Reversal of Small,Dense LDL Subclass Phenotype by Weight Loss Is Associated With Impaired Fat Oxidation

Adiposity is more prevalent among individuals with a predominance of small, dense low‐density lipoprotein (LDL) (pattern B) particles than among those with larger LDL (pattern A). We tested for differences in resting energy expenditure (REE) and respiratory quotient (RQ) in overweight men with pattern A (n = 36) or pattern B (n = 60). Men consumed a standardized isoenergetic diet for 3 weeks after which a ～9 kg weight loss was induced by caloric deficit for 9 weeks, followed by 4 weeks of weight stabilization. REE and RQ were measured by indirect calorimetry before and after weight loss. Results were analyzed separately in pattern B men who converted to pattern A (B→A; n = 35) and those who did not (B→B; n = 25). At baseline, B→B men had higher trunk fat, triacylglycerol (TG) and insulin concentrations, homeostasis model assessment of insulin resistance (HOMA_IR), and smaller LDL particles compared to B→A men and baseline pattern A men who remained pattern A (A→A; n = 35). REE normalized to fat‐free mass did not change after weight loss. RQ decreased in A→A men, increased in B→A men, and did not change significantly in B→B men after weight loss. Calculated fat oxidation rates paralleled the RQ results. Baseline plasma TG concentrations were positively correlated with RQ and inversely correlated with the magnitude of weight loss achieved for a given prescribed energy reduction in the entire study population. Pattern B men who converted to pattern A with weight loss may have an underlying impairment in fat oxidation that predisposes to both dyslipidemia and an impaired ability to achieve weight loss by energy restriction.     

Surgical treatment of aortic dissection in a patient with metastatic prostate cancer

Acute aortic dissection bears all the stigmata of a true clinical emergency. The natural history of this acute aortic syndrome warrants prompt surgical intervention, with only a few absolute contraindications to this line of treatment. We present a 74-year-old man with documented metastatic prostate cancer who underwent emergent surgery for acute Stanford A aortic dissection. Having acknowledged the relatively favorable evolution of our patient's malignant disease, we were not deterred by its presence from pursuing surgical treatment of his aortic dissection.     

Proliferation and Death in a Binary Environment: A Stochastic Model of Cellular Ecosystems

The activation, growth and death of animal cells are accompanied by changes in the chemical composition of the surrounding environment. Cells and their microscopic environment constitute therefore a cellular ecosystem whose time-evolution determines processes of interest for either biology (e.g. animal development) and medicine (e.g. tumor spreading, immune response). In this paper, we consider a general stochastic model of the interplay between cells and environmental cellular niches. Niches may be either favourable or unfavourable in sustaining cell activation, growth and death, the state of the niches depending on the state of the cells. Under the hypothesis of random coupling between the state of the environmental niche and the state of the cell, the rescaled model reduces to a set of four non-linear differential equations. The biological meaning of the model is studied and illustrated by fitting experimental data on the growth of multicellular tumor spheroids. A detailed analysis of the stochastic model, of its deterministic limit, and of normal fluctuations is provided.     

Neuropsychological Deficits in Mice Depleted of the Schizophrenia Susceptibility Gene CSMD1

Recent meta-analyses of schizophrenia genome-wide association studies (GWASs) have identified the CUB and SUSHI multiple domains 1 (CSMD1) gene as a statistically strong risk factor. CSMD1 is a complement control-related protein suggested to inhibit the classical complement pathway, being expressed in developing neurons. However, expression of CSMD1 is largely uncharacterized and relevance for behavioral phenotypes is not previously demonstrated. Here, we assess neuropsychological behaviors of a Csmd1 knockout (KO) mouse in a selection of standard behavioral tests. Deregulation of neuropsychological responses were observed in both the open field and the elevated plus maze tests, in which KO mice spent 55% and 33% less time than WT littermate mice in open areas, respectively. Altered behaviors were also observed in tail suspension and to higher acoustic stimuli, for which Csmd1 KO mice showed helplessness and moderate increase in startle amplitude, respectively. Furthermore, Csmd1 KO mice also displayed increased weight-gain and glucose tolerance, similar to a major phenotype of the metabolic syndrome that also has been associated to the human CSMD1 locus. Consistent with a role in the control of behaviors, Csmd1 was found highly expressed in the central nervous system (CNS), and with some expression in visceral fat and ovary, under tissue-specific control by a novel promoter-associated lncRNA. In summary, disruption of Csmd1 induces behaviors reminiscent of blunted emotional responses, anxiety and depression. These observations suggest an influence of the CSMD1 schizophrenia susceptibility gene on psychopathology and endophenotypes of the negative symptom spectra.     

PICK1 Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance

Secretory vesicles in endocrine cells store hormones such as growth hormone (GH) and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN) and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs) domain protein PICK1 (protein interacting with C kinase 1) as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of peptidergic endocrine cells and support an important role of PICK1/ICA69 in maintenance of metabolic homeostasis.     

Very small injected samples to study chloroquine and quinine in human serum using capillary-LC and native fluorescence

A comparison between HPLC with conventional fluorescence detection and capillary-LC (microHPLC) with native laser-induced fluorescence (LIF) detection was done to determine chloroquine (CQ) and quinine (Q) in human serum. HPLC experiments were run with parameters of the conventional fluorimeter set at the highest level of sensitivity. Results were compared with those obtained on microHPLC coupled to a ZETALIF (He-Cd 325 nm) detector which provided a 50-fold increase in sensitivity. In microHPLC-LIF injection volumes were 200 nL instead of 10 microL in conventional HPLC. The separation was completed within 3 min (6 min on HPLC). The limit of detection on microHPLC-LIF was 1.9 and 1.3 fmol for CQ and Q, respectively. Both experiments were validated on serum samples. The mean recovery was more than 95% for CQ and Q. The intra- and inter-day precision and accuracy were found to be within the acceptable limits (<10%).