Impact of adherence to WHO infant feeding recommendations on later risk of obesity and non‐communicable diseases: systematic review

Adherence to WHO infant feeding recommendations has short‐term benefits and may also help in the prevention of non‐communicable diseases (NCDs). This study reviewed the evidence on whether adherence to all elements of the WHO infant feeding recommendations (comparison group those exclusively breastfed to 6 months, introduced to appropriate complementary feeding from 6 months, with continued breastfeeding to at least 24 months; exposure group characterised by non‐adherence to any of the three recommendations) is associated with reduced risk of later obesity or cardiometabolic disease. The population of interest was children not classified as very low weight (weight‐for‐age z‐score >?3.0). MEDLINE, EMBASE, Global Health, CINAHL plus, ProQuest Dissertations and Thesis were systematically searched from 2001 to July 2014, manual reference searching of a birth cohort register ( http://www.birthcohorts.net/ ) as well as papers identified in the search and selected journals was carried out. The database search yielded 9050 records, 275 English‐language full‐text articles were screened, but no studies were eligible, failing to meet the following criteria: comparison (213); exposure (14); population (3); relevant outcome (5); outcome before 24 months (9); insufficient information provided (30); plus one study was qualitative. Eight studies met the inclusion criterion of exclusive breastfeeding to 6 months, but did not meet the other inclusion criteria. The present study has revealed an important gap in the evidence on NCD prevention, and suggestions for addressing this evidence gap are provided.     

Personal digital assistant-enabled report content knowledgebase results in more complete pathology reports and enhances resident learning

We developed a personal digital assistant-based knowledgebase of surgical pathology report content recommendations and performed an experimental trial to test if the knowledgebase improved report completeness. The 15 experimental group and 13 control group residents were given microscope slides and corresponding reports with the final diagnosis section blanked-out, and were asked to complete the final diagnosis section during 3 study episodes (T0, T1, and T2). At T0 (baseline), experimental group and control group produced reports of comparable completeness. During T1, experimental group was allowed to use the knowledgebase while completing reports. During T1, experimental group produced more complete reports and were better judges of report completeness than control group. At T2, when neither group used the knowledgebase, experimental group's performance was still statistically better than control group's. Use of the knowledgebase did not ensure report completeness, but was associated with more complete reports and more accurate judgments of report completeness, and this performance advantage persisted in the absence of the knowledgebase.     

Out of sight but not out of mind: Home countries' macroeconomic volatilities and immigrants' mental health

We provide the first empirical evidence that better economic performances by immigrants' countries of origin, as measured by lower consumer price index (CPI) or higher gross domestic product, improve immigrants' mental health. We use an econometrically‐robust approach that exploits exogenous changes in macroeconomic conditions across immigrants' home countries over time and controls for immigrants' observable and unobservable characteristics. The CPI effect is statistically significant and sizeable. Furthermore, the CPI effect diminishes as the time since emigrating increases. By contrast, home countries' unemployment rates and exchange rate fluctuations have no impact on immigrants' mental health.     

Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5‐associated malformations include bottom‐of‐the‐sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway. Ann Neurol 2014;75:782–787     

Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans

Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.     

Degradation of tissue-type plasminogen activator by human monocyte- derived macrophages is mediated by the mannose receptor and by the low- density lipoprotein receptor-related protein

The balance of tissue-type plasminogen activator (t-PA) production and degradation determines its concentration in blood and tissues. Disturbance of this balance may result in either increased or decreased proteolysis. In the present study, we identified the receptor systems involved in the degradation of t-PA by human monocytes/macrophages in culture. Monocytes were cultured and became macrophages within 2 days. At 4 degrees C, 125I-t-PA bound to macrophages with high (apparent dissociation constant [kd], 1 to 5 nmol/L) and low affinity (kd > 350 nmol/L). At 37 degrees C, the cells internalized and degraded t-PA via the high affinity binding sites, which were partially inhibited by mannan. The low affinity binding sites were 6-aminohexanoic acid- inhibitable and not involved in t-PA degradation. Degradation of t-PA was upregulated during differentiation of monocytes to macrophages. Dexamethasone further upregulated the mannan-inhibitable t-PA degradation. Lipopolysaccharide downregulated both mannan-inhibitable and non-mannan-inhibitable t-PA degradation. Non-mannan-inhibitable degradation was completely blocked by recombinant 39-kD receptor- associated protein (RAP, inhibitor of lipoprotein receptor-related protein [LRP]), whereas mannan-inhibitable degradation was blocked by the addition of a monoclonal antibody against the mannose receptor. No differences between the degradation of t-PA and functionally inactivated t-PA were observed. We conclude that human monocyte-derived macrophages are able to bind, internalize, and degrade t-PA. Degradation of t-PA does not require complex formation with plasminogen activator inhibitors. The macrophages use two independently regulated receptors, namely, the mannose receptor and LRP, for the uptake and degradation of t-PA.     

T-cell activation Rho GTPase–activating protein expression varies with inflammation location and severity in Crohn's disease

Background

The T-cell activation Rho GTPase–activating protein (TAGAP) gene has a regulatory role in T cell activation. We have previously suggested a correlation between the TAGAP-associated single nucleotide polymorphism rs212388 and protection from anal sepsis in Crohn's disease (CD) patients. The present study sought to evaluate TAGAP's expression in colonic tissue of CD patients with varying disease severity and location.

Materials and methods

Five transverse, 17 left, and five sigmoid colectomy specimens from 27 CD patients with varying disease severity (16 male, mean age at diagnosis 26.4 ± 2.2 y) were evaluated for TAGAP messenger RNA expression. Fisher exact, Mann–Whitney, and Welch two-sample t-tests were used for statistical evaluation. Immunohistochemistry confirmed results.

Results

Patients with tissue demonstrating lower TAGAP messenger RNA expression (less than the overall mean) were younger at diagnosis (mean age 21.1 ± 6.3 versus 32.5 ± 13 y, P = 0.009). Increased TAGAP expression was seen in moderate or severely diseased tissue versus tissue with no or mild disease (RQ = 1.3 ± 0.34 versus 0.53 ± 0.09, P = 0.050). This was the most dramatic in the sigmoid colon (P = 0.041). TAGAP expression was increased in more distal tissue with a significant difference seen when comparing transverse versus sigmoid colon with moderate or severe disease (0.51 ± 0.14 versus 1.9 ± 0.37, P = 0.049).

Conclusions

Colonic expression of TAGAP in CD patients varied according to disease severity and location, being the most elevated in patients with severe disease in the sigmoid colon. Whether changes in TAGAP expression are a result of disease response or inherent to the disease pathophysiology itself remains to be determined. This gene warrants further investigation for its role in CD.