Neural processing of food cues in pre-pubertal children.

BACKGROUND/OBJECTIVES: Neuroimaging investigations of brain pathways involved in reward and motivation have primarily focused on adults. This study sought to identify brain responses to visual food cues and explore its relationships with adiposity and sex in pre-pubertal children. METHODS: Brain responses to palatable food vs. non-food cues were measured in 53 children (age: 8.18 ± .66 years; sex: 22 boys, 31 girls) after an overnight fast. Whole-brain analysis (cluster-correction Z > 2.3, P < .05) was performed to examine brain food cue reactivity and its relationships with adiposity and sex. RESULTS: Greater brain activity in response to food vs. non-food cues was observed in regions implicated in reward (orbital frontal cortex, striatum), taste (insula, postcentral gyrus), appetite (hypothalamus), emotion (amygdala), memory (hippocampus), visual processing (occipital cortex) and attention (parietal cortex). A negative association was found between percent body fat and food cue reactivity in the medial prefrontal cortex and lateral orbital frontal cortex adjusting for age and sex. Boys compared with girls had increased food cue reactivity in right hippocampus and visual cortex. CONCLUSIONS: These data suggest that body fat and sex are important moderators of brain food cue reactivity in children.

Dietary influences on cognition.

Obesity is a world-wide crisis with profound healthcare and socio-economic implications and it is now clear that the central nervous system (CNS) is a target for the complications of metabolic disorders like obesity. In addition to decreases in physical activity and sedentary lifestyles, diet is proposed to be an important contributor to the etiology and progression of obesity. Unfortunately, there are gaps in our knowledge base related to how dietary choices impact the structural and functional integrity of the CNS. For example, while chronic consumption of hypercaloric diets (increased sugars and fat) contribute to increases in body weight and adiposity characteristic of metabolic disorders, the mechanistic basis for neurocognitive deficits in obesity remains to be determined. In addition, studies indicate that acute consumption of hypercaloric diets impairs performance in a wide variety of cognitive domains, even in normal non-obese control subjects. These results from the clinical and basic science literature indicate that diet can have rapid, as well as long lasting effects on cognitive function. This review summarizes our symposium at the 2017 Society for the Study of Ingestive Behavior (SSIB) meeting that discussed these effects of diet on cognition. Collectively, this review highlights the need for integrated and comprehensive approaches to more fully determine how diet impacts behavior and cognition under physiological conditions and in metabolic disorders like type 2 diabetes mellitus (T2DM) and obesity.

Maternal obesity, gestational diabetes, breastfeeding and childhood overweight at age 2 years.

BACKGROUND: Maternal obesity, excessive gestational weight gain (EGWG), gestational diabetes mellitus (GDM) and breastfeeding are four important factors associated with childhood obesity. OBJECTIVES: The objective of the study was to assess the interplay among these four factors and their independent contributions to childhood overweight in a cohort with standard clinical care. METHODS: The cohort included 15 710 mother-offspring pairs delivered in 2011. Logistic regression was used to assess associations between maternal exposures and childhood overweight (body mass index >85th percentile) at age 2 years. RESULTS: Mothers with pre-pregnancy obesity or overweight were more likely to have EGWG, GDM and less likely to breastfeed ≥6 months. Mothers with GDM had 40-49% lower EGWG rates and similar breastfeeding rates compared with mothers without GDM. Analysis adjusted for exposures and covariates revealed an adjusted odds ratio (95% confidence interval) associated with childhood overweight at age 2 years of 2.34 (2.09-2.62), 1.50 (1.34-1.68), 1.23 (1.12-1.35), 0.95 (0.83-1.10) and 0.76 (0.69-0.83) for maternal obesity, overweight, EGWG, GDM and breastfeeding ≥6 months vs. <6 months, respectively. CONCLUSIONS: In this large clinical cohort, GDM was not associated with, but maternal pre-pregnancy obesity or overweight and EGWG were independently associated with an increased risk, and breastfeeding ≥6 months was associated with a decreased risk of childhood overweight at age 2 years.

Higher incidence of HCV in females compared to males who inject drugs: A systematic review and meta-analysis.

Women who inject drugs have been shown to have higher incidence of HIV and risk behaviours than men, but there are conflicting reports about hepatitis C virus (HCV) incidence. We systematically reviewed the literature to examine the female-to-male (F:M) HCV incidence in female and male persons who inject drugs (PWID), and also to explore the heterogeneity (i.e. methodological diversity) in these differences. We searched PubMed and EMBASE for studies published between 1989 and March 2015 for research that reported incidence of HCV infection by sex or HCV incidence F:M rate ratio. A total of 28 studies, which enrolled 9325 PWID, were included. The overall pooled HCV incidence rate (per 100 person-years observation) was 20.36 (95% CI: 13.86, 29.90) and 15.20 (95% CI: 10.52, 21.97) in females and males, respectively. F:M ratio was 1.36:1 (95% CI: 1.13, 1.64) with substantial heterogeneity (I-squared=71.6%). The F:M ratio varied by geographic location from 4.0 (95% CI: 1.80, 8.89) in China to 1.17 (95% CI: 0.95, 1.43) in the U.S. In studies which recruited participants from community settings, the F:M ratio was 1.24 (95% CI: 1.03, 1.48), which was lower than that reported in the clinical settings (1.72, 95% CI: 0.86, 3.45). The number of studies included provided sufficient statistical power to detect sex differences in this analysis. Our findings raise questions and concerns regarding sex differences with respect to the risk of HCV. Both behavioural and biological studies are needed to investigate causes and potential mechanisms as well as sex-specific prevention approaches to HCV infection.

Insulin sensitivity and brain reward activation in overweight Hispanic girls: a pilot study.

BACKGROUND: Insulin resistance is a link between obesity and the associated disease risk. In addition to its role as an energy regulatory signal to the hypothalamus, insulin also modulates food reward. OBJECTIVE: To examine the relationship of insulin sensitivity (SI) and fasting insulin with cerebral activation in response to food and non-food cues in children. METHODS: Twelve overweight Hispanic girls (age: 8-11) participated in two study visits, a frequently sampled intravenous glucose tolerance test and a functional neuroimaging session (GE HDxt 3.0Tesla) with visual stimulation tasks. Blocks of images (high calorie [HC], low calorie [LC] and non-food [NF]) were presented in randomized order. RESULTS: Comparing HC with NF, SI was inversely associated with activation in the anterior cingulate (r(2) = 0.65; P < 0.05), the insula (r(2) = 0.69; P < 0.05), the orbitofrontal cortex (r(2) = 0.74; P < 0.05), and the frontal and rolandic operculum (r(2) = 0.76; P < 0.001). Associations remained significant after adjustment for body mass index. Association of fasting insulin and cerebral activation disappeared after adjustment for waist circumference. CONCLUSION: In addition to weight loss, insulin sensitivity may pose an important target to regulate neural responses to food cues in the prevention of excessive weight gain.

Evaluation of adipocyte apoptosis by laser scanning cytometry.

OBJECTIVE: Adipocyte apoptosis plays an important role in adipose tissue homeostasis and can be altered under a variety of physiological and pathological conditions. This study was carried out to determine whether laser scanning cytometry (LSC) can be used to measure changes in apoptosis of adipocytes over time. DESIGN: LSC was used to investigate adipocyte apoptosis induced by tumor necrosis factor-alpha (TNF-alpha), a cytokine that is associated with obesity and insulin resistance. LSC, a slide-based solid phase cytofluorometer, provides quantitative flow fluorescence data together with morphological information for apoptotic detection. Both 3T3-L1 cells and rat adipocytes from primary cell culture were incubated with 0 or 25 nM TNF-alpha for up to 24 h. Both the FITC-conjugated annexin V/propidium iodide assay and the TUNEL assay were used to distinguish cells with apoptotic characteristics from nonapoptotic cells. RESULTS: Apoptosis did not increase over time in the absence of TNF-alpha for both 3T3-L1 cells and rat primary adipocytes. For both 3T3-L1 cells and rat primary adipocytes, a significant increase in the percentage of apoptotic cells was observed by 3-4 h incubation with TNF-alpha (P<0.05). By 24 h, more than 50% of cells incubated with TNF-alpha were apoptotic (P<0.001). This process was also associated with morphological changes typical of adipocytes undergoing apoptosis. By estimating the percentage of cell subpopulations after different times of incubation with TNF-alpha, we were able to develop grading parameters, based on the adipose apoptotic measurements. CONCLUSION: With morphological information, LSC can be a useful tool to evaluate adipocyte apoptosis.

An analysis of movement and discomfort of the female breast during exercise and the effects of breast support in three cases.

Breast pain is common during exercise, occurring in up to 56% of subjects in some surveys. This pain is mainly associated with the movement of breast tissue. In an attempt to analyse this movement and the resulting pain, the movement of the female breast tissue was quantified in four conditions of breast support ("sports bra", "fashion bra", "crop top" and bare breasted) during four different activities (running, jogging, aerobics march and walking). These activities represented general patterns of exercise for adult females in Australian society. All three subjects were healthy, active, young women of varying breast size (12B, 14B & 14C) that were typical of young women. Two of the subjects had noted breast pain whilst exercising. The results showed that wearing external support for the breast tissue reduced absolute vertical movement and maximum downward deceleration force on the breast. Support also reduced perceived pain. When compared to other forms of breast support a "sports bra" (brassiere designed for breast support whilst exercising) provided superior support for the breast in relation to the amplitude of movement, deceleration forces on the breast, and perceived pain. The data indicates that adult females should wear appropriate breast support to reduce perceived breast discomfort or pain. Of the three garments examined in this study, the fitted sports bra provided superior support and pain reduction.

Breast motion and sports brassiere design. Implications for future research.

Exercise usually results in a large displacement of the breasts, often leading to breast pain. Although breast pain is a common concern of exercising females, little research has been conducted in the area of breast pain. It has been suggested that a cause of breast pain is excessive breast motion. As the female breast does not contain strong intrinsic structural support, this breast motion is difficult to reduce. It is suggested that the primary anatomical support for the breast is the Cooper's ligaments; however, their true functional properties are unknown. Because of the lack of internal breast support it has been suggested that the skin covering the breast may also act as a support structure for the breast, but this has not been quantified. In an attempt to reduce breast motion, external breast supports (brassieres) have been developed. This article discusses components of current sports brassieres with implications for future research required to improve brassiere design and performance.

Use of a green fluorescent protein as a marker for human immunodeficiency virus type 1 infection.

We constructed a recombinant human immunodeficiency virus type 1 (HIV-1) provirus called R7-GFP that expresses a modified form of a green fluorescent protein (GFP) from the jellyfish Aequorea victoria by substituting GFP-coding sequences for Nef-coding sequences. Alanine was substituted for serine at amino acid position 65 in the modified GFP, resulting in markedly increased fluorescence at an excitation wavelength of 488 nm as compared to wild-type GFP. The replication kinetics of R7-GFP were identical to that measured with an isogenic, nef-negative strain lacking GFP. Expression of GFP by replication-competent HIV-1 allowed simultaneous quantitation of viral infection and cell surface CD4 levels, revealing rapid and nearly complete CD4 downregulation on R7-GFP-infected PBMCs.

Human immunodeficiency virus type 1 Nef does not alter T-cell sensitivity to antigen-specific stimulation.

We have developed an in vitro model to study the influence that human immunodeficiency virus type 1 (HIV-1) may have on the ability of T cells to respond to antigenic challenge. We have examined consequences of HIV-1 gene expression on T-cell activation in antigen-dependent T cells that have stably integrated copies of replication-defective proviral HIV-1. Virus production by HIV-infected, antigen-dependent T cells was induced in response to antigenic stimulation and then decreased as infected cells returned to a state of quiescence. Contrary to the predictions of models proposing that Nef alters signal transduction pathways in T lymphocytes and thereby alters cellular activation, Nef expression in antigen-dependent T-cell clones did not influence their proliferative responses to low or intermediate concentrations of antigen and did not affect other measures of T-cell activation, such as induction of interleukin 2 receptor alpha-chain expression and cytokine production. In addition, we found no evidence for alteration of T-cell responsiveness to antigen by the gag, pol, vif, tat, or rev gene of HIV-1.

Is the human immunodeficiency virus-related Kaposi's sarcoma epidemic coming to an end? Insights from the Tricontinental Seroconverter Study.

A decline in the proportion of Kaposi's sarcoma among AIDS cases since the 1980s has been attributed to changes in sexual behavior among homosexual men and a decreasing exposure to a hypothesized Kaposi's sarcoma cofactor. Recent studies have shown that the incidence rate of Kaposi's sarcoma has remained relatively stable, which seems to argue against the hypothesis of a declining exposure to the putative cofactor. To examine this paradox, we evaluated the incidence of Kaposi's sarcoma, using Cox proportional hazard analyses, and performed a simulation to compare incidences of different AIDS outcomes among 407 homosexual men with documented dates of seroconversion. Our data show that men who seroconverted early in the epidemic did not progress faster to Kaposi's sarcoma than men who seroconverted more recently. A lower incidence rate of Kaposi's sarcoma would be expected among the latter group if exposure to the hypothesized cofactor is decreasing over time. The percentage of Kaposi's sarcoma among incident AIDS cases decreased over the years following seroconversion, but not over calendar time. This study demonstrates that the decline in the proportion of Kaposi's sarcoma among AIDS cases should not be interpreted as a decline in the incidence of Kaposi's sarcoma and that there is no evidence that a hypothesized Kaposi's sarcoma cofactor is declining over calendar time.

Expression of the human immunodeficiency virus type 1 (HIV-1) nef gene during HIV-1 production increases progeny particle infectivity independently of gp160 or viral entry.

The nef gene product of human immunodeficiency virus type 1 (HIV-1) promotes more-rapid kinetics of viral replication in primary peripheral blood mononuclear cells. We have previously shown that these enhancing effects of Nef on HIV-1 replication reflect an increase in viral infectivity detectable both in limiting dilution assays and through a single-cycle infection of the HeLa-CD4-long terminal repeat-beta-galactosidase indicator cell line. We now demonstrate that nef-defective HIV-1 can be rescued to near wild-type levels of infectivity by coexpressing Nef in trans in the cell line producing the virus. This observation indicates that HIV-1 virions produced in the presence of Nef are intrinsically different. However, we show that the major viral structural proteins are quantitatively similar in purified viral preparations. We also demonstrate the functional equivalence of the gp120-gp41 envelope glycoprotein complexes of Nef+ and Nef- HIV-1 through an assay for viral entry. Finally, we show that env-defective Nef+ HIV-1 pseudotyped with an amphotropic envelope is also more infectious than similarly pseudotyped Nef- HIV-1. Thus, the production of HIV-1 in the presence of Nef results in viral particles that are more infectious, and this increased infectivity is manifested at a stage after viral entry but prior to or coincident with HIV-1 gene expression.

Increasing age is associated with faster progression to neoplasms but not opportunistic infections in HIV-infected homosexual men.

OBJECTIVE: To characterize the associations of age and progression rates to AIDS-defining neoplasms and opportunistic infections (OI) in HIV-infected homosexual men. METHODS: Data from 407 homosexual men with documented dates of HIV seroconversion participating in cohort studies from four geographic locations were merged. Kaplan-Meier and Cox proportional hazards analyses were conducted with respect to the association of age with time from seroconversion to the first AIDS-defining neoplasm and OI. RESULTS: Among the 407 participants, 139 (34%) were diagnosed with AIDS; 45 (11%) with neoplasms and 90 (22%) with OI. Older age at seroconversion was significantly associated with faster progression to neoplasms, but not to OI. For each 10-year increase in age the risk for neoplasms increased 1.65-fold [95% confidence interval (CI), 1.12-2.43], after adjustment for clinical treatments. For OI this risk estimate was 0.98 (95% CI, 0.72-1.34). CONCLUSIONS: Increasing age is associated with faster progression to AIDS-defining neoplasms, but not with progression to OI. This has not been previously reported and may explain conflicting results in other studies among homosexual men that considered AIDS as a single entity. Our findings suggest that age and AIDS manifestations should be considered, particularly in the context of natural history studies, clinical trials and mathematical modelling.

Determinants of HIV disease progression among homosexual men registered in the Tricontinental Seroconverter Study.

Data on 403 homosexual/bisexual men with documented dates of human immunodeficiency virus (HIV) seroconversion were merged. All subjects originated from cohort studies that started between 1982 and 1984 in Amsterdam, The Netherlands; San Francisco, California; Sydney, Australia; and Vancouver, British Columbia, Canada. With respect to the four geographic locations, no statistically significant differences in progression time from HIV seroconversion to acquired immunodeficiency syndrome (AIDS) and death as well as in AIDS diagnoses patterns could be demonstrated. The median time from HIV seroconversion to AIDS was 8.3 years, that from HIV seroconversion to death was 8.9 years, and that from AIDS to death was 17 months. The authors evaluated HIV disease progression with respect to demographic, clinical, and behavioral cofactors. Younger age and use of prophylaxis against Pneumocystis carinii pneumonia were significantly related to slower progression from seroconversion to death. In addition, an association between slower progression and earlier dates of seroconversion was found. No relation of sexual behavior; history of sexually transmitted diseases; or use of alcohol, tobacco, and recreational drugs with rates of disease progression could be demonstrated.

Stereotaxic radiosurgical ablation: an alternative treatment for recurrent and multifocal hemangioblastomas. A report of four cases.

Craniotomy and resection is usually a safe and effective treatment for hemangioblastoma. However, since the surgical removal of recurrent and multifocal tumors can be associated with greater risks, stereotaxic radiosurgery was used to ablate hemangioblastomas in four patients with von Hippel-Lindau disease. In two of these cases a symptomatic lesion was surgically resected just prior to radiosurgery. The 11 radiosurgically treated tumors (four patients) were spherical and varied in diameter from 0.75 to 2.0 cm with a mean of 1.25 cm. Dose ranged from 30 to 75 Gy with a mean of 35 Gy. After a mean clinical and radiologic follow-up of greater than 1 1/2 years, tumor size and/or cyst formation was controlled in all cases. Nevertheless, it was necessary to temporarily shunt a tumor cyst in one patient. In another case, aggressive treatment resulted in symptomatic radiation necrosis. Despite such potential problems we believe that radiosurgical tumor ablation is a reasonable alternative to craniotomy and/or radiation therapy in poor risk patients. This report is believed to be the first published description of the use of radiosurgery in the treatment of hemangioblastoma.

Differences in time from HIV seroconversion to CD4+ lymphocyte end-points and AIDS in cohorts of homosexual men.

OBJECTIVE: To evaluate the decline in CD4+ counts in relation to the incidence of AIDS in different cohorts of homosexual men and to quantify possible consequences of laboratory variation in CD4+ measurement. METHODS: Our study includes 403 men with well documented dates of HIV seroconversion originating from five cohort studies among homosexual men. Differences in time from HIV seroconversion to the first CD4+ count dropping < 500 or 200 x 10(6)/l and to AIDS were evaluated using Kaplan-Meier survival analyses. RESULTS: We found considerable differences between cohorts in CD4+ depletion, but not in the incidence of AIDS (1987 definition). CONCLUSIONS: Variation in CD4+ depletion appears to be mainly the result of laboratory differences. Policy recommendations on a basis of CD4+ counts probably requires a calibration of measurement. The 1993 AIDS case definition leads to a site-specific shortening of the incubation time, which complicates the study of the natural history of HIV infection and of trends in the AIDS epidemic.

Effect of mutations in the V3 loop of HIV-1 gp120 on infectivity and susceptibility to proteolytic cleavage.

It has been suggested that the V3 domain of human immunodeficiency virus type 1 (HIV-1) isolates has to interact with a cell-surface-associated or endosomal proteinase during virus entry into susceptible cells. To investigate this hypothesis, we examined the effect of several mutations in the V3 loop on its susceptibility to proteolytic cleavage by thrombin and cathepsin E and compared it with the effect of these mutations on viral infectivity. The data obtained indicate that, if an interaction between the V3 loop and a proteinase is indeed crucial for viral entry, the substrate requirements for such a proteinase(s) would have to be very complex. In particular, it seems unlikely that a single enzyme with a unique specificity would be able to interact with all of the different HIV-1 and HIV-2/SIV strains isolated so far. Therefore, one would have to postulate the involvement of several cellular proteinases, or proteases with multiple specificities, in V3-based viral tropism.

Intracerebral (parenchymal) infusion of methotrexate: report of a case.

This report describes the neuropathological findings in a 32 year old woman with acute myelogenous leukemia (AML) and central nervous system (CNS) involvement, who received a total of 48 mg of methotrexate (MTX) intended to be delivered to the ventricle. At autopsy, the tip of the infusion catheter was found to have been inadvertently placed in the left basal ganglia. The delivery of the MTX at that site caused white matter lesions characteristic of those previously reported in MTX encephalopathy following diverse modes of administration. This case is unusual in that there was the direct infusion of MTX into cerebral parenchyma, circumventing both the blood:brain and cerebrospinal fluid:brain barriers. Axonal abnormalities were widespread in the MTX-infused tissue, frequently but not always accompanied by myelin loss. Since radiation therapy had not been employed, this case permitted the assessment of pathologic changes largely attributable to MTX.

Analysis of mutations in the V3 domain of gp160 that affect fusion and infectivity.

The third hypervariable (V3) domain of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein has been proposed to play an important role in mediating viral entry. Antibodies to the V3 domain block HIV-1 infection but not virus binding to CD4. At the center of the V3 domain is a relatively conserved sequence of amino acids, GPGRA. It has previously been shown that mutation of some of these amino acids reduced the ability of gp160 expressed on the surface of cells to induce fusion with CD4-bearing cells. In order to analyze the role of V3 domain sequences in mediating HIV entry, we introduced several amino acid substitution mutations in the GPGRA sequence of gp160 derived from HIV-1 strain HXB2 and in the analogous sequence of strain SF33, GPGKV. Virus was generated by cotransfecting the env constructs and a selectable env-negative HIV vector, HIV-gpt. When complemented with a retrovirus env gene, infectious virus capable of a single round of replication was produced. The viral particles produced were analyzed biochemically for core and envelope proteins and for infectious titer. The transfected envs were also analyzed for ability to bind to CD4 and mediate cell fusion. Several of the amino acid substitutions resulted in moderate to severe decreases in virus infectivity and fusion activity. Envelope glycoprotein assembly onto particles and CD4 binding were not affected. These results provide evidence that V3 sequences are involved in mediating the fusion step of HIV-1 entry.

Pseudotyping with human T-cell leukemia virus type I broadens the human immunodeficiency virus host range.

Several epidemiologic and clinical studies suggest that patients coinfected with human immunodeficiency virus (HIV), the primary etiologic agent in AIDS, and other viruses, such as cytomegalovirus or human T-cell leukemia virus (HTLV), have a more severe clinical course than those infected with HIV alone. Cells infected with two viruses can, in some cases, give rise to phenotypically mixed virions with altered or broadened cell tropism and could therefore account for some of these findings. Such pseudotypes could alter the course of disease by infecting more tissues than are normally infected by HIV. We show here that HIV type 1 (HIV-1) efficiently incorporates the HTLV type I (HTLV-I) envelope glycoprotein and that both HIV-1 and HTLV-II accept other widely divergent envelope glycoproteins to form infectious pseudotype viruses whose cellular tropisms and relative abilities to be transmitted by cell-free virions or by cell contact are determined by the heterologous envelope. We also show that the mechanism by which virions incorporate heterologous envelope glycoproteins is independent of the presence of the homologous glycoprotein or heterologous gag proteins. These results may have important implications for the mechanism of HIV pathogenesis.