A pilot study of an integrated mental health, social and medical model for diabetes care in an inner-city setting: Three Dimensions for Diabetes (3DFD).

AIMS: We examined the effectiveness of a service innovation, Three Dimensions for Diabetes (3DFD), that consisted of a referral to an integrated mental health, social care and diabetes treatment model, compared with usual care in improving biomedical and health economic outcomes. METHODS: Using a non-randomized control design, the 3DFD model was offered in two inner-city boroughs in London, UK, where diabetes health professionals could refer adult residents with diabetes, suboptimal glycaemic control [HbA1c ≥ 75 mmol/mol (≥ 9.0%)] and mental health and/or social problems. In the usual care group, there was no referral pathway and anonymized data on individuals with HbA1c ≥ 75 mmol/mol (≥ 9.0%) were collected from primary care records. Change in HbA1c from baseline to 12 months was the primary outcome, and change in healthcare costs and biomedical variables were secondary outcomes. RESULTS: 3DFD participants had worse glycaemic control and higher healthcare costs than control participants at baseline. 3DFD participants had greater improvement in glycaemic control compared with control participants [-14 mmol/mol (-1.3%) vs. -6 mmol/mol (-0.6%) respectively, P < 0.001], adjusted for confounding. Total follow-up healthcare costs remained higher in the 3DFD group compared with the control group (mean difference £1715, 95% confidence intervals 591 to 2811), adjusted for confounding. The incremental cost-effectiveness ratio was £398 per mmol/mol unit decrease in HbA1c , indicating the 3DFD intervention was more effective and costed more than usual care. CONCLUSIONS: A biomedical, psychological and social criteria-based referral system for identifying and managing high-cost and high-risk individuals with poor glycaemic control can lead to improved health in all three dimensions.

Activity of delta8- and delta9-tetrahydrocannabinol and related compounds in the mouse.

The 11-hydroxy metabolites of Delta(8).- and Delta(9)-tetrahydrocannabinol are more active than the parent compounds when administered to mice by either the intravenous or intracerebral route. Both Delta(8)- and Delta(9)-tetrahydrocannabinol are rapidly and extensively metabolized by the liver and not by the brain. The hypothesis that the 11-hydroxy metabolites may be the active form of tetrahydrocannabinol is discussed

High-pressure liquid chromatography analysis of benzo(a)pyrene metabolism by microsomal enzymes from rhesus liver and lung.

The metabolism of benzo(a)pyrene was determined, using rhesus monkey hepatic and pulmonary microsomal enzymes. Metabolites were separated by high-pressure liquid chromatography and identified using known reference standards. Metabolites were quantitated by scintillation spectrometry. Both liver and lung microsomes metabolized benzo(a)pyrene to the following metabolites: 9,10-, 7,8-, and 4,5-dihydrodihydroxybenzo(a)pyrene; benzo(a)pyrene-1,6-dione, -3,6-dione, and -6,12-dione; and 9- and 3-hydroxybenzo(a)pyrene. Two unidentified metabolites and one metabolite region which chromatographed prior to 9,10-dihydrodihydroxybenzo(a)pyrene were produced by both liver and lung microsomes. The two unknown peaks were located between, 9,10- and 4,5-dihydrohidroxybenzo(a)pyrene. Two additional unknown metabolites were produced only in the liver and had retention times slightly greater than the 4,5- and 7,8-dihydrodihydroxybenzo(a)pyrene metabolites, respectively. Quantitative determination of benzo(a)pyrene metabolism revealed large differences for the three monkeys and the respective tissue activities. Liver activity for each animal was substantially higher than lung activity for all benzo(a)pyrene metabolites. The ratio of the metabolites also differed between the liver and lung. 3-Hdyroxybenzo(a) pyrene represented over 60% of the total liver metabolite fraction and 30% of the total lung metabolite fraction. The total quinone fraction represented between 7 and 13% of the total metabolites in the liver and comprised over 40% of the total lung metabolites. The metabolite ratios for the dihydrodiols were very similar for both tissues.

Hippocampal dynamics of synaptic NF-kappa B during inhibitory avoidance long-term memory consolidation in mice.

Since the discovery that long-term memory is dependent on protein synthesis, several transcription factors have been found to participate in the transcriptional activity needed for its consolidation. Among them, NF-kappa B is a constitutive transcription factor whose nuclear activity has proven to be necessary for the consolidation of inhibitory avoidance in mice. This transcription factor has a wide distribution in the nervous system, with a well-reported presence in dendrites and synaptic terminals. Here we report changes in synaptosomal NF-kappa B localization and activity, during long-term memory consolidation. Activity comparison of synaptosomal and nuclear NF-kappa B, indicates different dynamics for both localizations. In this study we identify two pools of synaptosomal NF-kappa B, one obtained with the synaptoplasm (free fraction) and the second bound to the synaptosomal membranes. During the early steps of consolidation the first pool is activated, as the membrane associated transcription factor fraction increases and concomitantly the free fraction decreases. These results suggest that the activation of synaptic NF-kappa B and its translocation to membranes are part of the consolidation of long-term memory in mice.

The IkappaB kinase inhibitor sulfasalazine impairs long-term memory in the crab Chasmagnathus.

Evidence for the participation of Rel/NF-kappaB transcription factors in long-term memory has recently been reported in the context-signal learning paradigm of the crab Chasmagnathus, in which a high correlation between long-term memory formation and NF-kappaB activation was observed. Two components of the NF-kappaB pathway in the crab brain have now been identified by cross-immunoreactivity using mammalian antibodies for IkappaB-alpha and IkappaB kinase alpha. Furthermore, IkappaB kinase-like phosphotransferase activity, which was inhibited by the IkappaB kinase inhibitor sulfasalazine, was detected in brain extracts. We have evaluated the effect of sulfasalazine administration on long-term memory tested at 48 h. Amnesia was found when sulfasalazine was administered pre-training and 5 h after training but not at 0 or 24 h after training. Thus, two periods for sulfasalazine-induced amnesia were found in coincidence with the two phases of NF-kappaB activation previously described (immediately and 6 h after training). The cyclooxygenase inhibitor indomethacin did not induce amnesia when administered pre-training. Thus, the possibility that sulfasalazine induces amnesia by means of cyclooxygenase inhibition is unlikely to be tenable. In vivo sulfasalazine inhibition of basal NF-kappaB activity was found between 30 and 45 min after injection, as assessed by electrophoretic mobility shift assay. On the other hand, in vivo sulfasalazine administration 6 h after training inhibited the second phase of training-induced NF-kappaB activation, providing evidence that the sulfasalazine effect on memory is due to a direct effect of the drug on the NF-kappaB pathway. These results provide the first evidence that IkappaB kinase and NF-kappaB activation are necessary for memory formation.

Angiotensin II and the transcription factor Rel/NF-kappaB link environmental water shortage with memory improvement.

One of the essential requirements even in the most ancient life forms is to be able to preserve body fluid medium. In line with such requirement, animals need to perform different behaviors to cope with water shortages. As angiotensin II (ANGII) is involved on a widespread range of functions in vertebrates, including memory modulation, an integrative role, in response to an environmental water shortage, has been envisioned. Previous work on the semi-terrestrial and brackish-water crab Chasmagnathus granulatus showed that endogenous ANGII enhanced an associative long-term memory and, in addition, that high salinity environment induces both an increase of brain ANGII levels and memory improvement. Here, we show that in the crab Chasmagnathus air exposure transiently increases blood sodium concentration, significantly increases brain ANGII immunoreactivity, and has a facilitatory effect on memory that is abolished by a non-selective ANGII receptor antagonist, saralasin. Furthermore, Rel/NF-kappaB, a transcription factor activated by ANGII in mammals and during memory consolidation in Chasmagnathus brain, is induced in the crab's brain by air exposure. Moreover, nuclear brain NF-kappaB is activated by ANGII, and this effect is reversed by saralasin. Our results constitute the first demonstration in an invertebrate that cognitive functions are modulated by an environmental stimulus through a neuropeptide and give evolutionary support to the role of angiotensins in memory processes. Moreover, these results suggest that angiotensinergic system is preserved across evolution not only in its structure and molecular mechanisms, but also in its capability of coordinating specific adaptative responses.

Distribution of delta 9-tetrahydrocannabinol in the mouse.

1. The distribution of Delta(9)-tetrahydrocannabinol-(14)C in the pregnant and nonpregnant mouse is very similar. High concentrations of radiolabel can be seen in the maternal liver, spleen, lungs, brown fat, adrenal glands, mammary glands, yolk sac placenta and corpora lutea. In the pregnant mouse Delta(9)-THC crosses the placenta and enters the foetuses in very low concentrations, with no apparent selective intrafoetal radiolabel accumulation sites. Autoradiograms showing the distribution of (14)C-cannabinoid 2 h after dosing are presented.2. A small amount of maternal liver and foetal tissue was removed from the mice, used for autoradiography and extracted with ethyl acetate. Most of the radiolabel in these tissues was solvent extractable and was separated by thin layer chromatography into two fractions, THC and metabolites.3. It appears that most of the cannabinoid is present in a free rather than conjugated form.

Participation of Rel/NF-kappaB transcription factors in long-term memory in the crab Chasmagnathus.

The induction of gene expression has been correlated with long-lasting neuronal plasticity and long-term memory (LTM) formation. The fast activation of constitutive transcription factors by signaling mechanisms is thought to be the link between synaptic events and gene expression. However, only one constitutive transcription factor, CREB, has been shown to play a key role in several memory paradigms, both in vertebrates and invertebrates. Here, we report evidences for Rel/NFkappa-B constitutive transcription factors participation in memory. Using the LTM paradigm in the crab Chasmagnathus, an enhancement of NFkappa-B DNA-binding activity was found after spaced training, which induces LTM, but not after massed training which yields an intermediate-term memory (ITM). Such finding is correlated with the requirement of protein synthesis for LTM consolidation but not for ITM. Furthermore, NFkappa-B activation was observed after 15 or 30 training trials, which are sufficient to induce LTM, but not after 5 or 10 trials, a number of trials insufficient to induce LTM. The kinetics of activation was studied and two waves of DNA-binding activity were found, similar to the time course described in other systems. NFkappa-B activation after training was also found in synaptosomal extracts. The latter result supports the hypothesis of a novel synapse-to-nucleus signaling system, in which the transcription factor is locally activated by synaptic events and then transported to the nucleus.

Kappa-B like DNA-binding activity is enhanced after spaced training that induces long-term memory in the crab Chasmagnathus.

Regulation of gene expression has been involved in long-term memory consolidation. Present results support the role of Rel/ NFkappa-B like activation in this process. In the crab Chasmagnathus, the spaced presentation of 15 or more danger stimuli induces long-term habituation (LTH), while no LTH is observed after a massed training of 600 trials. When a group trained with 30 spaced trials was compared with a passive control group and massed trained groups, a higher level of specific Rel/kappa-B like DNA-binding activity was found in brain nuclear extracts. These results strongly suggest that the enhancement of Rel/kappa-B like DNA-binding activity in the brain is specifically related to LTH formation.

The use of high pressure liquid chromatography to study chemically induced alterations in the pattern of benzo[a]pyrene metabolism.

The metabolism of radiolabeled benzo[a]pyrene (BP) by control, 3-methyl-cholanthrene (3-MC) induced, and 1,1,1-trichloropropene-2,3-oxide (TCPO)-inhibited rat liver microsomes was measured using fluorescence, radiometric, and high-pressure liquid chromatographic (HPLC) assays. Significant differences in the total measurable metabolism of BP by the three microsomal enzyme incubations resulted from the use of the three assay procedures. Appreciable differences in the concentration of the metabolite fractions after 3-MC induction and TCPO inhibition are clearly demonstrated. NMR analysis revealed that while the 3-hydroxy-BP fraction is greater than 90% pure, the 9-hydroxy fraction contains a number of metabolites having essentially identical retention times.

A 6-month dietary toxicity study of acidic sodium aluminium phosphate in beagle dogs.

Sodium aluminium phosphate [NaAl3H14(PO4)8. 4H2O], a leavening acid, was administered to groups of six male and six female beagle dogs at dietary concentrations of 0, 0.3, 1.0 or 3.0% for 6 months. No adverse treatment-related clinical signs were observed. There were no statistically significant differences in mean body weights between test and control groups at any of the weekly determinations. Weekly mean food consumption values of all male treated groups did not differ significantly from those of the control group at any stage of the study. Statistically significant reductions in food consumption occurred sporadically in all treated groups of female dogs. No significant absolute or relative organ-weight differences were found between any of the treated groups and their respective controls. Haematological, blood chemistry and urinalysis data showed no toxicologically significant trends. Histopathological examination revealed no changes considered to be related to treatment. Thus dietary administration of sodium aluminum phosphate for 6 months at concentrations of 3% or lower caused no significant toxicological effects in beagle dogs.

The metabolism of ftorafur in the beagle dog and rhesus monkey.

1. Ftorafur, a fluorinated pyrimidine nucleoside antimetabolite, is metabolized by the beagle dog and rhesus monkey to 5-fluorouracil, which is subsequently biotransformed to the corresponding nucleosides, to alpha-fluoro-beta-ureidopropionic acid, to urea and to CO2. 2. In the dog, urea was the primary urinary metabolite while in the monkey, alpha-fluoro-beta-ureidopropionic acid predominated. 3. The dog and monkey excrete about 35 percent of the recovered dose as CO2. 4. The possibility that ftorafur is a relatively inactive transport form of 5-fluorouracil is discussed.