Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.     

Value appropriation in hepatitis C

The European Journal of Health Economics - In 2015, the Swedish government in an unprecedented move decided to allocate 150 million € to provide funding for new drugs for hepatitis C. This...     

Engagement with arts and culture activities in the Danish general population: Longitudinal associations with new onset or persistent depression and mental wellbeing

Objectives

International literature suggests that arts and culture activities may benefit mental health, however, such survey studies conducted in the Danish population are scarce. Further, studies have investigated the associated risk for incident depression, but not for persistent depression. The objective of the current prospective study was to assess associations of engagement in arts and culture activities with incident/persistent depression and also mental wellbeing among Danish adults in the general population.

Design

Observational prospective study.

Methods

Data stem from a Danish nationally representative panel study of 5000 adults (aged 15+ years) conducted in 2019 and 2020, which was linked to Danish register data. An exposure variable was constructed for frequency of attending concerts, theatres, museums, and cinemas. Validated scales were used to assess the presence of depression (PHQ-8) and levels of mental wellbeing (SWEMWBS). Binary logistic regression analyses were conducted to assess the risk of incident depression (among participants free of depression at baseline), as well as the risk of persistent depression (among participants with depression at baseline), while multinomial logistic regression was used to assess odds for moderate and high mental wellbeing (low as base outcome) while adjusting for baseline values.

Result

In terms of incident depression, quarterly engagement in arts and culture activities (compared to never) was associated with an OR of .43 (95%CI .23–.80), while 8 times or more was associated with an OR of .53 (.29–.97). In terms of persistent depression, quarterly engagement was associated with an OR of .30 (.10–.90), while 8 times per year or more was associated with an OR of .26 (.07–.92). Similar to the patterns for incident/persistent depression, associations with moderate mental wellbeing showed higher odds for quarterly engagement and 8 times per year or more. Quarterly engagement was also associated with higher odds for high mental wellbeing but did not reach statistical significance.

Conclusions

The results support the involvement of the cultural and creative sectors in health strategies. Mental health promotion initiatives as well as arts and culture sectors may encourage the general public to engage in arts and culture activities with frequencies of at least once per quarter.     

The induction of nitric oxide-mediated relaxation of human isolated pulmonary arteries by PACAP

1. The effects of pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) were analysed in human isolated circular segments of pulmonary arteries. Guinea-pig pulmonary arteries were used for comparison. The responses obtained were analysed in relation to the vascular endothelium and the nitric oxide (NO) synthase inhibitor N^G-monomethyl L-arginine (L-NMMA).
2. PACAP and VIP induced concentration-dependent relaxations of precontracted pulmonary arteries. The maximal dilator response (I_max,%) and the potency (pEC₅₀ value) were the same for both peptides, and there were no differences in the effects obtained on human and guinea-pig segments. PACAP and VIP were both more potent that acetylcholine (ACh).
3. Removal of the vascular endothelium abolished the PACAP induced dilator response in pulmonary arteries from both species. The VIP induced dilatation was unaffected, whereas the response to ACh was abolished. L-NMMA given before PACAP inhibited the dilatation. Furthermore, L-NMMA also reversed the dilatation already induced by PACAP and excess concentrations of L-arginine restored the dilator response of the L-NMMA treated arteries.
4. PACAP is a potent dilator of human pulmonary arteries. Although the dilator effect seems to be similar in amplitude to the one induced by VIP, the present results suggest differences in the underlying mechanisms of action (endothelium-dependency) between the two peptides.

     

Effects of prolonged uniocular dark adaptation on the direct-current electroretinogram of pigmented and albino rabbits

The direct-current electroretinogram of seven pigmented and seven albino rabbits was recorded from both eyes for almost 4 h in response to repeated identical light stimuli. Stimulus duration was 10 s, light intensity was 6.8 × 10² lux, and the interval between the beginning of succeeding light stimuli was 3 min. The dark-adaptation period preceding light stimulation was 30 min for one of the eyes (unoccluded eye) and 150 min for the contralateral eye (occluded eye), which was patched during the first part (117 min) of the experiment. In pigmented animals, the b- and c-wave amplitudes of the unoccluded eye slowly increased during the first part of the experiment but not significantly during the second. The a-wave amplitude was not significantly changed. After removal of the cover, the a- and b-wave amplitudes of the occluded eye immediately attained but did not exceed the level of those in the unoccluded eye, irrespective of the light adaptation induced by the stimulus flashes previously presented to the unoccluded eye. (Control experiments on six pigmented rabbits confirmed that stimuli identical to those used in the main part of the study caused a light adaptation, since a decrease in a- and b-wave amplitudes occurred after the first light stimulus following an initial dark-adaptation period of 2 h for both eyes.) In albino rabbits, electroretinogram responses were clearly discernible in the occluded eye also during the first part of the experiment, probably because of transillumination of the head. In other respects, the results were essentially similar to those of pigmented animals. The observation that occluded eyes did not dark adapt better, as judged by the electroretinogram responses, than contralateral eyes given repeated light adaptive stimuli may indicate the presence of a mechanism for transfer of adaptation information between the eyes.     

Haemodynamic consequences and uterine contractions following 0.5 or 1.0 litre crystalloid infusion before obstetric epidural analgesia

Purpose

The efficacy of infusion of 0.5 L and 1.0 L Ringer’s lactate (LR) to prevent hypotension during induction of obstetric analgesia was studied. The effect of the different fluid boluses on fetal heart rate (FHR) and frequency of uterine contractions were also determined.

Methods

Ninety-two ASA 1–2 parturients were randomized to receive 0.5 L (Group 1) and 1.0 L (Group 2) LR immediately before incremental epidural injections with lidocaine to achieve T₁₀ sensory block. Systolic blood pressure (SBP) was measured with an automated BP cuff every two minutes for 30 min after infusion of fluid bolus. Fetal heart rate monitoring and tocometry were used continuously. The number of uterine contractions were recorded 30 min before and 60 min after iv bolus.

Results

The SBP decreased in both groups, but there was no difference between groups in mean SBP or maternal heart rate. The incidence of hypotension (SBP < 90 mmHg or decrease of 20%) was 4% in both groups. The FHR record of a patient in Group 1 showed a single late deceleration, and a decrease in beat-to-beat variability occured in one patient in Group 2. A decrease in the frequency of uterine contractions of two or more contractions per 30 min was noted more frequently in Group 2 (P < 0.05). The duration of iv bolus was longer in Group 2 than Group 1 (18.8 ± 4.3 min vs 12.3 ± 4.5 min, P < 0.01).

Conclusion

Administration of 1.0 L LR iv does not provide added protection against maternal hypotension, and is associated with delay in providing pain relief and a risk of decreasing uterine contraction frequency.     

Methyl transfer from methylcobalamin to diaquocobinamide.

The transfer of the methyl group from methylcobalamin to diaquocobinamide in aqueous solution has been demonstrated by proton, carbon-13, and phosphorus-31 nuclear magnetic resonance spectroscopy. The products of this reaction are aquocobalamin and the methylaquocobinamides. Dicyanocobinamide and the cyanoaquocobinamides do not serve as methyl acceptors, while ligands such as pyridine and histidine reduce the rate of the transfer reactions. The methyl transfer is not affected by oxidizing agents such as O2, N2O, and H2O2, suggesting that the reaction does not involve free Co(I) or Co(II) corrinoids. The pH dependence of the rate of the transfer reaction from methylcobalamin to diaquocobinamide demonstrates that methylcobalamin in the "base-on" form and diaquocobinamide are the most effective methyl donor and acceptor, respectively. The most plausible mechanism for the transfer reaction involves the one-electron oxidation of methylcobalamin by diaquocobinamide to a methylcobalamin radical cation and cob(II)inamide. The very unstable methylcobalamin radical cation releases a methyl radical, which reacts with cob(II)inamide to generate the methylaquocobinamides.     

The prevalence of respiratory symptoms and asthma among school children in three different areas of Norway

The role of exposure to ambient air pollution has been a topic of interest as a potential risk factor for respiratory symptoms and asthma. We expected that the prevalence rates would vary in Norway between the capital, Oslo, the mountainous area Hallingdal and the industrial area Odda. Surveys were conducted in school children, aged 6-16 years, in; Oslo (n=2577), Hallingdal (n=1177) and Odda (n=831). The parent-reported prevalence of wheeze in past year was almost similar in Oslo (13. 1 (95% CI 11. 7-14. 5)) and Upper Hallingdal (14. 2 (13. 1–15. 3)), but lower in Odda (9. 0 (7. 0–11. 0)). The findings for severe respiratory symptoms were almost equal. The age patters within each area differed. The risk of wheeze ever (p < 0.001) and wheeze in past year (p=0.04) decreased with increasing age in Odda, while there was an increase in the risk of exercise induced wheeze in Oslo (p=0.02) and Hallingdal (p < 0.001). The lifetime prevalence of asthma was lowest in Odda (5. 4 (3. 8–7. 0)) compared to Oslo (9. 4 (8. 2–10. 6)) and Hallingdal (8. 5 (6. 8–10. 2)). There was a positive association between physical activity and wheeze in past year. The results do not support the hypothesis that respiratory morbidity is more common in urban than rural areas, age and physical activity can influence the prevalence rates of respiratory symptoms in school children.     

Growth and survival of B-chronic lymphocytic leukaemia cells

Although chronic lymphocytic leukaemia of B-cell type (B-CLL) is the most common form of leukaemia in the Western world, several questions about the biology of B-CLL remain to be clarified. To obtain a conceptual model for B-CLL, defined as a relentless accumulation of resting B-CLL cells, it is particularly relevant to ask which cell type is the normal counterpart of B-CLL; what is the site of proliferation; which signals are involved in the recruitment and induction of proliferation and which signals contribute to the survival of the B-CLL cells? The significance of the studies on B-CLL cellsin vitro for the interpretation of thein vivo situation may be questioned since they oversimplify the multiple and complex cellular interactions that occurin vivo. However, thein vitro studies have been instrumental in elucidating signals that may regulate growth, differentiation and survival of B-CLL cells. This knowledge, herein reviewed, can be used to put forward a hypothesis on B-CLL cell regulationin vivo.