Social isolation in mice: behavior, immunity, and tumor growth.

The aim of this study was to investigate the behavioral, immunological, and neurological effects of long-term isolation in an animal model. Male C3H/eB mice wereraised in either social isolation or standard conditions for 6 weeks. At 10 weeks, each group was further divided into 3 sets. (A) Physical strength and behavior were evaluated with the grip strength, hot plate, staircase, and elevated plus-maze tests. Natural-killer cell activity and lymphocyte proliferation were measured. (B) Half the animals were subjected to electric shock with 3 reminders, and freezing time was evaluated at each reminder. Cortisone levels were evaluated after 16 weeks. (C)Mice were injected with 38 C-13 B lymphoma cells and followed for tumor size and survival. Strength evaluation yielded asignificantly lower body weight and grip strength in the socially isolated mice. Behavioral test results were similar in the two groups. The pattern of reactions to stress conditioning differed significantly, with the socially isolated mice showing an incline in freezing with each successive reminder, and the control mice showing a decline. The socially isolated mice had significantly attenuated tumor growth, with no significant difference in survival from control mice. There were no significant between-group differences in immunological parameters. In conclusion, social isolation serves as a model for chronic stress. It was associated with significant changes in stress conditioning reaction, resembling symptoms of post-traumatic stress disorder, and attenuated tumor development. No differences from controls were found in behavior tests, immune parameters, or survival after tumor cell inoculation.Lay summaryThis article explores biological and behavioral consequences of social isolation in a mice model. Our results show that social isolation leads to changes in the Hypothalamic-hypophyseal-adrenal axis, which in turn alter the response to stress. Additionally, social isolation was shown to impact tumor progression.

Integration of CT-Based Measurements into Surveillance PET/CT in Patients with Diffuse Large B Cell Lymphoma.

BACKGROUND: Despite the lack of clinical studies supporting the use of routine surveillance FDG-positron emission tomography (PET) in patients with diffuse large B cell lymphoma (DLBCL) who achieved remission, many centers still use this strategy, especially in high risk patients. Surveillance FDG-PET computed tomography (CT) is associated with a high false positive (FP) rate in DLBCL patients. OBJECTIVES: To investigate whether use of specific CT measurements could improve the positive predictive value (PPV) of surveillance FDG-PET/CT. METHODS: This retrospective study included DLBCL patients treated with CHOP or R-CHOP who achieved complete remission and had at least one positive surveillance PET. CT-derived features of PET-positive sites, including long and short diameters and presence of calcification and fatty hilum within lymph nodes, were assessed. Relapse was confirmed by biopsy or consecutive imaging. The FP rate and PPV of surveillance PET evaluated with/without CT-derived measurements were compared. RESULTS: Seventy surveillance FDG-PET/CT scans performed in 53 patients were interpreted as positive for relapse. Of these studies 25 (36%) were defined as true-positive (TP) and 45 (64%) as FP. Multivariate analysis found long or short axis measuring ≥ 1.5 and ≥ 1.0 cm, respectively, in PET-positive sites, International Prognostic Index (IPI) ≥ 2, lack of prior rituximab therapy and FDG uptake in a previously involved site, to be independent predictors of true positive surveillance PET (odds ratio 5.4, 6.89, 6.6, 4.9, P < 0.05 for all). CONCLUSIONS: PPV of surveillance PET/CT may be improved by its use in selected high risk DLBCL patients and combined assessment of PET and CT findings.

The association between deficiencies in paternal and maternal reflective functioning and anorexia nervosa symptomatology.

BACKGROUND: A large theoretical body of knowledge exists emphasizing the importance of parental mentalizing in the context of anorexia-nervosa (AN). However, the empirical support to these assumptions is still scarce. The aim of the present study was to examine whether parents of patients with AN are characterized by a lower mentalizing ability, and whether it is associated with impaired mentalizing, AN symptomatology and eating disorder (ED) related psychological traits in the daughters. METHODS: Thirty-two family triads (fathers, mothers, and daughters) of female adolescent and young adult inpatients with AN were compared with thirty-three non-clinical family triads (N = 195). The mentalizing ability of all the participants was assessed using semi-structured interviews and coded using the Reflective Functioning Scale (RFS). Self-report questionnaires were administered to the daughters to evaluate ED symptomatology and ED related psychological traits (e.g., low self-esteem, interpersonal insecurity, emotional dysregulation). RESULTS: Decreased reflective functioning (RF) levels were found among mothers and fathers of patients with AN compared to their control peers. Examining the entire sample, clinical and non-clinical groups together, showed that both paternal and maternal RF were associated with the daughters' RF and each were found to have a significant and distinct contribution to the daughters' RF. Significant associations were found between lower levels of maternal and paternal RF and increased ED symptoms and ED related psychological traits. The use of a mediation model suggested a serial relationship in which low maternal and paternal RF contributes to the daughters' low RF, which in turn is associated with higher levels of psychological maladjustment, and ultimately contributes to the increased severity of ED symptoms. CONCLUSIONS: The present results provide strong empirical support for theoretical models that suggest that deficits in parental mentalizing may represent important correlates of the presence and severity of ED symptoms in AN. Furthermore, the results highlight the relevance of fathers' mentalizing ability in the context of AN. Finally, clinical and research implications are discussed.

The goal of the study was to examine the relationship between deficits in parents' ability to reflect on their own and others' emotional experience and the severity of their daughter's eating disorder and psychological maladjustment. A clinical group of young female inpatients diagnosed with anorexia-nervosa and both their biological parents was compared to a control group of young females without eating disorder and their parents. Personal interviews assessed the participants' reflective ability and self-report questionnaires assessed the daughters' eating disorder severity and psychological difficulties. The results show that patients with anorexia nervosa and their parents are less able to reflect on their emotional experiences compared to the control group. The parents' reflective ability was found to be related to their daughter's reflective ability. For both fathers and mothers, the less able the parent is to reflect on his or her emotional experiences the higher the severity of the daughter's eating disorder symptoms and psychological maladjustment are. The results imply that deficits in the parents' ability to process their own and others' emotional experiences are related to the severity of eating disorders symptoms and psychological maladjustment among daughters.. The study results highlight the importance of assessing reflective abilities of fathers.

Risk and protective factors for self-harm and suicide in children and adolescents: a systematic review and meta-analysis protocol.

INTRODUCTION: Self-harm and suicide are major public health concerns among children and adolescents. Many risk and protective factors for suicide and self-harm have been identified and reported in the literature. However, the capacity of these identified risk and protective factors to guide assessment and management is limited due to their great number. This protocol describes an ongoing systematic review and meta-analysis which aims to examine longitudinal studies of risk factors for self-harm and suicide in children and adolescents, to provide a comparison of the strengths of association of the various risk factors for self-harm and suicide and to shed light on those that require further investigation. METHODS AND ANALYSIS: We perform a systematic search of the literature using the databases EMBASE, PsycINFO, Medline, CINAHL and HMIC from inception up to 28 October 2020, and the search will be updated before the systematic review publication. Additionally, we will contact experts in the field, including principal investigators whose peer-reviewed publications are included in our systematic review as well as investigators from our extensive research network, and we will search the reference lists of relevant reviews to retrieve any articles that were not identified in our search. We will extract relevant data and present a narrative synthesis and combine the results in meta-analyses where there are sufficient data. We will assess the risk of bias for each study using the Newcastle-Ottawa Scale and present a summary of the quantity and the quality of the evidence for each risk or protective factor. ETHICS AND DISSEMINATION: Ethical approval will not be sought as this is a systematic review of the literature. Results will be published in mental health journals and presented at conferences focused on suicide prevention. PROSPERO REGISTRATION NUMBER: CRD42021228212.

Genetics of redox systems and their relationship with cardiovascular disease.

As atherosclerosis is still one of the major causes of death in Western populations, it is important to identify those individuals who are at increased risk for the disease so that aggressive treatment may be administered as early as possible. Following the understanding that oxidative stress has a pivotal role in the development and progression of atherosclerosis, many polymorphisms in genes that are related to redox systems were examined for their association with increased risk for cardiovascular disease (CVD). Although many polymorphisms were studied, only a handful showed consistent relevance to CVD in different trials. This article focuses on six of these polymorphisms, examining their effect on the risk for CVD as well as their effect on protein expression and function. Reports regarding pharmacogenetic implications of these polymorphisms, where such exist, are discussed as well.

Antioxidant vitamins and their use in preventing cardiovascular disease.

Atherosclerosis remains one of the leading causes of death in Western populations. Subsequent to the discovery that oxidative stress plays a pivotal role in the development and progression of atherosclerosis, vitamins C and E, along with other antioxidants, were studied as potential therapies for the disease. However, while in vitro and in vivo studies showed promising antiatherogenic effects for vitamins C and E, clinical trials in which patients were given high doses of vitamin E or C showed no benefit and even possible harm. This review will attempt to summarize the known mechanistic data regarding the biochemical effects of vitamins C and E and their relevance to atherosclerosis, and offer an explanation for the failure of clinical trials to show that supplementation with these vitamins provides any benefit when given indiscriminately. We provide one example of how pharmacogenomics may be used to identify a sub-population which may indeed benefit from antioxidant supplementation.

Major and minor life events, personality and psychopathology in children with tourette syndrome.

Environmental, psychological, and biological interactions underlie many psychopathologies. Tourette's Syndrome (TS) has an obvious biological substrate but environmental factors and personality play substantial roles in its expression. We aimed to study the interrelationships between stressful life events, personality traits, tics, and comorbid disorders in children with TS. To this end, 132 children with TS and 49 healthy controls were recruited for the study. Major life events in the 12-months prior to testing and minor life events in the month prior to testing were retrospectively assessed using the Life Experiences Survey (LES) and the Brief Adolescent Life Events Scale (BALES), respectively. Personality was assessed with the Junior Temperament and Character Inventory (JTCI). Tics, obsessive compulsive symptoms, attention deficit and hyperactivity symptoms, anxiety, depression and aggression were assessed by self-report questionnaires and semi-structured interviews. We found that major life events correlated with the severity of tics expression and complexity, and comorbid psychopathology. Minor life events correlated with more severe symptomatology. High levels of harm avoidance were related to more obsessions, anxiety, and depression whereas high levels of self-directedness were protective. To conclude, TS expression in childhood should be understood as the result of an interaction between biological, personality and environmental factors.

Effect of vitamin E supplementation on HDL function by haptoglobin genotype in type 1 diabetes: results from the HapE randomized crossover pilot trial.

AIMS: Haptoglobin (Hp) genotype 2-2 increases cardiovascular diabetes complications. In type 2 diabetes, α-tocopherol was shown to lower cardiovascular risk in Hp 2-2, potentially through HDL function improvements. Similar type 1 diabetes data are lacking. We conducted a randomized crossover pilot of α-tocopherol supplementation on HDL function [i.e., cholesterol efflux (CE) and HDL-associated lipid peroxides (LP)] and lipoprotein subfractions in type 1 diabetes. METHODS: Hp genotype was assessed in members of two Allegheny County, PA, type 1 diabetes registries and the CACTI cohort; 30 were randomly selected within Hp genotype, and 28 Hp 1-1, 31 Hp 2-1 and 30 Hp 2-2 were allocated to daily α-tocopherol or placebo for 8 weeks with a 4-week washout. RESULTS: Baseline CE decreased with the number of Hp 2 alleles (p-trend = 0.003). There were no differences in LP or lipoprotein subfractions. In intention-to-treat analysis stratified by Hp, α-tocopherol increased CE in Hp 2-2 (ß = 0.79, p = 0.03) and LP in Hp 1 allele carriers (ß Hp 1-1 = 0.18, p = 0.05; ß Hp 2-1 = 0.21, p = 0.07); reduced HDL particle size (ß = -0.07, p = 0.03) in Hp 1-1 carriers; increased LDL particle concentration in Hp 1-1; and decreased it in Hp 2-2 carriers. However, no significant interactions were observed by Hp. CONCLUSIONS: In this type 1 diabetes study, HDL function worsened with the number of Hp 2 alleles. α-Tocopherol improved HDL function in Hp 2-2 carriers and appeared to adversely affect lipid peroxides and lipoprotein subfractions among Hp 1 allele carriers. As no significant interactions were observed, findings require replication in larger studies.

Non-Hodgkin lymphomas in pregnancy: tackling therapeutic quandaries.

Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) often present with systemic symptoms such as fatigue, shortness of breath and night sweats, mimicking pregnancy-related features which may result in delayed disease diagnosis. Furthermore, the wish to avoid investigational imaging, aiming to protect the fetus from radiation exposure, may lead to a further delay, which does not often result in significant changes in HL clinical nature and patient outcome. In contrast, a more aggressive behavior (i.e., advanced disease stage and reproductive organ involvement) of most NHL types diagnosed in pregnancy may require urgent therapeutic intervention to prevent disease progression. Current management of pregnancy-associated NHL depends on histological subtype of the disease, gestational stage at diagnosis and the urgency of treatment for a specific patient. Patients diagnosed with indolent lymphoma may often be just followed, whereas those presenting with aggressive or highly aggressive disease need to be urgently treated with chemoimmunotherapy, either after undergoing an elective pregnancy termination if diagnosed at an early gestational stage, or with pregnancy preservation, if diagnosed later. Supportive care of NHL is also important; however, granulocyte colony stimulating factor (G-CSF) which is commonly used outside of pregnancy, should be cautiously employed, considering its established teratogenicity in animals, though this is less proven in humans. In conclusion, given the paucity of studies prospectively evaluating the outcome of pregnant women with NHL, international efforts are warranted to elucidate critical issues and develop guidelines for the management of such patients.

HDL dysfunction in diabetes: causes and possible treatments.

HDL is known to be inversely correlated with cardiovascular disease due to its diverse antiatherogenic functions. These functions include cholesterol efflux and reverse cholesterol transport, antioxidative and anti-inflammatory activities. However, HDL has been shown to undergo a loss of function in several pathophysiological states, as in the acute phase response, obesity and chronic inflammatory diseases. Some of these diseases were also shown to be associated with increased risk for cardiovascular disease. One such disease that is associated with HDL dysfunction and accelerated atherosclerosis is diabetes mellitus, a disease in which the HDL particle undergoes diverse structural modifications that result in significant changes in its function. This review will summarize the changes that occur in HDL in diabetes mellitus and how these changes lead to HDL dysfunction. Possible treatments for HDL dysfunction are also briefly described.

Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus.

The haptoglobin (Hp) genotype is a major determinant of progression of nephropathy in individuals with diabetes mellitus (DM). The major function of the Hp protein is to bind and modulate the fate of extracorpuscular hemoglobin and its iron cargo. We have previously demonstrated an interaction between the Hp genotype and the DM on the accumulation of iron in renal proximal tubule cells. The primary objective of this study was to determine the intracellular localization of this iron in the proximal tubule cell and to assess its potential toxicity. Transmission electron microscopy demonstrated a marked accumulation of electron-dense deposits in the lysosomes of proximal tubules cells in Hp 2-2 DM mice. Energy-dispersive X-ray spectroscopy and electron energy loss spectroscopy were used to perform elemental analysis of these deposits and demonstrated that these deposits were iron rich. These deposits were associated with lysosomal membrane lipid peroxidation and loss of lysosomal membrane integrity. Vitamin E administration to Hp 2-2 DM mice resulted in a significant decrease in both intralysosomal iron-induced oxidation and lysosomal destabilization. Iron-induced renal tubular injury may play a major role in the development of diabetic nephropathy and may be a target for slowing the progression of renal disease.

Vitamin E therapy results in a reduction in HDL function in individuals with diabetes and the haptoglobin 2-1 genotype.

OBJECTIVE: Vitamin E provides cardiovascular protection to individuals with diabetes and the haptoglobin 2-2 genotype but appears to increase cardiovascular risk in individuals with diabetes and the haptoglobin 2-1 genotype. We have previously demonstrated that the haptoglobin protein is associated with HDL and that HDL function and its oxidative modification are haptoglobin genotype dependent. We set out to test the hypothesis that the pharmacogenetic interaction between the haptoglobin genotype on cardiovascular risk might be secondary to a parallel interaction between the haptoglobin genotype and vitamin E on HDL function. RESEARCH DESIGN AND METHODS: Fifty-nine individuals with diabetes and the haptoglobin 2-1 or 2-2 genotypes were studied in a double-blind placebo controlled crossover design. Participants were treated with either vitamin E (400IU) or placebo for 3 months and crossed over for an equivalent duration. Serum was collected at baseline and after the completion of each treatment. HDL functionality as well as HDL associated markers of oxidation and inflammation were measured after each interval in HDL purified from the cohort. RESULTS: Compared to placebo, vitamin E significantly increased HDL function in haptoglobin 2-2 but significantly decreased HDL function in haptoglobin 2-1. This pharmacogenetic interaction was paralleled by similar non-significant trends in HDL associated lipid peroxides, glutathione peroxidase, and inflammatory cargo. CONCLUSION: There exists a pharmacogenetic interaction between the haptoglobin genotype and vitamin E on HDL function (clinicaltrials.gov NCT01113671).

The genetics of vascular complications in diabetes mellitus.

Prospective identification of which individuals with diabetes mellitus (DM) are at greatest risk for developing cardiovascular disease (CVD) complications would have considerable public health importance by allowing the allocation of limited resources to be focused on those individuals who would most benefit from aggressive intervention. Over the past 20 years genetic disease association studies have demonstrated that polymorphisms at specific genetic loci may identify those individuals at greatest risk for developing CVD in the setting of DM. This article reviews the evidence accumulated to date on four polymorphic loci with the aim of explaining how these polymorphisms modify the risk for CVD in DM by modifying the functional activity of a specific gene. Use of the knowledge of these genetic differences among individuals in targeting drug therapy (pharmacogenomics) is also discussed.

Haptoglobin: basic and clinical aspects.

Haptoglobin is an abundant hemoglobin-binding protein present in the plasma. The function of haptoglobin is primarily to determine the fate of hemoglobin released from red blood cells after either intravascular or extravascular hemolysis. There are two common alleles at the Hp genetic locus denoted 1 and 2. There are functional differences between the Hp 1 and Hp 2 protein products in protecting against hemoglobin-driven oxidative stress that appear to have important clinical significance. In particular, individuals with the Hp 2-2 genotype and diabetes mellitus appear to be at significantly higher risk of microvascular and macrovascular complications. A pharmacogenomic strategy of administering high dose antioxidants specifically to Hp 2-2 DM individuals may be clinically effective.