycline, nalidixic acid and trimethoprim/sulfamethoxazole, and highly (80%-90%) resistant to kanamycin, ciprofloxacin and norfloxacin. CONCLUSIONS: This study confirms that antibiotic resistance in this clinical pathogen is emerging in Jamaica, and suggests that due care must be taken in hospital settings to adequately diagnose pseudomonal infections and prescribe the antibiotic treatment most effective in preventing the increase in multidrug resistant organisms.     

Tuberculosis notifications in Australia, 2003.

The National Notifiable Disease Surveillance System (NNDSS) received 982 tuberculosis (TB) notifications in 2003, of which 947 were new cases, 33 were relapses and two were cases with unknown history. The incidence of TB in Australia has remained at a stable rate since 1985 and was 4.9 cases per 100,000 population in 2003. The high-incidence groups remain people born overseas and Indigenous Australians at 19.9 and 8.7 cases per 100,000 population, respectively. By contrast the incidence in non-Indigenous Australians was 0.9 per 100,000. Comparison of the 2003 TB notification data against the performance indicators set by National Tuberculosis Advisory Committee highlights that enhanced TB control measures should be considered among these high-risk groups.