Genetics of schizophrenia in the South African Xhosa.

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.

Leptin resistance elicits depressive-like behaviors in rats.

There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and include increased risk for development of neuropsychiatric co-morbidities such as depressive illness. The neurological consequences of obesity may develop as a continuum and involve a progression of pathological features which is initiated by leptin resistance. Leptin resistance is a hallmark feature of obesity, but it is unknown whether leptin resistance or blockage of leptin action is casually linked to the neurological changes which underlie depressive-like phenotypes. Accordingly, the aim of the current study was to examine whether chronic administration of a pegylated leptin receptor antagonist (Peg-LRA) elicits depressive-like behaviors in adult male rats. Peg-LRA administration resulted in endocrine and metabolic features that are characteristic of an obesity phenotype. Peg-LRA rats also exhibited increased immobility in the forced swim test, depressive-like behaviors that were accompanied by indices of peripheral inflammation. These results demonstrate that leptin resistance elicits an obesity phenotype that is characterized by peripheral immune changes and depressive-like behaviors in rats, supporting the concept that co-morbid obesity and depressive illness develop as a continuum resulting from changes in the peripheral endocrine and metabolic milieu.

Role of MCP-1 on inflammatory processes and metabolic dysfunction following high-fat feedings in the FVB/N strain.

BACKGROUND: Monocyte chemoattractant protein 1 (MCP-1) is known to be an important chemokine for macrophage recruitment. Thus, targeting MCP-1 may prevent the perturbations associated with macrophage-induced inflammation in adipose tissue. However, inconsistencies in the available animal literature have questioned the role of this chemokine in this process. The purpose of this study was to examine the role of MCP-1 on obesity-related pathologies. METHODS: Wild-type and MCP-1-deficient mice on an friend virus B NIH (FVB/N) background were assigned to either low-fat diet or high-fat diet (HFD) treatment for a period of 16 weeks. Body weight and body composition were measured weekly and monthly, respectively. Fasting blood glucose and insulin, and glucose tolerance were measured at 16 weeks. Macrophages, T-cell markers, inflammatory mediators and markers of fibrosis were examined in the adipose tissue at the time of killing the mice. RESULTS: As expected, HFD increased adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysfunction (impaired glucose metabolism and insulin resistance) macrophage number (CD11b(+)F480(+) cells, and gene expression of EMR1 and CD11c), T-cell markers (gene expression of CD4 and CD8), inflammatory mediators (pNFκB and pJNK, and mRNA expression of MCP-1, CCL5, C-X-C motif chemokine-14, tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6)) and fibrosis (expression of IL-10, IL-13, TGF-ß and matrix metalloproteinase-2 (MMP2); P<0.05). However, contrary to our hypothesis, MCP-1 deficiency exacerbated many of these responses resulting in a further increase in adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysregulation, macrophage markers (EMR1), inflammatory cell infiltration and fibrosis (formation of type I and III collagens, mRNA expression of IL-10 and MMP2; P<0.05). CONCLUSIONS: These data suggest that MCP-1 may be a necessary component of the inflammatory response required for adipose tissue protection, remodeling and healthy expansion in the FVB/N strain in response to HFD feedings.

Effects of the MCP-1 synthesis inhibitor bindarit on tumorigenesis and inflammatory markers in the C3(1)/SV40Tag mouse model of breast cancer.

Breast cancer, the most deadly cancer in women, is characterized by elevated levels of inflammation within and surrounding the tumor, which can lead to accelerated growth, invasion and metastasis. Macrophages are central to the inflammatory milieu and are recruited to the tumor microenvironment by several factors including monocyte chemoattractant protein-1 (MCP-1). Using the anti-inflammatory molecule bindarit to target MCP-1, we investigated the role of this chemokine on macrophage related inflammation and mammary tumorigenesis in a transgenic mouse model of breast cancer. C3(1)/SV40Tag mice and wild type FVB/N were randomized to either control or 0.5% bindarit diet from 4 to 21weeks of age. Tumor number and volume were recorded over time and at sacrifice. Macrophage markers as well as inflammatory meditators were examined in the tumor tissue and mammary glands. Circulating MCP-1 and IL-6 were measured by ELISA. Bindarit treatment reduced tumor number (P<0.05), but did not affect tumor size, tumor weight or tumor latency in C3(1)/SV40Tag mice. Within the tumor, mRNA expression of bindarit's primary targets, MCP-1 and IL-12/p35, were significantly decreased by bindarit treatment (P<0.05), and this was consistent with trends for reduced expression of TNF-α, IL-6, F4/80, CD206, and IL-10. In mammary tissue, expression of MCP-1, TNF-α, IL-6, F4/80, IL-10 and IL-12/p35 was significantly elevated in C3(1)/SV40Tag mice compared to wild type FVB/N mice, but IL-6 was the only marker decreased by bindarit treatment (P<0.05). Plasma MCP-1 was highly correlated with tumor volume (P<0.05); however, it was not affected by bindarit at 21weeks of age. Similarly, circulating IL-6 was increased in C3(1)/SV40Tag mice but there was no effect of bindarit treatment. These results show that tumor multiplicity in the C3(1)/SV40Tag mouse model of breast cancer is reduced by bindarit, however these effects are independent of changes in plasma levels of MCP-1 and IL-6, but may be related to the attenuated expression of MCP-1 along with several inflammatory mediators and macrophage markers within the tumor.

Muscle activity during running in water and on dry land: matched physiology.

We investigated muscle activity during deep water running (DWR) and treadmill running on dry land (TMR) at similar physiological responses. 9 subjects (30.7±10.4 years) participated in this study. The baseline conditions consisted of TMR at 3 ratings of perceived exertion (RPE) level (RPE 11, 13, and 15) with heart rate (HR) recorded during each condition. The target HR for each level of DWR condition was determined by the HR recorded during the TMR. Muscle activity from the rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and gastrocnemius (GA) were measured. As originally planned, HR was not different between modes (P>0.05) and was different between exercise intensities (P<0.001). Only TA muscle activity was influenced by the interaction of mode and intensity (P<0.05). Muscle activity from the GA during DWR was significantly lower than that of TMR (a 34-48% decrease; P<0.05), although muscle activity from the remaining tested muscles were not influenced by modes of exercise (P>0.05). These observations suggest that matching HR can be recommended to produce similar magnitude of lower extremity muscle activity during DWR to that of TMR, with the exception of the GA.

Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer.

Epidemiologic studies suggest an association between physical activity (PA) and breast cancer risk. We examined the relationship between voluntary wheel running and breast cancer in C3(1)/SV40Tag mice. Female FVB/N and C3(1)/SV40Tag mice were assigned to either PA [C3(1)-PA] (n=12) or sedentary (Sed) [C3(1)-Sed] (n=15) treatment and were placed in a cage with access to a running wheel (PA) or without (Sed) from 4 to 24 weeks of age (sacrifice). Physical activity data were analyzed for running distance, time and speed. Body composition was examined at 12 weeks of age. Tumors were counted twice weekly and at sacrifice to assess multiplicity. Tumor volume was calculated using external calipers [0.52 x (largest diameter) x (smallest diameter)2]. Heart and body weight were also recorded at sacrifice. Results showed that voluntary wheel running reduced tumor volume per tumor [C3(1)-Sed, 422.3±89.9 mm(3); C3(1)-PA, 260.2±61.7 mm(3)] (P<0.05), but was associated with increased tumor number (P<0.05). Body composition analysis showed no differences in body fat between the groups. Heart weight/body weight ratio was increased following physical activity (P<0.05) providing evidence of a training effect. In conclusion, voluntary wheel running activity was effective at slowing tumor growth in the C3(1)/SV40Tag mouse model of breast cancer, but did not inhibit tumor initiation. These data provide support for further development of the C3(1)/SV40Tag mouse model for use in understanding the role of physical activity on breast cancer progression and the mechanisms for its effects.

Negative interaction between indomethacin and exercise in mice.

We examined the possible negative interaction of the combined use of the NSAID indomethacin (IND) and exercise in mice. Mice were assigned to one of 4 groups: Exercise 2.5 mg/kg IND (Ex-2.5), Sedentary 2.5 mg/kg IND (Sed-2.5), Exercise 5.0 mg/kg IND (Ex-5.0) and Sedentary 5.0 mg/kg IND (Sed-5.0). Mice were given IND (gavage) 1 h prior to exercise (treadmill run at 30 m/min, 8% grade for 90 min) or rest for 14 consecutive days. Run times, body weight and mortality were recorded daily. Sed-5.0 was highly toxic and caused 70% mortality compared to Sed-2.5, which was well tolerated (0% mortality) (P<0.05). While the addition of exercise had no greater effect on mortality in Ex-5.0, it increased it in the 2.5 group (52% vs. 0%; P<0.05). Run time was reduced from baseline beginning on day 2 (Ex-5.0), or day 3 (Ex-2.5) (P<0.05). Body weight (recorded in the 2.5 mg/kg groups only) was decreased from baseline in Ex-2.5 and Sed-2.5 (P<0.05), but this effect occurred earlier and was of greater magnitude in Ex-2.5. Exercise combined with IND use can lead to serious side effects in mice. Future research is needed to test the hypothesis that this effect is due to increased GI permeability and whether humans are also at risk.

Effects of 5-fluorouracil chemotherapy on fatigue: role of MCP-1.

Chemotherapy has been known to cause severe side effects, including fatigue. While the mechanisms for chemotherapy induced fatigue (CIF) are likely to be multi-factorial in origin, it is thought that inflammation and anemia may play a role. The purpose of this study was to examine the effect of chemotherapy on fatigue in mice, and further, to begin to determine if inflammation and anemia may contribute to this response. For experiment 1, C57BL/6 mice were assigned to: vehicle (PBS), low (20 mg/kg), medium (40 mg/kg), or high (60 mg/kg) doses of 5-fluorouracil (5-FU). Voluntary physical activity (PA) was measured throughout the treatment period (day 1-5) as well as during the recovery period (day 6-14). In experiment 2, we examined the effects of 5-FU (60 mg/kg) on the inflammatory mediator MCP-1 and on markers of anemia (RBC, Hct and Hb). Finally, using MCP-1(-/-) mice we examined the role of MCP-1 on CIF (experiment 3). 5-FU reduced voluntary PA in a dose response manner (p<0.05). Plasma MCP-1 was increased following 5-FU treatment on both days 5 (p=0.10) and 14 (p<0.05). In addition, RBCs, Hct and Hb were reduced with 5-FU on days 5 and 14 (p<0.05). Both C57BL/6 and MCP-1(-/-) mice saw similar decrements in PA through the duration of the treatment period (days 1-5), however the MCP-1(-/-) mice recovered much earlier than wildtype mice. This study provides evidence of the dose response effect of a standard chemotherapy agent on fatigue and demonstrates a potential role of MCP-1 and presumably inflammation, and anemia.

Benefits of exercise training on breast cancer progression and inflammation in C3(1)SV40Tag mice.

Many observational epidemiologic studies suggest an association between exercise and breast cancer risk. However, the lack of controlled experimental studies that examine this relationship and the mechanisms involved weaken the basis for inferring a causal relationship. Inflammation plays a role in breast cancer progression and exercise has been reported to reduce inflammation; however, the anti-inflammatory effects of exercise in breast cancer have yet to be established. We examined the relationship between exercise training and systemic inflammation in relation to breast cancer progression in C3(1)SV40Tag mice. Female C3(1)SV40Tag mice were assigned to either exercise (Ex) or sedentary (Sed) treatment (n=12-14/group). Beginning at 4 wks of age mice (Ex) were run on a treadmill for 60 min/d (20 m/min and 5% grade), 6 d/wk for a period of 20 wks. Mice were examined weekly for palpable tumors, and tumor number and volume were recorded. At 24 wks of age mice were sacrificed and a more direct measure of tumor number and volume, and spleen weight was recorded. Plasma was analyzed for MCP-1 and IL-6 concentration using ELISA. Ex reduced palpable tumor number at sacrifice (24 wks) by approximately 70% (P<0.05). Tumor volume was also reduced in Ex at 21-23 wks (P<0.05). This reduction in tumor progression by Ex was associated with a reduction in plasma concentration of MCP-1 and IL-6, and spleen weight (P<0.05). These data provide strong support for a beneficial effect of exercise training on tumor progression in the C3(1)SV40Tag mouse model of breast cancer that may be partly mediated by its anti-inflammatory potential.

Approaches to psychiatric assessment in epidemiological studies of children.

An assessment protocol for the longitudinal measurement of developmental psychopathology in a population-based study of children and adolescents is proposed. The protocol is designed for use in a large cohort of up to 100,000 individuals followed from early gestation to 21 years of age. Although the protocol was constrained by specified methodological parameters, the recommendations may apply to other psychiatric epidemiological research designs. The issues and challenges inherent with psychiatric assessments in longitudinal epidemiological studies of children and adolescents are discussed.

Quercetin reduces susceptibility to influenza infection following stressful exercise.

Exercise stress is associated with increased risk for upper respiratory tract infection. We have shown that exercise stress can increase susceptibility to infection. Quercetin, a flavonoid present in a wide variety of fruits and vegetables, has been reported to inhibit infectivity and replication of a broad spectrum of viruses and may offset the increase in susceptibility to infection associated with stressful exercise. This study examined the effects of quercetin feedings on susceptibility to the influenza virus A/Puerto Rico/8/34 (H1N1) following stressful exercise. Mice were randomly assigned to one of four treatment groups: exercise-placebo, exercise-quercetin, control-placebo, or control-quercetin. Exercise consisted of a run to fatigue (approximately 140 min) on a treadmill for 3 consecutive days. Quercetin (12.5 mg/kg) was administered via gavage for 7 days before viral challenge. At 30 min after the last bout of exercise or rest, mice (n=23-30) were intranasally inoculated with a standardized dose of influenza virus (0.04 hemagglutinating units). Mice were monitored daily for morbidity (time to sickness), symptom severity, and mortality (time to death) for 21 days. Exercise stress was associated with an increased susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P<0.05)]; quercetin offset the increase in susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P<0.05)] that was associated with stressful exercise. These data suggest that short-term quercetin feedings may prove to be an effective strategy to lessen the impact of stressful exercise on susceptibility to respiratory infection.

Effective vaccination against long-term gammaherpesvirus latency.

The fundamental question of whether a primed immune system is capable of preventing latent gammaherpesvirus infection remains unanswered. Recent studies showing that vaccination can reduce acute replication and short-term latency but cannot alter long-term latency further call into question the possibility of achieving sterilizing immunity against gammaherpesviruses. Using the murine gammaherpesvirus 68 (gammaHV68) system, we demonstrate that it is possible to effectively vaccinate against long-term latency. By immunizing mice with a gammaHV68 mutant virus that is deficient in its ability to reactivate from latency, we reduced latent infection of wild-type challenge virus to a level below the limit of detection. Establishment of latency was inhibited by vaccination regardless of whether mice were challenged intraperitoneally or intranasally. Passive transfer of antibody from vaccinated mice could partially reconstitute the effect, demonstrating that antibody is an important component of vaccination. These results demonstrate the potential of a memory immune response against gammaherpesviruses to alter long-term latency and suggest that limiting long-term latent infection in a clinically relevant situation is an attainable goal.

Summary of the practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.

This practice parameter describes treatment with stimulant medication. It uses an evidence-based medicine approach derived from a detailed literature review and expert consultation. Stimulant medications in clinical use include methylphenidate, dextroamphetamine, mixed salts of amphetamine, and pemoline. They carry U.S. Food and Drug Administration indications for the treatment of attention-deficit hyperactivity disorder.

Summary of the practice parameter for the prevention and management of aggressive behavior in child and adolescent psychiatric institutions with special reference to seclusion and restraint.

This parameter reviews the current state of the prevention and management of child and adolescent aggressive behavior in psychiatric institutions, with particular reference to the indications and use of seclusion and restraint. It also presents guidelines that have been developed in response to professional, regulatory, and public concern about the use of restrictive interventions with aggressive patients with regard to personal safety and patient rights. The literature on the use of seclusion, physical restraint, mechanical restraint, and chemical restraint is reviewed, and procedures for carrying out each of these interventions are described. Clinical and regulatory agency perspectives on these interventions are presented. Effectiveness, indications, contraindications, complications, and adverse effects of seclusion and restraint procedures are addressed. Interventions are presented to provide more opportunities to promote patient independence and satisfaction with treatment while diminishing the necessity of using restrictive procedures.

Tandem mass spectrometric determination of the 4S/6S sulfation sequence in chondroitin sulfate oligosaccharides.

Chondroitin sulfate (CS) is a glycosaminoglycan consisting of repeating uronic acid, N-acetylgalactosamine sulfate disaccharide units [-UroA(beta1,3)-GalNAcS(beta1,4)]n. Chondroitin sulfate type A (CSA) contains glucuronic acid, and 90% of the GalNAc residues are sulfated at the 4-position with 10% at the 6-position. Chondroitin sulfate type C (CSC) contains glucuronic acid, and 90% of the GalNAc residues are sulfated at the 6-position with 10% sulfated at the 4-position. These molecules are fragile due to their high degree of sulfation and are challenging to analyze as a result. This work presents the first evidence that tandem mass spectrometry can be used for the determination of a CS oligosaccharide sequence with respect to the positions of GalNAc sulfation. Using this technique, it is possible to analyze individual components from mixtures, saving much purification effort. Oligosaccharides produced from CSA and CSC are used in this work to demonstrate that CID MS/MS can be used to distinguish positional sulfation isomers. For charge states where charge equals the number of sulfates, abundant odd-numbered Bn and Yn ions are observed. The percent total ion abundances of these ions indicate the position of sulfation.

Improved uniformity in tomographic myocardial perfusion imaging with attenuation correction and enhanced acquisition and processing.

UNLABELLED: Tissue attenuation results in nonuniform myocardial perfusion images with significant sex differences. New SPECT imaging protocols to correct attenuation are currently under investigation. This study was performed to assess the effects of attenuation correction (AC) on overall image uniformity compared with more conventional imaging protocols in both men and women. METHODS: Thirty-nine patients (19 men, 20 women) with less than a 5% likelihood of coronary artery disease were studied. (99m)Tc-sestamibi studies were acquired with a triple-head scanner equipped with a simultaneous transmission and emission protocol. Four imaging protocols were compared: a 180 degrees acquisition and filtered backprojection reconstruction (FBP), a 360 degrees acquisition and FBP, a 360 degrees acquisition and iterative reconstruction (IT), and a 360 degrees acquisition with IT and AC. Quantitative analysis was performed to evaluate myocardial tracer uniformity for men and women. RESULTS: 180 degrees, 360 degrees FBP, and 360 degrees IT showed sex differences, with decreased tracer concentration in the anterior wall in women and decreased tracer concentration in the inferior wall in men. AC images showed the greatest uniformity (9.9% coefficient of variation for AC versus 12.5% for IT, P < 0.0001), and no statistically significant differences in uniformity were seen between male and female AC studies. CONCLUSION: More uniform myocardial perfusion images were obtained with AC, resulting in images with no differences in uniformity between men and women. These techniques are expected to improve specificity and overall diagnostic accuracy.

Increased sensitivity to IL-4 in patients with allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a heightened Th2 CD4+ cell response to Aspergillus fumigatus allergens and a hyper-IgE state compared to atopic asthmatic and cystic fibrosis patients without ABPA. We hypothesized that one reason for this response is increased sensitivity to IL-4 in ABPA, resulting in increased expression of CD23 and CD86, leading to a positive amplification mechanism which increases Th2 CD4+ T cell responses. METHODS: Peripheral blood mononuclear cells isolated from 10 ABPA, 9 atopic, and 8 nonatopic subjects and stimulated for 48 h with varying concentrations of rIL-4 ranging from 0.1 to 50 ng/ml. The percentages of CD23+ and CD86+ B cells and the number of CD23+ molecules on CD20+ and CD86+CD20+ B cells were quantified by flow cytometry. RESULTS: Total serum IgE levels were elevated in ABPA patients compared to atopic and nonatopic controls. At day 0 prior to culture, CD23 molecules per CD20+ B cell were significantly elevated in ABPA patients compared to atopic and to nonatopic patients. CD23 molecules per CD20+ B cell in ABPA and atopic patients decreased after 48 h in culture without IL-4 added and were similar. With IL-4 stimulation, ABPA patients had significantly increased rates of CD23 expression per B cell compared to atopic and nonatopic subjects (p < 0.001). Furthermore, ABPA had significantly increased numbers of CD23+ molecules per B cell and CD86+ B cell following IL-4 stimulation compared to atopic and nonatopic patients. Both ABPA and atopic patients at day 0 prior to culture had increased expression of CD86+ and CD23+CD86+ B cells compared to nonatopic patients. After 48 h in culture without IL-4, the percentages of CD86+ and CD23+CD86+ B cells decreased in ABPA and atopic patients. After stimulation with IL-4, ABPA patients had significant upregulation of CD23+CD86+ B cells compared to atopic and nonatopic patients. Similarly, the number of CD23 molecules per CD86+CD20+ B cell was significantly upregulated following IL-4 stimulation in ABPA patients compared to atopic and to nonatopic subjects. CONCLUSIONS: This is the first study to demonstrate that ABPA patients have increased sensitivity to IL-4 stimulation compared to other atopic individuals, such that ABPA > atopic >> nonatopic patients. The B cells from ABPA patients were significantly more sensitive to IL-4 stimulation compared to atopic and nonatopic patients with upregulation of CD23 and CD86 expression. ABPA subjects had increased CD86+ and CD23+CD86+ B cell expression on day 0 prior to culture and with upregulation of CD23+ molecules on CD86+CD20+ B cells. IL-4 also stimulated upregulated CD86+ expression on B cells in atopic patients with little effect on nonatopic patients. This study supports the premise that IL-4, IL-4R alpha and CD86 are central targets in the treatment of ABPA and atopic disease.

Focusing resonance signatures in ultra-wideband SAR images by allpass filtering.

This correspondence shows that resonance signatures in ultra-wideband synthetic aperture radar (SAR) images, which are smeared out due to their late arrival time, can be focused and extracted by postfiltering the SAR images with special two-dimensional (2-D) allpass filters. A design algorithm for FIR approximations to the desired allpass filters based on radial slice approximations (RSA) is presented.