A mouse model of insulin resistance and its associated dyslipidemia was generated by crossing mice expressing human apolipoprotein B (apoB) with mice lacking only brown adipose tissue (BATless). On a high fat diet, male apoB/BATless mice became obese, hypercholesterolemic, hypertriglyceridemic, and hyperinsulinemic compared with control apoB mice. showed that the hypertriglyceridemia in apoB/BATless mice was due to the increased synthesis and secretion of triglyceride. Furthermore, lipoprotein lipase and hepatic lipase activities were not defective. ApoB was also secreted at increased rates in the apoB/BATless mice. Similar levels of apoB mRNA in apoB and apoB/BATless mice indicated that apoB secretion was regulated posttranscriptionally. LDL receptor mRNA was increased in the apoB/BATless mice, indicating that the observed increase in apoB-lipoprotein secretion was not due to their decreased reuptake. Finally, mRNA levels of the large subunit of microsomal triglyceride transfer protein, a required component for very low density protein assembly, were not different between apoB and apoB/ BATless mice. This rodent model should prove useful in exploring mechanisms underlying the regulation of apoB secretion in the context of insulin resistance. Increased secretion of apolipoprotein B (apoB)1 has been associated with the hyperlipidemia that presents in a number of physiological disorders, including familial combined hyperlipidemia (1-4) and the dyslipidemia associated with insulin resistance (5, 6). As such, understanding the processes that regulate the secretion of apoB has been the subject of extensive clinical and molecular investigation.Cell culture experiments have provided convincing data that the primary regulation of apoB secretion occurs post-translationally and that the intracellular degradation of apoB is an important determinant of the amount of the protein that is ultimately secreted (7-9). In several cell systems, the availability of intracellular triglyceride has been shown to affect the rates of apoB degradation and thus secretion. Specifically, in HepG2 cells, incubation with oleate led to the increased secretion of apoB into the medium by preventing the intracellular degradation of the protein (10). This stimulatory effect of oleate on apoB secretion has also been demonstrated in McARH-7777 cells, a rat hepatoma cell line (11); perfused livers from fasted rats (12); and livers from rats fed a high carbohydrate diet (13). In contrast, apoB secretion rates were unaltered by oleate availability in primary rat hepatocytes (14) and in perfused livers (12, 15) from fed rats.We sought to create a mouse model that would allow for the in vivo investigation of mechanisms underlying the increased apoB secretion observed in humans with insulin resistance. Mice have distinctly different lipid profiles compared with humans with most cholesterol carried in HDL (16). Transgenic mice expressing human apoB100 display an accumulation of lipid in LDL (17) and have been used to investigate the regulation of apoB secre...
Non-synonymous mutations affecting both alleles of PCSK1 (proprotein convertase 1/3) are associated with obesity and impaired prohormone processing. We report a proband who was compound heterozygous for a maternally inherited frameshift mutation and a paternally inherited 474kb deletion that encompasses PCSK1, representing a novel genetic mechanism underlying this phenotype. Although pro-vasopressin is not a known physiological substrate of PCSK1, the development of central diabetes insipidus in this proband suggests that PCSK1 deficiency can be associated with impaired osmoregulation.
ImportanceIrritable bowel syndrome (IBS) is associated with significant morbidity in children and adolescents, and the therapeutic efficacy of available treatment options is limited. The role of vitamin D supplementation in pediatric IBS is unclear as the vitamin D status of pediatric patients with IBS is unknown. Equally, the relationship of vitamin D status with psychosomatic symptoms in children and adolescents is unclear.AimTo characterize the vitamin D status of pediatric patients with IBS using a case-control study design.HypothesisSerum 25-hydroxyvitamin D [25(OH)D] concentration will be similar between patients with IBS and controls.Subjects and methodsA retrospective case-controlled study of 116 controls (age 14.6 ± 4.3 y), female (n = 67; 58%) and 55 subjects with IBS (age 16.5 ± 3.1y), female (n = 44; 80%). Overweight was defined as BMI of ≥85th but <95th percentile, and obesity as BMI ≥95th percentile. Vitamin D deficiency was defined as 25(OH)D of <50 nmol/L, while seasons of vitamin D draw were categorized as summer, winter, spring, and fall. Major psychosomatic manifestations included in the analysis were depression, anxiety, and migraine.ResultsMore than 50% of IBS subjects had vitamin D deficiency at a cut-off point of <50 nmol/L (53% vs. 27%, p = 0.001); and >90% of IBS subjects had vitamin D deficiency at a cut-off point of <75 nmol/L (93% vs. 75%, p = 0.006). IBS subjects had significantly lower mean 25(OH)D: 53.2 ± 15.8 nmol/L vs. 65.2 ± 28.0 nmol/L, p = 0.003; and albumin: 6.2 ± 0.6 vs. 6.5 ± 0.6 μmol/L, p = 0.0.01. IBS subjects with migraine had significantly lower mean 25(OH)D concentration compared to controls (p = 0.01). BMI z-score was similar between the controls and IBS subjects (0.5 ± 1.4 vs. 1.2 ± 2.9, p = 0.11).ConclusionsPediatric patients with IBS had significantly lower 25(OH)D concentration compared to controls despite having similar mean BMI values as controls. Only 7% of the children and adolescents with IBS were vitamin D sufficient, and >50% of the subjects with IBS had vitamin D deficiency. This is a much higher prevalence of vitamin D deficiency compared to IBD and other malabsorption syndromes. Monitoring for vitamin D deficiency should be part of the routine care for patients with IBS. Randomized control trials are warranted to determine the role of adjunctive vitamin D therapy in pediatric IBS.
Background: Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic. Methods: We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation. Results: Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8–3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC ( P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date. Conclusions: Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD.
BackgroundThe health consequences of lactose intolerance (LI) are unclear.AimsTo investigate the effects of LI on stature and vitamin D status.HypothesesLI subjects will have similar heights and vitamin D status as controls.Subjects and MethodsPrepubertal children of ages 3-12 years with LI (n=38, age 8.61 ± 3.08y, male/female 19/19) were compared to healthy, age- and gender-matched controls (n=49, age 7.95±2.64, male/female 28/21). Inclusion criteria: prepubertal status (boys: testicular volume <3cc; girls: Tanner 1 breasts), diagnosis of LI by hydrogen breath test, and no history of calcium or vitamin D supplementation. Vitamin D deficiency was defined as 25-hydroxyvitamin D [25(OH)D] <50 nmol/L. Gender-adjusted midparental target height (MPTH) z-score was calculated using NCHS data for 18 year-old adults. Data were expressed as mean ± SD.ResultsThere was no significant difference in 25(OH)D between the LI and non-LI subjects (60.1±21.1, vs. 65.4 ± 26.1 nmol/L, p = 0.29). Upon stratification into normal weight (BMI <85th percentile) vs. overweight/obese (BMI ≥85th percentile), the normal weight controls had significantly higher 25(OH)D level than both the normal weight LI children (78.3 ± 32.6 vs. 62.9 ± 23.2, p = 0.025), and the overweight/obese LI children (78.3±32.6 vs. 55.3±16.5, p = 0.004). Secondly, there was no overall difference in height z-score between the LI children and controls. The normal weight LI patients had similar height as normal controls (-0.46 ± 0.89 vs. -0.71 ± 1.67, p = 0.53), while the overweight/obese LI group was taller than the normal weight controls (0.36 ± 1.41 vs. -0.71 ± 1.67, p = 0.049), and of similar height as the overweight/obese controls (0.36 ± 1.41 vs. 0.87 ± 1.45, p = 0.28). MPTH z-score was similar between the groups.ConclusionShort stature and vitamin D deficiency are not features of LI in prepubertal children.
Background Determining the relative cost-effectiveness between advanced therapeutic options for ulcerative colitis (UC) may optimize resource utilization. We evaluated total cost per response, cost per remission, and cost of safety events for patients with moderately-to-severely active UC after 52 weeks of treatment with advanced therapies at standard dosing. Methods An analytic model was developed to estimate costs from the US healthcare system perspective associated with achieving efficacy outcomes and managing safety outcomes for advanced therapies approved for the treatment of UC. Numbers needed to treat (NNT) for response and remission, and numbers needed to harm (NNH) for serious adverse events (SAEs) and serious infections (SIs) were derived from a network meta-analysis of pivotal trials. NNT for induction and maintenance were combined with drug regimen costs to calculate cost per clinical remission. Cost of managing AEs was calculated using NNH for safety outcomes and published costs of treating respective AEs. Results Costs per remission were $205,240, $249,417, $267,463, $365,050, $579,622, $750,200, and $787,998 for tofacitinib 10 mg, tofacitinib 5 mg, infliximab, vedolizumab, golimumab, adalimumab, and ustekinumab, respectively. Incremental costs of SAEs and SIs collectively were $136,390, $90,333, $31,888, $31,061, $20,049, $12,059, and $0 for tofacitinib 5 mg, golimumab, adalimumab, tofacitinib 10 mg, infliximab, ustekinumab, and vedolizumab (reference), respectively. Conclusions Tofacitinib was associated with the lowest cost per response and cost per remission, while vedolizumab had the lowest costs related to SAEs and SIs. Balancing efficacy versus safety is important when evaluating the costs associated with treatment of moderate-to-severe UC.
Background Patients with Crohn’s disease (CD) are at risk of complications. Performance characteristics of a decision support tool assessing risk of CD complications were evaluated. Methods CDPATH (formerly: Personalized Risk and Outcome Prediction Tool [PROSPECT]) was calibrated and validated in 2 cohorts. Tool prediction of disease characteristics was assessed using Cox regression and Harrell’s C-statistic. Results All associations of CD complications and CDPATH components were significant except perianal location. There was significant association between individualized risk assessment scores and CD complications in both cohorts. Conclusion CDPATH is validated as a clinical decision support tool for risk of CD complications.
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