MC 1046

MC 903 has been found to be a potent inducer of cell differentiation and to inhibit proliferation and DNA-synthesis of cells possessing the receptor for 1,25(OH)2D3. MC 1046 is the metabolite of calcipotrioI (MC 903), which is a novel analogue of the physiologically active metabolite of vitamin D3.

In vitro: The biological effects on the U937 cells of the two major metabolites of MC 903 (MC 1046 and MC 1080) were investigated. Results showed that the metabolites had effects that were more than 100 times weaker than those of the parent compound [1].

In vivo: MC 903 is a novel analogue of the physiologically active metabolite of 1,25(OH)2D3. Unlike the similar effects on cell proliferation and cell differentiation in vitro, MC 903 has 100-200 times less effect on calcium metabolism in vivo. Moreover, rat study indicats that the effect of MC 903 on proliferative disorders, its fast elimination and the formation of inactive metabolites makes MC 903 suitable for topical treatment of psoriasis [1].

Clinical trial: No clinical data are available for MC 1046 and its analogues.

Reference:
[1] Kissmeyer AM, Binderup L.   Calcipotriol (MC 903): pharmacokinetics in rats and biological activities of metabolites. A comparative study with 1,25(OH)2D3. Biochem Pharmacol. 1991;41(11):1601-6.

The Double Mandibular Osteotomy for Vascular and Tumor Surgery of the Parapharyngeal Space.[Pubmed:27923112]

J Oral Maxillofac Surg. 2017 May;75(5):1046-1061.

PURPOSE: The purposes of this study are to describe our experience using a double mandibular osteotomy for access to the parapharyngeal space in vascular and tumor surgery and to report on the outcomes and complications of this procedure. PATIENTS AND METHODS: We designed and implemented a case series to review the medical records of all patients treated with a double mandibular osteotomy for parapharyngeal space access from 1994 to 2016. Patient demographic characteristics, indications for the procedure, outcomes, and complications were recorded. RESULTS: A total of 17 patients underwent a double mandibular osteotomy procedure for access to the parapharyngeal space during the study period. There were 7 men (41%) and 10 women (59%) comprising the cohort. The average age was 57 years (range, 29 to 75 years). The follow-up period ranged from 6 to 98 months (mean, 40 months), and 7 patients (41%) were tobacco users at the time of surgery. The most common indication was high internal carotid artery stenosis (n = 6) followed by carotid body paraganglioma (n = 3). Average blood loss was 186 mL, and there were no deaths during the study period. Eight postoperative complications were noted in 7 patients (41%). No procedures were aborted or compromised because of inadequate parapharyngeal space access. All patients showed clinical and radiographic signs of healing of the osteotomy sites. CONCLUSION: The double mandibular osteotomy provides adequate access to the parapharyngeal space for effective tumor removal and high carotid surgical intervention with acceptable patient morbidity and complications.

Physical Activity and Mental Well-being in a Cohort Aged 60-64 Years.[Pubmed:26070782]

Am J Prev Med. 2015 Aug;49(2):172-80.

INTRODUCTION: Although evidence suggests physical activity (PA) may be associated with mental well-being at older ages, it is unclear whether some types of PA are more important than others. The purpose of this study is to investigate associations of monitored total PA under free-living conditions, self-reported leisure-time PA (LTPA), and walking for pleasure with mental well-being at age 60-64 years. METHODS: Data on 930 (47%) men and 1,046 (53%) women from the United Kingdom Medical Research Council (MRC) National Survey of Health and Development collected in 2006-2011 at age 60-64 were used in 2013-2014 to test the associations of PA (PA energy expenditure and time spent in different intensities of activity assessed using combined heart rate and acceleration monitors worn for 5 days, self-reported LTPA, and walking for pleasure) with the Warwick-Edinburgh Mental Well-being Scale (WEMWBS; range, 14-70). RESULTS: In linear regression models adjusted for gender, long-term limiting illness, smoking, employment, socioeconomic position, personality, and prior PA, those who walked for >1 hour/week had mean WEMWBS scores 1.47 (95% CI=0.60, 2.34) points higher than those who reported no walking. Those who participated in LTPA at least five times/month had WEMWBS scores 1.25 (95% CI=0.34, 2.16) points higher than those who did not engage in LTPA. There were no statistically significant associations between free-living PA and WEMWBS scores. CONCLUSIONS: In adults aged 60-64 years, participation in self-selected activities such as LTPA and walking are positively related to mental well-being, whereas total levels of free-living PA are not.

C13orf31 (FAMIN) is a central regulator of immunometabolic function.[Pubmed:27478939]

Nat Immunol. 2016 Sep;17(9):1046-56.

Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.

Cost-effectiveness analysis of epilepsy surgery in a controlled cohort of adult patients with intractable partial epilepsy: A 5-year follow-up study.[Pubmed:27595433]

Epilepsia. 2016 Oct;57(10):1669-1679.

OBJECTIVE: Despite its well-known effectiveness, the cost-effectiveness of epilepsy surgery has never been demonstrated in France. We compared cost-effectiveness between resective surgery and medical therapy in a controlled cohort of adult patients with partial intractable epilepsy. METHODS: A prospective cohort of adult patients with surgically remediable and medically intractable partial epilepsy was followed over 5 years in the 15 French centers. Effectiveness was defined as 1 year without a seizure, based on the International League Against Epilepsy (ILAE) classification. Clinical outcomes and direct costs were compared between surgical and medical groups. Long-term direct costs and effectiveness were extrapolated over the patients' lifetimes with a Monte-Carlo simulation using a Markov model, and an incremental cost-effectiveness ratio (ICER) was computed. Indirect costs were also evaluated. RESULTS: Among the 289 enrolled surgery candidates, 207 were operable-119 in the surgical group and 88 in the medical group-65 were not operable and not analyzed here, 7 were finally not eligible, and 10 were not followed. The proportion of patients completely seizure-free during the last 12 months (ILAE class 1) was 69.0% in the operated group and 12.3% in the medical group during the second year (p < 0.001), and it was respectively 76.8% and 21% during the fifth year (p < 0.001). Direct costs became significantly lower in the surgical group the third year after surgery, as a result of less antiepileptic drug use. The value of the discounted ICER was 10,406 (95% confidence interval [CI] 10,182-10,634) at 2 years and 2,630 (CI 95% 2,549-2,713) at 5 years. Surgery became cost-effective between 9 and 10 years after surgery, and even earlier if indirect costs were taken into account as well. SIGNIFICANCE: Our study suggests that in addition to being safe and effective, resective surgery of epilepsy is cost-effective in the medium term. It should therefore be considered earlier in the development of epilepsy.

Interpersonal Attacks on the Dignity of Members of HIV Key Populations: A Descriptive and Exploratory Study.[Pubmed:27752870]

AIDS Behav. 2017 Sep;21(9):2561-2578.

Attacks on peoples' dignity help to produce and maintain stigmatization and interpersonal hostility. As part of an effort to develop innovative measures of possible pathways between structural interventions or socially-disruptive Big Events and HIV outbreaks, we developed items to measure dignity denial. These measures were administered to 300 people who inject drugs (PWID), 260 high-risk heterosexuals who do not inject drugs, and 191 men who have sex with men who do not inject drugs (MSM). All of the PWID and many of the high risk heterosexuals and MSM were referred to our study in 2012-2015 by a large New York city study that used respondent-driven sampling; the others were recruited by chain-referral. Members of all three key populations experienced attacks on their dignity fairly often and also reported frequently seeing others' dignity being attacked. Relatives are major sources of dignity attacks. MSM were significantly more likely to report having their dignity attacked by police officers than were the other groups. 40 % or more of each key population reported that dignity attacks are followed "sometimes" or more often both by using more drugs and also by using more alcohol. Dignity attacks and their health effects require more research and creative interventions, some of which might take untraditional forms like social movements.

MC 1046(Impurity A of Calcipotriol) is an impurity of Calcipotriol; Calcipotriol (MC 903; Calcipotriene) is a ligand of VDR-like receptors.

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