Silence, Second Skin, and the Unrepresented.

Using the concepts of microdialect and second skin, this paper explores the idea that a patient's silence in the session may function at multiple levels of psychic and relational organization, and-by virtue of its somatically experienced qualities and the special countertransference states these may elicit-might serve as a vehicle for movement between levels. It can thus be fruitfully approached as a potential portal for access to, and creative transformation of, unrepresented experience.

Improved ß-cell function leads to improved glucose tolerance in a transgenic mouse expressing lipoprotein lipase in adipocytes.

Lipoprotein lipase (LPL) hydrolyzes the triglyceride core of lipoproteins and also functions as a bridge, allowing for lipoprotein and cholesterol uptake. Transgenic mice expressing LPL in adipose tissue under the control of the adiponectin promoter (AdipoQ-LPL) have improved glucose metabolism when challenged with a high fat diet. Here, we studied the transcriptional response of the adipose tissue of these mice to acute high fat diet exposure. Gene set enrichment analysis (GSEA) provided mechanistic insight into the improved metabolic phenotype of AdipoQ-LPL mice. First, the cholesterol homeostasis pathway, which is controlled by the SREBP2 transcription factor, is repressed in gonadal adipose tissue AdipoQ-LPL mice. Furthermore, we identified SND1 as a link between SREBP2 and CCL19, an inflammatory chemokine that is reduced in AdipoQ-LPL mice. Second, GSEA identified a signature for pancreatic ß-cells in adipose tissue of AdipoQ-LPL mice, an unexpected finding. We explored whether ß-cell function is improved in AdipoQ-LPL mice and found that the first phase of insulin secretion is increased in mice challenged with high fat diet. In summary, we identify two different mechanisms for the improved metabolic phenotype of AdipoQ-LPL mice. One involves improved adipose tissue function and the other involves adipose tissue-pancreatic ß-cell crosstalk.

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.

XX sex chromosome complement promotes atherosclerosis in mice.

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids. Together, our results show that an XX sex chromosome complement promotes the bioavailability of dietary fat to accelerate atherosclerosis.

Calpain Inhibition Attenuates Adipose Tissue Inflammation and Fibrosis in Diet-induced Obese Mice.

Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance. However, the mechanisms underlying these processes are not completely defined. Calpains are calcium-dependent neutral cysteine proteases that modulate cellular function and have been implicated in various inflammatory diseases. To define whether activated calpains influence diet-induced obesity and adipose tissue macrophage accumulation, mice that were either wild type (WT) or overexpressing calpastatin (CAST Tg), the endogenous inhibitor of calpains were fed with high (60% kcal) fat diet for 16 weeks. CAST overexpression did not influence high fat diet-induced body weight and fat mass gain throughout the study. Calpain inhibition showed a transient improvement in glucose tolerance at 5 weeks of HFD whereas it lost this effect on glucose and insulin tolerance at 16 weeks HFD in obese mice. However, CAST overexpression significantly reduced adipocyte apoptosis, adipose tissue collagen and macrophage accumulation as detected by TUNEL, Picro Sirius and F4/80 immunostaining, respectively. CAST overexpression significantly attenuated obesity-induced inflammatory responses in adipose tissue. Furthermore, calpain inhibition suppressed macrophage migration to adipose tissue in vitro. The present study demonstrates a pivotal role for calpains in mediating HFD-induced adipose tissue remodeling by influencing multiple functions including apoptosis, fibrosis and inflammation.

An obligatory role for neurotensin in high-fat-diet-induced obesity.

Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively). Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

Increasing adipocyte lipoprotein lipase improves glucose metabolism in high fat diet-induced obesity.

Lipid accumulation in liver and skeletal muscle contributes to co-morbidities associated with diabetes and obesity. We made a transgenic mouse in which the adiponectin (Adipoq) promoter drives expression of lipoprotein lipase (LPL) in adipocytes to potentially increase adipose tissue lipid storage. These mice (Adipoq-LPL) have improved glucose and insulin tolerance as well as increased energy expenditure when challenged with a high fat diet (HFD). To identify the mechanism(s) involved, we determined whether the Adipoq-LPL mice diverted dietary lipid to adipose tissue to reduce peripheral lipotoxicity, but we found no evidence for this. Instead, characterization of the adipose tissue of the male mice after HFD challenge revealed that the mRNA levels of peroxisome proliferator-activated receptor-γ (PPARγ) and a number of PPARγ-regulated genes were higher in the epididymal fat pads of Adipoq-LPL mice than control mice. This included adiponectin, whose mRNA levels were increased, leading to increased adiponectin serum levels in the Adipoq-LPL mice. In many respects, the adipose phenotype of these animals resembles thiazolidinedione treatment except for one important difference, the Adipoq-LPL mice did not gain more fat mass on HFD than control mice and did not have increased expression of genes in adipose such as glycerol kinase, which are induced by high affinity PPAR agonists. Rather, there was selective induction of PPARγ-regulated genes such as adiponectin in the adipose of the Adipoq-LPL mice, suggesting that increasing adipose tissue LPL improves glucose metabolism in diet-induced obesity by improving the adipose tissue phenotype. Adipoq-LPL mice also have increased energy expenditure.

Countertransference identification and fantasy in psychoanalytic process.

The development of more nuanced understandings of psychoanalytic process is among the primary tasks of contemporary psychoanalytic theorizing. One piece of this complex undertaking involves the examination of moments when the analyst's countertransference position changes. Shifts in the analyst's feelings and thoughts in relation to the patient are complex events in which experiences registered at many levels of organization and via many modes of perception combine to contribute to meaning-making and furthering of the treatment process. The author explores the role of fantasy in giving form and meaning to alterations experienced as a change of attitude or affect, through close examination of one such moment of shift.

Impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin on cutaneous wound healing.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a representative of a large group of polyhalogenated aromatic hydrocarbons that are widespread environmental contaminants. Administration of TCDD to laboratory animals or cultured cells results in a number of adverse effects that are well documented. For example, the effects of TCDD observed in developing organisms indicate that exposure to this class of environmental contaminants significantly alters embryo morphogenesis. However, it is not clear whether tissue regeneration in adult animals may be similarly affected. With this in mind, we examined the impact of TCDD exposure on wound healing using a murine cutaneous wound healing model. Our results indicate that TCDD exposure did not significantly alter the time needed for wound closure. However, in the TCDD-treated mice, a significant decrease in tensile strength in the healed wounds was observed which is indicative of an aberrantly healed wound. Immunostaining revealed that exposure to TCDD increased the population of macrophages detected within the wounded tissue at the latter stages of wound healing. Our findings support the idea that exposure to environmental contaminants such as TCDD is proinflammatory in the wounded tissue, disrupts normal healing and ultimately produces in a poorly healed wound.

"My story for my better self": love, loss, and working through in the diary of Elizabeth Barrett Browning.

An approach to the diary as more than a private record, but a psychologically meaningful act and object, is demonstrated by a close reading of the diary of the English poet Elizabeth Barrett Browning. Attending to both formal and thematic aspects, this study attempts to illustrate the variable uses of diary-keeping, as well as to identify its uses of specific importance to this particular diarist. The more expansive and profound insight thus gained into the poet's life and work points to the potential of a psychoanalytic approach to such uniquely intimate documents. Evidence is offered to support the position that Browning's diary served important integrating functions during a critical period of her life: modulating overwhelming affect, organizing experiences beyond her control, and serving as a concrete symbol of preservation in the face of accumulative painful losses. The diary-keeping was a self-therapeutic endeavor, mediating and metabolizing these losses into a work of mourning as the poet elaborated and memorialized them.

Payment as perverse defense.

A case is discussed in which the patient's management of aspects of the payment process is seen as a focal point in a perverse defensive structure operating in the treatment. Detailed process material is examined with attention to transference and countertransference components of this defensive process. Recent literature on perverse thought and defense is reviewed in order to understand this case in the context of current thinking, to generate new ideas about the nature of perverse defenses, and to consider the potentially special role that money may play in the operation of such defenses in psychoanalysis.

C. elegans LIN-18 is a Ryk ortholog and functions in parallel to LIN-17/Frizzled in Wnt signaling.

Wnt proteins are intercellular signals that regulate various aspects of animal development. In Caenorhabditis elegans, mutations in lin-17, a Frizzled-class Wnt receptor, and in lin-18 affect cell fate patterning in the P7.p vulval lineage. We found that lin-18 encodes a member of the Ryk/Derailed family of tyrosine kinase-related receptors, recently found to function as Wnt receptors. Members of this family have nonactive kinase domains. The LIN-18 kinase domain is dispensable for LIN-18 function, while the Wnt binding WIF domain is required. We also found that Wnt proteins LIN-44, MOM-2, and CWN-2 redundantly regulate P7.p patterning. Genetic interactions indicate that LIN-17 and LIN-18 function independently of each other in parallel pathways, and different ligands display different receptor specificities. Thus, two independent Wnt signaling pathways, one employing a Ryk receptor and the other a Frizzled receptor, function in parallel to regulate cell fate patterning in the C. elegans vulva.