Nonverbal behavioral patterns predict social rejection elicited aggression.

Aggression elicited by social rejection is costly, prevalent, and often lethal. Attempts to predict rejection-elicited aggression using trait-based data have had little success. This may be because in-the-moment aggression is a complex process influenced by current states of attention, arousal, and affect which are poorly predicted by trait-level characteristics. In a study of young adults (N = 89; 18-25 years), machine learning tested the extent to which nonverbal behavioral indices of attention (eye gaze), arousal (pupillary reactivity), and affect (facial expressions) during a novel social interaction paradigm predicted subsequent aggression towards rejecting and accepting peers. Eye gaze and pupillary reactivity predicted aggressive behavior; predictions were more successful than measures of trait-based aggression and harsh parenting. These preliminary results suggest that nonverbal behavior may elucidate underlying mechanisms of in-the-moment aggression.

Neural correlates of peer evaluation in irritable adolescents: Linking anticipation to receipt of social feedback.

Elevated irritability during adolescence predicts mental health issues in adulthood. Social interactions commonly elicit symptoms of irritability. Prior research has traditionally examined neural activity during the anticipation of, and immediate reaction to, social feedback separately in irritable adolescents. However, studies suggest that irritable adolescents demonstrate altered brain activation when anticipating feedback, and these alterations may have downstream effects on the neural activity when actually presented with feedback. Thus, the goal of this study was to characterize the influence of irritability on the relationship between brain function during anticipation and receipt of social feedback. We leveraged the Virtual School task to mimic social interactions using dynamic stimuli. Parallel region of interest (ROI) analyses tested effects of anticipatory bilateral amygdala (or dorsal anterior cingulate cortex; dACC) activation on the dACC (or bilateral amygdala) activation during receipt of peer feedback. Parallel exploratory whole-brain analyses were conducted to identify the effects of anticipatory bilateral amygdala or dACC activation on other regions during receipt of peer feedback. In ROI analyses, more vs. less irritable adolescents showed distinct relationships between anticipatory bilateral amygdala activation and dACC activation when receiving predictably mean feedback. Across both whole-brain analyses, anticipatory bilateral amygdala and dACC activation were separately associated with activation in socioemotional regions of the brain during subsequent feedback. These relationships were modulated by irritability, and the valence and predictability of the feedback. This suggests that irritable adolescents may engage in altered emotion processing and regulation strategies, depending on the valence and predictability of social feedback.

Social anxiety and age are associated with neural response to social evaluation during adolescence.

Adolescence is a sensitive period for the development of adaptive social behaviors and social anxiety, possibly due to aspects of brain development. However, research is needed to examine interactions among age, social anxiety, and social dynamics previously shown to influence neural responding. The current functional magnetic resonance imaging (fMRI) study examines brain function in 8-18 year-olds with varying levels of social anxiety. Interactions are examined among age, social anxiety, and two key task factors: valence and predictability of social interactions. Results demonstrate age, social anxiety severity, and each of the two key task-based factors interact to predict neural response in the caudate, middle and superior temporal gyri. In particular, among adolescents less-than 13 years of age, higher social anxiety predicted greater responding to unpredictable negative evaluations. However, in this same age group, the opposite pattern emerged during receipt of unpredictable positive evaluations, with less neural response in more anxious youth. Adolescents aged 13 and older overall showed less robust effects. We discuss these findings in terms of age- and anxiety-related differences in socioemotional processing.

Discriminant validity, diagnostic utility, and parent-child agreement on the Screen for Child Anxiety Related Emotional Disorders (SCARED) in treatment- and non-treatment-seeking youth.

The Screen for Child Anxiety and Related Emotional Disorder (SCARED) may be differentially sensitive to detecting specific or comorbid anxiety diagnoses in treatment-seeking and non-treatment-seeking youth. We assessed the SCARED's discriminant validity, diagnostic utility, and informant agreement using parent- and self-report from healthy and treatment-seeking anxious youth (Study 1, N=585) and from non-treatment-seeking anxious youth (Study 2, N=331) diagnosed with generalized anxiety disorder (GAD), social anxiety disorder (SAD), or comorbid GAD+SAD. Among treatment-seeking youth, the SCARED showed good diagnostic utility and specificity, differentiating healthy, comorbid, and non-comorbid anxious youth. Child-parent agreement was modest: healthy child self-reports were higher than parent-reports whereas anxious child self-reports were similar or lower than parent-reports. Less consistent results emerged for diagnostic utility, specificity, and informant agreement among non-treatment-seeking youth. Given the number of non-treatment seeking anxious youth (N=33), generalizability of these findings may be limited. Together, results suggest informants may provide distinct information about children's anxiety symptoms.

Acute tryptophan depletion alters the effective connectivity of emotional arousal circuitry during visceral stimuli in healthy women.

OBJECTIVE: Alterations in serotonin signalling within the brain-gut axis have been implicated in the pathophysiology of irritable bowel syndrome (IBS) and is a treatment target. Acute tryptophan depletion (ATD) decreases brain serotonin (5-hydroxytryptamine; 5-HT) levels, and increases visceral perception and negative emotional bias in patients with IBS. The aim of the present study was to determine the effect of ATD on brain activity and connectivity during visceral stimuli in healthy women, and to compare the ATD-induced brain connectivity of an arousal circuit in female patients with IBS without ATD. METHODS: 12 healthy females (19-25 years) were studied under placebo (PLA) conditions and ATD. Functional MRI measurements were performed during a rectal barostat protocol, consisting of random non-painful and maximal tolerable distensions. Partial least squares analyses and structural equation modelling were used to evaluate the effect of ATD on functional and effective brain connectivity during distension. Results in healthy controls under ATD were compared with the effective connectivity of brain responses to 45 mm Hg rectal distension in 14 female patients with constipation-predominant IBS (IBS-C) (24-50 years). RESULTS: In healthy controls, ATD resulted in increased response of an extensive brain network to balloon distension, including the amygdala and nodes of emotional arousal and homeostatic afferent networks. The effect was greater during high inflation, suggesting greater engagement of the central serotonion system with more aversive visceral stimuli. Effective connectivity analysis revealed a profound effect of ATD on coupling between emotional arousal network nodes, resulting in loss of negative feedback inhibition of the amygdala. A near-identical pattern was identified in the patients with IBS-C. CONCLUSIONS: The findings are consistent with an ATD-induced disinhibition of and increased connectivity within an emotional arousal network during aversive stimulation. Together with the previous demonstration of ATD-induced visceral hyperalgesia in healthy controls, and the near-identical effective connectivity pattern observed in patients with IBS-C, these findings suggest that dysregulation of this brain network may play a role in central pain amplification and IBS pathophysiology.

Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study.

BACKGROUND: Symptom improvement in irritable bowel syndrome (IBS) treatment trials varies widely, with only 50-70% of patients qualifying as responders. Factors predicting treatment responsiveness are not known, although we have demonstrated that symptom improvement with the 5-HT3R antagonist alosetron is correlated with reduced amygdala activity. AIM: To determine whether neural activity during rectal discomfort or psychological distress predicts symptom improvement following treatment with alosetron. METHODS: Basal psychological distress and neural activity (15O PET) during uncomfortable rectal stimulation were measured in 17 nonconstipated IBS patients who then received 3 weeks of alosetron treatment. RESULTS: Greater symptom improvement was predicted by less activity in bilateral orbitofrontal cortex (OFC) and medial temporal gyrus during pre-treatment scans. Lower levels of interpersonal sensitivity predicted greater symptom improvement and were positively related to activity in left OFC. Connectivity analysis revealed a positive relationship between activity in the left OFC and right amygdala. CONCLUSIONS: Irritable bowel disease symptom improvement with 5-HT3R antagonist alosetron is related to pre-treatment reactivity of the left OFC, which may be partially captured by subjective measures of interpersonal sensitivity. The left OFC may fail to modulate amygdala response to visceral stimulation, thereby diminishing effectiveness of treatment. Psychological factors and their neurobiological correlates are plausible predictors of IBS treatment outcome.

Successful toxoplasmosis prophylaxis after orthotopic cardiac transplantation with trimethoprim-sulfamethoxazole.

BACKGROUND: The efficacy of trimethoprim-sulfamethoxazole (TMP/SMX) in the prevention of toxoplasmosis after orthotopic cardiac transplantation has been the subject of some controversy, with many transplant groups preferring to use the combination of pyrimethamine and sulfadiazine. Although effective, this latter regimen does not offer equal protection against other pathogens, such as or. To assess the value of TMP/SMX, we reviewed the experience in our heart transplant patients, all of whom received TMP/SMX (160/800 mg) three times weekly for approximately 8 months after transplantation. METHODS: We report on 417 orthotopic cardiac transplants during a 17-year period. We have 100% one-year patient follow-up after transplantation. Data was collected on pretransplantation donor and recipient anti- serology, immunosuppression, allograft rejection, survival, yearly posttransplantation anti- serology, development of acute toxoplasmosis, and the occurrence of other infections. RESULTS: In this cohort, acute toxoplasmosis developed after transplantation in one case (0.2%). Among the highest risk patients (D+R-) who were treated for at least one episode of rejection, the risk of acute toxoplasmosis was 5% (1 of 22 patients). No change in survival was found between the different anti- IgG serogroups (D-R-, D-R+, D+R-, or D+R+). Anti- IgG seroconversion occurred in eight -seronegative recipients after transplantation; all patients, except the case already noted, were asymptomatic and required no specific anti- therapy. No cases of, or infections were identified. Five proven and two suspected cases of pneumonia were found (only 2 of these 7 patients were receiving TMP/SMX at the time of pneumonia diagnosis). CONCLUSIONS: These data demonstrate that TMP/SMX prophylaxis (160/800 mg) three times per week is effective prophylaxis after orthotopic cardiac transplantation and has prophylactic benefits against other posttransplantation opportunistic pathogens.

Cardiac transplant outcome of patients supported on left ventricular assist device vs. intravenous inotropic therapy.

BACKGROUND: Although the left ventricular assist device (LVAD) has been increasingly used as a bridge to transplant, its effect on post-transplant outcome is uncertain. We, therefore, designed this study using the Cardiac Transplant Research Database to compare patients supported on an LVAD before transplant with those treated with intravenous inotropic medical therapy. METHODS AND RESULTS: Of the 5,880 patients transplanted between 1990 and 1997, a total of 502 received support from LVADs and 2,514 received intravenous inotropic medical therapy at the time of transplant. Kaplan-Meier analysis showed no significant difference in post-transplant survival between the LVAD and medical-therapy groups (p = 0.09). Results of a multivariate Cox regression analysis were consistent with that of the Kaplan-Meier analysis and did not identify LVAD as a significant risk factor for mortality. The percentage of patients who received LVADs as a function of total transplants increased from 2% in 1990 to 16% in 1997. Furthermore, although the number of extracorporeal LVADs remained relatively constant, the number of intracorporeal LVADs increased over time. Multivariate parametric analysis found that the risk factors for post-transplant death in the LVAD group were extracorporeal LVAD use (p = 0.0004), elevated serum creatinine (p = 0.05), older donor age (p = 0.03), increased donor ischemic time (p < 0.0001), and earlier year of transplant (p = 0.03). CONCLUSIONS: Given a limited donor supply, the intracorporeal LVAD helps the sickest patients survive to transplant and provides post-transplant outcome similar to that of patients supported on inotropic medical therapy. Therefore, patients supported on LVADs before transplant may receive the greatest marginal benefit when compared with other transplant candidates.

Restriction fragment length polymorphism analysis.

This unit describes Restriction Fragment Length Polymorphism (RFLP) analysis, which utilizes restriction endonuclease digestion to identify DNA sequence polymorphisms in genes or DNA regions of interest. When investigating families for inheritance of an RFLP, aliquots of genomic DNA from individual family members are digested to completion with the restriction enzyme known to generate the polymorphism of interest. After size fractionation on an agarose gel, DNA is transferred to a membrane by capillary action in a high-salt buffer. The gel is first treated with NaOH to denature DNA, and after neutralization, the gel is placed between buffer-soaked filter paper and a sheet of membrane. Labeled probe is hybridized overnight to the Southern blot. The blot is washed under conditions designed to remove all nonspecifically adherent probe and exposed to X-ray film. Identified fragment sizes differ among individuals and can be traced from generation to generation.

Hereditary postlingual sensorineural hearing loss mapping to chromosome Xq21.

BACKGROUND: Mutations on the X-chromosome clinically manifesting different phenotypes of hearing loss have been mapped to the long arm at different loci, DFN1-DFN3. Another defect in a family with sex-linked, postlingual, progressive sensorineural hearing loss was mapped to Xq. METHODS: Clinically, the family was evaluated by physical and audiometric examination of 17 members including computerized tomographic (CT) evaluation of the proband. Molecular evaluation consisted of polymerase chain reaction amplification of patient genomic DNA and resolution 32P-labeled fragments by polyacrylamide gels. Inheritance of DNA alleles and deafness were analyzed using the MLINK computer program. RESULTS: Five affected males demonstrated symmetrical sensorineural hearing loss as significant as 100 decibels (dB). Two carrier females had a milder loss with frequency findings of 10 dB to 60 dB. Computerized tomography (CT) evaluation of the temporal bones of the proband was normal. The odds were 200:1 that the responsible gene was linked to locus DXS986 (maximum lod score = 2.3 at 0 = 0). Analysis of recombination events defined by family members demonstrates that the responsible gene lies in a 21 cM (30 MB) interval, between loci DXS12175 and 1106. The disease locus in this family does not appear to map to DFN1 or DFN3. CONCLUSION: The family described here, with affected males who have progressive, postlingual sensorineural hearing loss and mildly affected females maps most compatibly to the DFN2 locus. Analysis of hereditary deafness in this family refines the DFN2 locus to a 9.2 Mb region in chromosome X band q21 between DXS990 and DXS106.

Metastasizing mixed tumor of the parotid gland: a rare tumor with unusually rapid progression in a cardiac transplant recipient.

We report the case of a 69-year-old man who had a mixed tumor (pleomorphic adenoma) removed from his parotid gland 3 years after orthotopic heart transplantation. Two years later, he presented with widely metastatic mixed tumor, which resulted in his death within 6 months. Metastatic mixed tumor is histologically identical to a benign mixed tumor, but it inexplicably metastasizes. Such tumors are rare and have not been reported to date in a transplant recipient. This case illustrates the rapid and aggressive course that malignancies can follow in an immunosuppressed population. Mixed tumors are common salivary neoplasms, so transplant recipients should be carefully followed after resection for evidence of metastatic spread.

Noninvasive assessment of transplant-associated arteriosclerosis.

BACKGROUND: Transplant-associated arteriosclerosis is the major limitation to long-term survival in the cardiac transplant recipient, and annual surveillance angiography is used in many centers to monitor its progression. Noninvasive methods would be preferable because angiography is invasive, costly, and insensitive; however, the reliability of such methods has been questioned. METHODS: All publications relating to the assessment of the cardiac allograft by noninvasive testing were identified through MEDLINE and a review of references from the published literature on transplant-associated arteriosclerosis. RESULTS: Resting and stress ECG, radionuclide scintigraphy, echocardiography, and positron emission tomography have all been used in cardiac transplant recipients with variable results. Most techniques are insensitive, but this limitation may be improved with pharmacologic stress imaging like dobutamine echocardiography. Although insensitive, some methods have good specificity (i.e., radionuclide scintigraphy). The noninvasive measurement of absolute coronary blood flow is promising as a specific and sensitive technique but is limited by availability and cost. CONCLUSIONS: In general, noninvasive techniques to assess transplant-associated coronary arteriosclerosis are limited by variable sensitivity and specificity. However, certain methods, such as dobutamine echocardiography and radionuclide scintigraphy, can provide important adjunctive physiologic information to angiography. Such techniques can therefore help to guide the care and treatment of the cardiac transplant recipient with allograft coronary arteriosclerosis.

Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disorder manifesting as cardiac hypertrophy with myocyte disarray and an increased risk of sudden death. Mutations in five different loci cause FHC and 3 disease genes have been identified: beta cardiac myosin heavy chain, alpha tropomyosin and cardiac troponin T. Because these genes encode contractile proteins, other FHC loci are predicted also to encode sarcomere components. Two further FHC loci have been mapped to chromosomes 11p13-q13 (CMH4, ref. 6) and 7q3 (ref. 7). The gene encoding the cardiac isoform of myosin binding protein-C (cardiac MyBP-C) has recently been assigned to chromosome 11p11.2 and proposed as a candidate FHC gene. Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments. Phosphorylation of MyBP-C appears to modulate contraction. We report that cardiac MyBP-C is genetically linked to CMH4 and demonstrate a splice donor mutation in one family with FHC and a duplication mutation in a second. Both mutations are predicted to disrupt the high affinity, C-terminal, myosin-binding domain of cardiac MyBP-C. These findings define cardiac MyBP-C mutations as the cause of FHC on chromosome 11p and reaffirm that FHC is a disease of the sarcomere.

Influence of HLA mismatch on rejection after heart transplantation: a multiinstitutional study. The Cardiac Transplant Research Database Group.

HLA mismatch has been shown to influence survival after heart transplantation. No large multicenter study has examined the effect of HLA mismatch on cardiac allograft rejection. HLA mismatch and other potential risk factors for rejection were analyzed in data from 27 institutions (1719 patients) participating in the Cardiac Transplant Research Database between January 1, 1990, and June 30, 1992. Complete HLA information on the A, B, and DR loci was available for both donor and recipient in 1190 patients. Of these, 619 (52%) had five or six mismatches; 68 (6%) had zero, one, or two mismatches. The mean number of mismatches was 4.4 and did not differ, regardless of donor-recipient race match (4.3 versus 4.8, p = 0.19). According to multivariate analysis, risk factors for time to first rejection included younger recipient age (p < 0.0001), female gender of both donor and recipient (p < 0.0006), number of HLA mismatches (p = 0.013) and black recipient race (p < 0.004). Patients with zero, one, or two mismatches (n = 67) had a 54% freedom from rejection at 1 year versus 36% for patients with three or more mismatches (n = 1005, p = 0.02). HLA mismatch number did not affect time to first rejection or rejection frequency among black patients. Risk factors (by multivariate analysis) for death or retransplantation because of rejection included female recipient gender (p = 0.008) and black recipient race (p = 0.006). The probability of rejection-related death or retransplantation by 2 years was 0% with zero, one, or two HLA mismatches versus 5% for three to six mismatches (p = 0.14). These findings should stimulate further investigation of methods to clarify the HLA effect in heart transplantation and eventually the use of HLA typing in donor-recipient selection.

Infection after heart transplantation: a multiinstitutional study. Cardiac Transplant Research Database Group.

The incidence, causes, and impact of acute infection were analyzed among 814 consecutive patients from 24 institutions undergoing primary heart transplantation between January 1, 1990, and June 30, 1991, with mean follow-up of 8.2 months (range 0 to 18 months). Sixty-nine percent of the patients had no infections during the follow-up, whereas 31% of patients had one or more infection episodes. The cumulative incidence of infections per patient was 0.41 at 3 months, 0.55 at 6 months, and 0.62 at 12 months after transplantation. Bacterial and viral infections were most common (47% and 41% of infections), with fungi and protozoa accounting for 12%. Overall mortality per infection was 13%, but mortality with fungal infections was higher (36%, p < 0.0001). The most common organ infected was the lung, with a mortality of 23%. The probability of infection by 12 months was higher when OKT3 or antithymocyte globulin induction therapy was used (41% versus 35%, p = 0.01). The single most frequent infecting organism was cytomegalovirus, accounting for 26% of all infections. The probability of cytomegalovirus infection by 12 months was increased with a cytomegalovirus-positive donor and cytomegalovirus-negative recipient (27% versus 15% in all others, p < 0.0001) and with the use of OKT3 or antithymocyte globulin induction therapy (19% versus 12% without induction therapy, p = 0.07). Infection remains the leading cause of death after heart transplantation. The hazard function of likelihood of developing each type of infection at various times after transplantation, as well as response to therapy, are discussed.

Immediate evaluation of endomyocardial biopsies for clinically suspected rejection after heart transplantation.

BACKGROUND: Acute rejection may be suspected in heart transplant recipients in the setting of new onset of clinical symptoms or alterations in cardiac function. Immediate diagnosis may be obtained by performing a frozen section on endomyocardial biopsy (EMB) specimens. However, little is known about the indications for, and the diagnostic reliability of, this procedure. METHODS AND RESULTS: EMBs with frozen section (n = 98) from 65 of 214 consecutive orthotopic heart transplant recipients were reviewed and divided into early (< or = 45 days; n = 47) and late (> 45 days; n = 51) posttransplant periods. Frozen section diagnoses (means = 1.5 EMB samples) were compared with corresponding permanent section diagnoses (means = 4.4 EMB samples), and clinical indications were analyzed. Comparison of frozen and permanent section interpretation revealed concordant pathological processes-rejection (n = 31) versus no rejection (n = 37) versus ischemic injury (n = 20)-in 88 of 98 (90%) cases. Discordant pathological processes on frozen versus permanent section in 10 of 98 (10%) cases could be attributed to ischemic injury (n = 5), sampling (n = 4), and infection (n = 1). In the 92 cases with defined clinical indications, the indication and number of EMBs positive for rejection early and late after transplantation were arrhythmia: 2 of 12 early, 4 of 10 late; congestive heart failure: 1 of 2 early, 5 of 12 late; fever: 0 of 2 early, 1 of 4 late; echo abnormality: 0 of 5 early, 0 of 1 late; syncope: 1 of 5 early, 0 of 1 late; hypotension: 1 of 3 early, 1 of 2 late; noncompliance: 0 of 0 early, 4 of 5 late; more than one of the above: 3 of 7 early, 2 of 5 late; other: 1 of 7 early, 1 of 9 late; total: 9 of 43 early, 18 of 49 late. CONCLUSIONS: Frozen section on EMB specimens accurately reflected the permanent section diagnosis in 90% of cases. No specific clinical indication predicted EMB rejection positivity with high sensitivity in either the early or late posttransplant periods.

An evaluation of ribonuclease protection assays for the detection of beta-cardiac myosin heavy chain gene mutations.

BACKGROUND: Ribonuclease (RNase) protection has been used to identify beta-cardiac myosin heavy chain (MHC) gene mutations that cause familial hypertrophic cardiomyopathy (FHC). Since more than 10 different mutations within this gene have been demonstrated to cause FHC in unrelated individuals, the genetic diagnosis of this condition will involve screening the beta-MHC gene. The accuracy with which RNase protection identifies such mutations is critical to defining the utility of this methodology in detecting mutations that cause FHC. METHODS AND RESULTS: Twelve unrelated individuals with FHC were selected for further study because their beta-MHC genes had been screened for mutations by use of RNase protection, and no mutation was found. We performed linkage analysis of the families of these 12 probands using polymorphic short tandem repeats within the beta-MHC gene to determine whether FHC was genetically linked to the MHC locus on chromosome 14. FHC was not genetically linked to the MHC locus in 11 families whose beta-cardiac MHC gene did not contain mutations detectable by RNase protection. CONCLUSIONS: We conclude that RNase protection is a sensitive method for screening for mutations within the beta-cardiac MHC gene. Further, mutations in the noncoding regions of the beta-MHC gene and mutations in the alpha-cardiac MHC gene are not a common cause of FHC. Negative RNase protection assays of affected individuals suggest that their FHC is due to mutations at other loci.