Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity.

OBJECTIVE: Lipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. METHODS: Male and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10-12 and 16-18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. RESULTS: All groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. CONCLUSIONS: TAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.

Kinetic modelling of ß-cell metabolism reveals control points in the insulin-regulating pyruvate cycling pathways.

Insulin, a key hormone in the regulation of glucose homoeostasis, is secreted by pancreatic ß-cells in response to elevated glucose levels. Insulin is released in a biphasic manner in response to glucose metabolism in ß-cells. The first phase of insulin secretion is triggered by an increase in the ATP:ADP ratio; the second phase occurs in response to both a rise in ATP:ADP and other key metabolic signals, including a rise in the NADPH:NADP+ ratio. Experimental evidence indicates that pyruvate-cycling pathways play an important role in the elevation of the NADPH:NADP+ ratio in response to glucose. The authors developed a kinetic model for the tricarboxylic acid cycle and pyruvate cycling pathways. The authors successfully validated the model against experimental observations and performed a sensitivity analysis to identify key regulatory interactions in the system. The model predicts that the dicarboxylate carrier and the pyruvate transporter are the most important regulators of pyruvate cycling and NADPH production. In contrast, the analysis showed that variation in the pyruvate carboxylase flux was compensated by a response in the activity of mitochondrial isocitrate dehydrogenase (ICDm ) resulting in minimal effect on overall pyruvate cycling flux. The model predictions suggest starting points for further experimental investigation, as well as potential drug targets for the treatment of type 2 diabetes.

Predictors of under-five healthcare utilization in Rongo sub-county of Migori County, Kenya: results of a population-based cross-sectional survey.

Introduction: to achieve the sustainable development goal for child survival, we must better understand the socioeconomic characteristics, household behaviors and access to community health services which predict care utilization for children. This study assessed predictors of health care utilization for children under five in Migori County, Kenya. Methods: we used multivariable logistic regression in the context of an integrated health intervention which employed paid, trained, and supervised community health workers (CHWs), inclusive of traditional birth attendants (TBAs). The intervention was delivered with Ministry of Health in one of five geographies included in the study. Results: community health workers (CHW) home visits were associated with a two-fold increase in care seeking for children with respiratory symptoms. Following implementation of a CHW-led malaria intervention, the use of malaria rapid diagnostic tests increased, while fever prevalence decreased. Households in the intervention area were three times more likely to seek care for their child´s fever. Increased care utilization for children with fever was positively associated with male partner attendance at antenatal care visits and negatively associated with skilled delivery and recognition of warning signs. Care utilization for respiratory symptoms was positively associated with caregiver education and negatively associated with household size. Care utilization for diarrhea was positively associated with having a recent under-five death in the household. Conclusion: the study suggests that trained and motivated CHWs may be an effective tool for improving care utilization for children. Further, the study builds on evidence of male partner involvement and caregiver education as predictors of child care utilization.

Prevention of Lipotoxicity in Pancreatic Islets with Gammahydroxybutyrate.

Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma-hydroxybutyrate (GHB), an endogenous antioxidant and energy source, has previously been shown to protect mice from streptozotocin and alloxan-induced diabetes; both compounds are generators of oxidative stress and yield models of type-1 diabetes. We sought to determine whether GHB could protect mouse islets from lipotoxicity caused by palmitate, a model relevant to type 2 diabetes. We found that GHB prevented the generation of palmitate-induced reactive oxygen species and the associated lipotoxic inhibition of glucose-stimulated insulin secretion while increasing the NADPH/NADP+ ratio. GHB may owe its antioxidant and insulin secretory effects to the formation of NADPH.

Isoform-specific Roles of Prolyl Hydroxylases in the Regulation of Pancreatic ß-Cell Function.

Pancreatic ß-cells can secrete insulin via 2 pathways characterized as KATP channel -dependent and -independent. The KATP channel-independent pathway is characterized by a rise in several potential metabolic signaling molecules, including the NADPH/NADP+ ratio and α-ketoglutarate (αKG). Prolyl hydroxylases (PHDs), which belong to the αKG-dependent dioxygenase superfamily, are known to regulate the stability of hypoxia-inducible factor α. In the current study, we assess the role of PHDs in vivo using the pharmacological inhibitor dimethyloxalylglycine (DMOG) and generated ß-cell-specific knockout (KO) mice for all 3 isoforms of PHD (ß-PHD1 KO, ß-PHD2 KO, and ß-PHD3 KO mice). DMOG inhibited in vivo insulin secretion in response to glucose challenge and inhibited the first phase of insulin secretion but enhanced the second phase of insulin secretion in isolated islets. None of the ß-PHD KO mice showed any significant in vivo defects associated with glucose tolerance and insulin resistance except for ß-PHD2 KO mice which had significantly increased plasma insulin during a glucose challenge. Islets from both ß-PHD1 KO and ß-PHD3 KO had elevated ß-cell apoptosis and reduced ß-cell mass. Isolated islets from ß-PHD1 KO and ß-PHD3 KO had impaired glucose-stimulated insulin secretion and glucose-stimulated increases in the ATP/ADP and NADPH/NADP+ ratio. All 3 PHD isoforms are expressed in ß-cells, with PHD3 showing the most distinct expression pattern. The lack of each PHD protein did not significantly impair in vivo glucose homeostasis. However, ß-PHD1 KO and ß-PHD3 KO mice had defective ß-cell mass and islet insulin secretion, suggesting that these mice may be predisposed to developing diabetes.

Nicotinamide Mononucleotide Prevents Free Fatty Acid-Induced Reduction in Glucose Tolerance by Decreasing Insulin Clearance.

The NAD-dependent deacetylase SIRT1 improves ß cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents ß cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on ß cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced ß cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased ß cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans.

Prolyl-4-hydroxylase 3 maintains ß cell glucose metabolism during fatty acid excess in mice.

The α-ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is an HIF target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. Although PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about the effects of this highly conserved enzyme in insulin-secreting ß cells in vivo. Here, we show that the deletion of PHD3 specifically in ß cells (ßPHD3KO) was associated with impaired glucose homeostasis in mice fed a high-fat diet. In the early stages of dietary fat excess, ßPHD3KO islets energetically rewired, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in ßPHD3KO islets was associated with impaired glucose-stimulated ATP/ADP rises, Ca2+ fluxes, and insulin secretion. Thus, PHD3 might be a pivotal component of the ß cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress.

The Loss of ARNT/HIF1ß in Male Pancreatic ß-Cells Is Protective Against High-Fat Diet-Induced Diabetes.

The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor (HIF)-1ß (ARNT/HIF1ß) plays a key role in maintaining ß-cell function and has been shown to be one of the most downregulated transcription factors in islets from patients with type 2 diabetes. We have shown a role for ARNT/HIF1ß in glucose sensing and insulin secretion in vitro and no defects in in vivo glucose homeostasis. To gain a better understanding of the role of ARNT/HIF1ß in the development of diabetes, we placed control (+/+/Cre) and ß-cell-specific ARNT/HIF1ß knockout (fl/fl/Cre) mice on a high-fat diet (HFD). Unlike the control (+/+/Cre) mice, HFD-fed fl/fl/Cre mice had no impairment in in vivo glucose tolerance. The lack of impairment in HFD-fed fl/fl/Cre mice was partly due to an improved islet glucose-stimulated NADPH/NADP+ ratio and glucose-stimulated insulin secretion. The effects of the HFD-rescued insulin secretion in fl/fl/Cre islets could be reproduced by treating low-fat diet (LFD)-fed fl/fl/Cre islets with the lipid signaling molecule 1-monoacylglcyerol. This suggests that the defects seen in LFD-fed fl/fl/Cre islet insulin secretion involve lipid signaling molecules. Overall, mice lacking ARNT/HIF1ß in ß-cells have altered lipid signaling in vivo and are resistant to an HFD's ability to induce diabetes.

Cross-species examination of single- and multi-strain probiotic treatment effects on neuropsychiatric outcomes.

Interest in elucidating gut-brain-behavior mechanisms and advancing neuropsychiatric disorder treatments has led to a recent proliferation of probiotic trials. Yet, a considerable gap remains in our knowledge of probiotic efficacy across populations and experimental contexts. We conducted a cross-species examination of single- and multi-strain combinations of established probiotics. Forty-eight human (seven infant/child, thirty-six young/middle-aged adult, five older adult) and fifty-eight non-human (twenty-five rat, twenty-seven mouse, five zebrafish, one quail) investigations met the inclusion/exclusion criteria. Heterogeneity of probiotic strains, substrains, and study methodologies limited our ability to conduct meta-analyses. Human trials detected variations in anxiety, depression, or emotional regulation (single-strain 55.6%; multi-strain 50.0%) and cognition or social functioning post-probiotic intake (single-strain 25.9%; multi-strain 31.5%). For the non-human studies, single- (60.5%) and multi-strain (45.0%) combinations modified stress, anxiety, or depression behaviors in addition to altering social or cognitive performance (single-strain 57.9%; multi-strain 85.0%). Rigorous trials that confirm existing findings, investigate additional probiotic strain/substrain combinations, and test novel experimental paradigms, are necessary to develop future probiotic treatments that successfully target specific neuropsychiatric outcomes.

Reflections on wisdom at the end of life: qualitative study of hospice patients aged 58-97 years.

ABSTRACTObjective:Wisdom is a complex trait, and previous research has identified several components of wisdom. This study explored the possible impact of a diagnosis of a terminal illness on the conceptualization and evolution of wisdom while facing the end of life. DESIGN AND PARTICIPANTS: Semi-structured qualitative interviews were conducted with 21 hospice patients aged 58-97 years who were in the last six months of their life. METHODS: Hospice patients were asked to describe the core characteristics of wisdom, as well as how their terminal illness might have impacted their understanding of this concept. The interviews were audiotaped, transcribed, and coded by the research team using a grounded theory analytic approach based on coding consensus, co-occurrence, and comparison. RESULTS: Broad concepts of wisdom described by the hospice patients align with the extant literature, thereby supporting those general conceptualizations. In addition, hospice patients described how their life perspectives shifted after being diagnosed with a terminal illness. Post-illness wisdom can be characterized as a dynamic balance of actively accepting the situation while simultaneously striving for galvanized growth. This delicate tension motivated the patients to live each day fully, yet consciously plan for their final legacy. CONCLUSION: The end of life offers a unique perspective on wisdom by highlighting the modulation between actively accepting the current situation while continuing the desire to grow and change at this critical time. This paradox, when embraced, may lead to even greater wisdom while facing one's own mortality.

Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia?

Growing interest in gut and digestive processes and their potential link to brain and peripheral based inflammation or biobehavioral phenotypes has led to an increasing number of basic and translational scientific reports focused on the role of gut microbiota within the context of neuropsychiatric disorders. However, the effect of dietary modification on specific gut metabolites, in association with immune, metabolic, and psychopathological functioning in schizophrenia spectrum disorders has not been well characterized. The short chain fatty acids (SCFA) acetate, butyrate, and propionate, major metabolites derived from fermentation of dietary fibers by gut microbes, interact with multiple immune and metabolic pathways. The specific pathways that SCFA are thought to target, are dysregulated in cardiovascular disease, type II diabetes, and systemic inflammation. Most notably, these disorders are consistently linked to an attenuated lifespan in schizophrenia. Although, unhealthy dietary intake patterns and increased prevalence of immune and metabolic dysfunction has been observed in people with schizophrenia; dietary interventions have not been well utilized to target immune or metabolic illness. Prior schizophrenia patient trials primarily focused on the effects of gluten free diets. Findings from these studies indicate that a diet avoiding gluten benefits a limited subset of patients, individuals with celiac disease or non-celiac gluten sensitivity. Therefore, alternative dietary and nutritional modifications such as high-fiber, Mediterranean style, diets that enrich the production of SCFA, while being associated with a minimal likelihood of adverse events, may improve immune and cardiovascular outcomes linked to premature mortality in schizophrenia. With a growing literature demonstrating that SCFA can cross the blood brain barrier and target key inflammatory and metabolic pathways, this article highlights enriching dietary intake for SCFA as a potential adjunctive therapy for people with schizophrenia.

Predictors of current functioning and functional decline in schizophrenia.

Positive, negative, and cognitive symptoms of schizophrenia may affect functional outcomes. However, these factors alone do not account for a large percentage of variance in outcomes. We investigated demographic, cognitive, symptom, and functional capacity predictors of current functional status in 280 outpatients with schizophrenia or schizoaffective disorder. Functional decline over the lifespan was also examined in a subset of participants. Stepwise regressions modeled predictors of current functional status and functional decline as measured by the Assessment of Lifespan Functioning Attainment (ALFA). ALFA functional domains included paid employment, independence in living situation, romantic relationships, close friendships, and recreational engagement. More severe depressive symptoms were consistently associated with worse current community integration (lower levels of close friendships and recreational engagement). Better working memory performance was associated with higher rates of current paid employment. There were no consistent modifiable predictors of decline in functioning, but women reported less functional decline in the domains of employment and close friendships than men. Better cognitive performance was associated with less decline in living independence and romantic relationships, but more decline in paid employment and recreational engagement. Increased assessment and treatment of comorbid depressive symptoms may improve functional outcomes in people with schizophrenia.

The Rab-GTPase activating protein, TBC1D1, is critical for maintaining normal glucose homeostasis and ß-cell mass.

Tre-2/USP6, BUB2, cdc16 domain family, member 1 (TBC1D1), a Rab-GTPase activating protein, is a paralogue of AS160, and has been implicated in the canonical insulin-signaling cascade in peripheral tissues. More recently, TBC1D1 was identified in rat and human pancreatic islets; however, the islet function of TBC1D1 remains not fully understood. We examined the role of TBC1D1 in glucose homeostasis and insulin secretion utilizing a rat knockout (KO) model. Chow-fed TBC1D1 KO rats had improved insulin action but impaired glucose-tolerance tests (GTT) and a lower insulin response during an intraperitoneal GTT compared with wild-type (WT) rats. The in vivo data suggest there may be an islet defect. Glucose-stimulated insulin secretion was higher in isolated KO rat islets compared with WT animals, suggesting TBC1D1 is a negative regulator of insulin secretion. Moreover, KO rats displayed reduced ß-cell mass, which likely accounts for the impaired whole-body glucose homeostasis. This ß-cell mass reduction was associated with increased active caspase 3, and unaltered Ki67 or urocortin 3, suggesting the induction of apoptosis rather than decreased proliferation or dedifferentiation may account for the decline in islet mass. A similar phenotype was observed in TBC1D1 heterozygous animals, highlighting the sensitivity of the pancreas to subtle reductions in TBC1D1 protein. An 8-week pair-fed high-fat diet did not further alter ß-cell mass or apoptosis in KO rats, suggesting that dietary lipids per se, do not lead to a further impairment in glucose homeostasis. The present study establishes a fundamental role for TBC1D1 in maintaining in vivo ß-cell mass.

Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion.

Type 2 diabetes is associated with impaired nutrient-regulated anaplerosis and insulin secretion in pancreatic ß-cells. One key anaplerotic substrate that may be involved in regulating insulin release is α-ketoglutarate (αKG). Since prolyl hydroxylase domain proteins (PHDs) can metabolize cytosolic αKG, we sought to explore the role of this enzyme in the regulation of ß-cell function. The oxygen-sensing PHDs regulate the stability of hypoxia-inducible factor 1α (HIF1α) as well as other proline-containing proteins by catalyzing the hydroxylation of proline residues. This reaction is dependent on sufficient levels of oxygen, iron, and αKG. In the present study, we utilized both pharmacological and genetic approaches to assess the impact of inhibiting PHD activity on ß-cell function. We demonstrate that ethyl-3,4-dihydroxybenzoate (EDHB), a PHD inhibitor, significantly blunted glucose-stimulated insulin secretion (GSIS) from 832/13 clonal cells, rat, and human islets. EDHB reduced glucose utilization, ATP/ADP ratio, and key TCA cycle intermediates such as pyruvate, citrate, fumarate, and malate. siRNA-mediated knockdown of PHD1 and PHD3 inhibited GSIS, whereas siRNA-mediated knockdown of PHD2 had no effect on GSIS. Taken together, the current results demonstrate an important role for PHDs as mediators of islet insulin secretion.

Associations of high sensitivity C-reactive protein levels in schizophrenia and comparison groups.

Schizophrenia is characterized by physical (mainly metabolic and cardiovascular) comorbidity and shortened lifespan. High sensitivity C-reactive protein (hs-CRP), an inflammatory marker of hepatic origin linked to metabolic and cardiovascular diseases and mortality in the general population, has been reported to be elevated in people with schizophrenia. However, the relationship of hs-CRP to psychiatric and medical risk factors, after controlling for potentially confounding variables such as smoking, is not well established in schizophrenia. We assessed hs-CRP levels along with various demographic, psychiatric, and metabolic measures in 88 clinically stable outpatients with schizophrenia or schizoaffective disorder and 71 age epoch-matched comparison subjects with no history of a major psychiatric illness. hs-CRP levels were significantly higher in individuals with schizophrenia than in comparison subjects. Higher hs-CRP levels in the schizophrenia group were associated with female gender, more severe negative symptoms, greater medical comorbidity, and worse metabolic risk factors including BMI, fasting glucose, and hemoglobin A1c levels. hs-CRP was not related to age, race, education, smoking status, antipsychotic dosage, or cognitive impairment. Longitudinal studies are needed to investigate the relationship between hs-CRP and long-term health outcomes including metabolic syndrome, cardiovascular disease, and mortality in schizophrenia.

Deletion of ARNT/HIF1ß in pancreatic beta cells does not impair glucose homeostasis in mice, but is associated with defective glucose sensing ex vivo.

AIMS/HYPOTHESIS: It has been suggested that the transcription factor ARNT/HIF1ß is critical for maintaining in vivo glucose homeostasis and pancreatic beta cell glucose-stimulated insulin secretion (GSIS). Our goal was to gain more insights into the metabolic defects seen after the loss of ARNT/HIF1ß in beta cells. METHODS: The in vivo and in vitro consequences of the loss of ARNT/HIF1ß were investigated in beta cell specific Arnt/Hif1ß knockout mice (ß-Arnt (fl/fl/Cre) mice). RESULTS: The only in vivo defects found in ß-Arnt (fl/fl/Cre) mice were significant increases in the respiratory exchange ratio and in vivo carbohydrate oxidation, and a decrease in lipid oxidation. The mitochondrial oxygen consumption rate was unaltered in mouse ß-Arnt (fl/fl/Cre) islets upon glucose stimulation. ß-Arnt (fl/fl/Cre) islets had an impairment in the glucose-stimulated increase in Ca(2+) signalling and a reduced insulin secretory response to glucose in the presence of KCl and diazoxide. The glucose-stimulated increase in the NADPH/NADP(+) ratio was reduced in ß-Arnt (fl/fl/Cre) islets. The reduced GSIS and NADPH/NADP(+) levels in ß-Arnt (fl/fl/Cre) islets could be rescued by treatment with membrane-permeable tricarboxylic acid intermediates. Small interfering (si)RNA mediated knockdown of ARNT/HIF1ß in human islets also inhibited GSIS. These results suggest that the regulation of GSIS by the KATP channel-dependent and -independent pathways is affected by the loss of ARNT/HIF1ß in islets. CONCLUSIONS/INTERPRETATION: This study provides three new insights into the role of ARNT/HIF1ß in beta cells: (1) ARNT/HIF1ß deletion in mice impairs GSIS ex vivo; (2) ß-Arnt (fl/fl/Cre) mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1ß is required for GSIS in human islets.

Hierarchical Classes Analysis (HICLAS): A novel data reduction method to examine associations between biallelic SNPs and perceptual organization phenotypes in schizophrenia.

The power of SNP association studies to detect valid relationships with clinical phenotypes in schizophrenia is largely limited by the number of SNPs selected and non-specificity of phenotypes. To address this, we first assessed performance on two visual perceptual organization tasks designed to avoid many generalized deficit confounds, Kanizsa shape perception and contour integration, in a schizophrenia patient sample. Then, to reduce the total number of candidate SNPs analyzed in association with perceptual organization phenotypes, we employed a two-stage strategy: first a priori SNPs from three candidate genes were selected (GAD1, NRG1 and DTNBP1); then a Hierarchical Classes Analysis (HICLAS) was performed to reduce the total number of SNPs, based on statistically related SNP clusters. HICLAS reduced the total number of candidate SNPs for subsequent phenotype association analyses from 6 to 3. MANCOVAs indicated that rs10503929 and rs1978340 were associated with the Kanizsa shape perception filling in metric but not the global shape detection metric. rs10503929 was also associated with altered contour integration performance. SNPs not selected by the HICLAS model were unrelated to perceptual phenotype indices. While the contribution of candidate SNPs to perceptual impairments requires further clarification, this study reports the first application of HICLAS as a hypothesis-independent mathematical method for SNP data reduction. HICLAS may be useful for future larger scale genotype-phenotype association studies.

Preoperative Radioactive Seed Localization for Nonpalpable Breast Lesions: Technique, Pitfalls, and Solutions.

Iodine 125 ((125)I) radioactive seed localization has emerged as a reliable and safe alternative to wire localization for guidance during the surgical resection of nonpalpable breast lesions. The breast imager has a responsibility to be familiar with the general principles of this evolving technique, including its advantages and disadvantages as well as the technical differences involved in placement of seeds versus traditional wire localization. Although placement of (125)I seeds is conceptually similar to wire placement, there are additional technical considerations and safety measures that need to be addressed and implemented when radioactive seeds are used. We draw from our experience with more than 1000 cases of radioactive seed localization since inception of our program in 2009 to provide illustrative examples of not only the proper technique of radioactive seed localization, but also mishaps that may occur during this procedure, along with practical suggestions to prevent these problems. We examine some of the difficulties that we have encountered during radioactive seed localization at our institution, including bone wax mimicking the seed, the inadvertent deployment of seeds, the need for multiple seeds or supplemental wires, problematic seed locations, and difficulty in surgical retrieval of the seed. Recognizing the potential pitfalls of radioactive seed localization and understanding the appropriate guidelines and precautions for the safe, secure handling and placement of radioactive seeds is essential for a successful radioactive seed localization program.

Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death.

Treatment regimens for acute myeloid leukemia (AML) continue to offer weak clinical outcomes. Through a high-throughput cell-based screen, we identified avocatin B, a lipid derived from avocado fruit, as a novel compound with cytotoxic activity in AML. Avocatin B reduced human primary AML cell viability without effect on normal peripheral blood stem cells. Functional stem cell assays demonstrated selectivity toward AML progenitor and stem cells without effects on normal hematopoietic stem cells. Mechanistic investigations indicated that cytotoxicity relied on mitochondrial localization, as cells lacking functional mitochondria or CPT1, the enzyme that facilitates mitochondria lipid transport, were insensitive to avocatin B. Furthermore, avocatin B inhibited fatty acid oxidation and decreased NADPH levels, resulting in ROS-dependent leukemia cell death characterized by the release of mitochondrial proteins, apoptosis-inducing factor, and cytochrome c. This study reveals a novel strategy for selective leukemia cell eradication based on a specific difference in mitochondrial function.

Assessment of Lifespan Functioning Attainment (ALFA) scale: A quantitative interview for self-reported current and functional decline in schizophrenia.

Schizophrenia has been characterized as a disorder with poor outcomes across various functional domains, especially social and occupational functioning. Although these outcomes have been investigated based on patients' current functioning, few studies have considered the assessment of functional outcomes across the lifespan in schizophrenia. We developed a novel and brief scale of adulthood lifespan functioning, the Assessment of Lifespan Functioning Attainment (ALFA). We assessed current functioning and percentage of pre- and post-psychosis onset engagement for five functional domains including paid employment, living independently, romantic partnerships, close friendships, and recreational engagement with others. Pre-to post-psychosis functional decline was observed for all domains, with paid employment having the greatest decline (d = 2.68) and living independently having the least decline (d = .59). Our exploratory factor analysis suggests that a single factor accounted for the most variance in Pre-Psychosis Functioning in ALFA domains. Two factors explain the majority of variance in Post-Psychosis Functioning and Pre-to-Post Psychosis Decline: a sociability factor (close friendships and recreational engagement with others) and an independence factor (paid employment, living independently, romantic relationships). To our knowledge, this is the first study to report on a self-reported quantitative assessment of adult lifespan functioning in schizophrenia. The ALFA scale may be a useful tool for future research on functional outcomes in schizophrenia.