Testing spatial working memory in pigs using an automated T-maze.

Pigs are an important large animal model for translational clinical research but underutilized in behavioral neuroscience. This is due, in part, to a lack of rigorous neurocognitive assessments for pigs. Here, we developed a new automated T-maze for pigs that takes advantage of their natural tendency to alternate. The T-maze has obvious cross-species value having served as a foundation for cognitive theories across species. The maze (17' × 13') was constructed typically and automated with flanking corridors, guillotine doors, cameras, and reward dispensers. We ran nine pigs in (1) a simple alternation task and (2) a delayed spatial alternation task. Our assessment focused on the delayed spatial alternation task which forced pigs to wait for random delays (5, 60, 120, and 240 s) and burdened spatial working memory. We also looked at self-paced trial latencies, error types, and coordinate-based video tracking. We found pigs naturally alternated but performance declined steeply across delays (R2 = 0.84). Self-paced delays had no effect on performance suggestive of an active interference model of working memory. Positional and head direction data could differentiate subsequent turns on short but not long delays. Performance levels were stable over weeks in diverse strains and sexes, and thus provide a benchmark for future neurocognitive assessments in pigs.

A phase II open-label trial of avelumab plus axitinib in previously treated non-small-cell lung cancer or treatment-naïve, cisplatin-ineligible urothelial cancer.

BACKGROUND: We hypothesized that avelumab plus axitinib could improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC) or urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled previously treated patients with advanced or metastatic NSCLC, or untreated, cisplatin-ineligible patients with advanced or metastatic UC. Patients received avelumab 800 mg every 2 weeks (Q2W) and axitinib 5 mg orally two times daily. The primary endpoint was objective response rate (ORR). Immunohistochemistry was used to assess programmed death-ligand 1 (PD-L1) expression (SP263 assay) and the presence of CD8+ T cells (clone C8/144B). Tumor mutational burden (TMB) was assessed by whole-exome sequencing. RESULTS: A total of 61 patients were enrolled and treated (NSCLC, n = 41; UC, n = 20); 5 remained on treatment at data cut-off (26 February 2021). The confirmed ORR was 31.7% in the NSCLC cohort and 10.0% in the UC cohort (all partial responses). Antitumor activity was observed irrespective of PD-L1 expression. In exploratory subgroups, ORRs were higher in patients with higher (≥median) CD8+ T cells in the tumor. ORRs were higher in patients with lower TMB (

Resiliency in young children whose mothers are living with HIV/AIDS.

Resiliency was investigated among well children 6-11 years of age (N = 111) whose mothers are living with AIDS or are HIV symptomatic to determine if mother's HIV status was a risk factor that could effect child resiliency, as well as investigate other factors associated with resiliency. Assessments were conducted with mother and child dyads over four time points (baseline, 6-, 12-, and 18-month follow-ups). Maternal illness was a risk factor for resiliency: as maternal viral load increased, resiliency was found to decrease. Longitudinally, resilient children had lower levels of depressive symptoms (by both mother and child report). Resilient children also reported higher levels of satisfaction with coping self-efficacy. A majority of the children were classified as non-resilient; implications for improving resiliency among children of HIV-positive mothers are discussed.

Methamphetamine Users Have Increased Dental Disease: A Propensity Score Analysis.

Methamphetamine (MA) users are assumed to have a high burden of tooth decay. Less clear is how the distribution and severity of dental caries in MA users differ from the general population. Using a covariate-balancing propensity score strategy, we investigated the differential effects of MA use on dental caries by comparing the patterns of decayed, missing, and filled teeth in a community sample of 571 MA users with a subset of 2,755 demographically similar control individuals selected from a National Health and Nutrition Examination Survey (NHANES) cohort. Recruited over a 2-y period with a stratified sampling protocol, the MA users underwent comprehensive dental examinations by 3 trained and calibrated dentists using NHANES protocols. Propensity scores were estimated with logistic regression based on background characteristics, and a subset of closely matched subjects was stratified into quintiles for comparisons. MA users were twice as likely to have untreated caries (odds ratio [OR] = 2.08; 95% confidence interval [95% CI]: 1.55 to 2.78) and 4 times more likely to have caries experience (OR = 4.06; 95% CI: 2.24 to 7.34) than the control group of NHANES participants. Additionally, MA users were twice as likely to have 2 more decayed, missing, or filled teeth (OR = 2.08; 95% CI: 1.29 to 2.79) than the NHANES participants. The differential involvement of the teeth surfaces in MA users was quite distinctive, with carious surface involvement being highest for the maxillary central incisors, followed by maxillary posterior premolars and molars. Users injecting MA had significantly higher rates of tooth decay compared with noninjectors (P = 0.04). Although MA users experienced decayed and missing dental surfaces more frequently than NHANES participants, NHANES participants had more restored surfaces, especially on molars. The high rates and distinctive patterns of dental caries observed could be used 1) to alert dentists to covert MA use in their patients and 2) as the basis for comprehensive management strategies.

Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI.

Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk. SUMMARY: Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions.

Right atrial thromboemboli: clinical, echocardiographic and pathophysiologic manifestations.

In six patients with clinically unsuspected right atrial thromboemboli the diagnosis was made with two-dimensional echocardiography. Five patients had pulmonary emboli, and one had systemic embolization. Three patients had congestive cardiomyopathy, two with tricuspid regurgitation; of the remaining three, one had cor pulmonale complicated by tricuspid regurgitation, one had thrombophlebitis and one had no discernible cardiac illness. Four patients had dizziness or syncope, four had dyspnea, three had chest pain, three had hypotension and tow had cyanosis. Five patients were treated with thrombolytic or anticoagulant therapy, or a combination of the two. In three patients, surgical removal of the thrombus was undertaken because of recurrent pulmonary emboli or tricuspid regurgitation, or both, and progressive right heart failure. The thromboemboli were removed in all three, but one patient died. On two-dimensional echocardiography, four of the six patients' thromboemboli were snake-like, unattached to the right atrium and prolapsed freely across the tricuspid valve into the right ventricle in diastole and back into the right atrium in systole. The other two patients' thromboemboli were attached to the right atrium and did not prolapse across the tricuspid valve. Our cases, together with a review of other reports, suggest that right atrial thromboemboli: 1) can be accurately diagnosed by two-dimensional echocardiography; and 2) result from two different pathophysiologic mechanisms developing a) in situ, either on a foreign body or secondary to reduced cardiac output, or b) as a result of an embolus from systemic vein thromboses.

Acquired immunodeficiency syndrome/human immunodeficiency virus risk behavior among gay men in small cities. Findings of a 16-city national sample.

BACKGROUND: Most research on acquired immunodeficiency syndrome has been conducted in several of the country's largest cities, and little is known about the current level of human immunodeficiency virus risk taking among gay men in other geographical areas. The purpose of this study was to determine the frequency of risk behavior practices among gay men in smaller communities. METHOD: A large sample of men who patronized gay bars in 16 small and moderate-size cities drawn from six states in four different regions of the country was surveyed to determine the frequency of high-risk behavior and factors influencing risk taking. Eighty-five percent of men in all cities' bars completed all survey measures. The community samples were 1991 men; mean age, 31.3 years; mean education, 10.6 years; 90% were white and 10% were of other ethnicities. All participants provided detailed information on their sexual behavior practices over the preceding 2 months and completed measures assessing their perceived peer norms concerning safer sex practices and risk avoidance, intentions to avoid risk, personal risk estimation, acquired immunodeficiency syndrome risk knowledge, perceived threat of acquired immunodeficiency syndrome/human immunodeficiency virus, and serostatus testing history. RESULTS: High-risk patterns were still common among gay men in these smaller cities; nearly one third of all men had engaged in unprotected anal intercourse an average of eight times in the past 2 months, usually outside monogamous relationships. High-risk behavior was most strongly associated with beliefs that safer sex practices would not be well accepted by peers, weak intentions to use condoms, underestimation of personal vulnerability to the acquired immunodeficiency syndrome, younger age, and higher levels of overall sexual activity. Nine percent of men tested said they were seropositive. CONCLUSIONS: Growing human immunodeficiency virus prevalence and continued high rates of risk behavior indicate that a new "front line" for human immunodeficiency virus prevention among homosexually active men has shifted to the country's smaller cities. Community prevention efforts in these areas are urgently needed to avert sharp increases in future human immunodeficiency virus infections in this population.

Effects of acutely raising intracranial pressure on cardiac sympathetic efferent neuron function.

OBJECTIVE: To determine whether acutely raising intracranial pressure modifies the function of cardiac efferent autonomic neurons. METHODS: The effects of suddenly raising intracranial pressure above systemic vascular pressure on heart rate, left atrial and left ventricular chamber pressures, as well as right and left ventricular intramyocardial pressures, were studied following removal of the adrenal glands from the circulation. Cardiac effects induced by systemic administration of nicotine, tyramine or isoproterenol were investigated before and after raising intracranial pressure: (1) in 9 dogs with neurally intact hearts in which cardiac release of catecholamines and intrinsic cardiac neuronal activity were studied; (2) in another 8 dogs in which intrathoracic autonomic neurons were disconnected from central neurons; (3) in another 8 dogs after decentralizing intrathoracic sympathetic but not parasympathetic neurons; (4) in 2 animals after decentralizing intrathoracic parasympathetic, not sympathetic neurons. RESULTS: Increasing intracranial pressure in neurally intact preparations induced ventricular augmentation followed by depression such that after 12 min of cerebral ischemia left ventricular systolic pressure was 62 +/- 5 mmHg. Isoproterenol and tyramine augmented right ventricular inotropism similarly before and after raising intracranial pressure, their effects on left ventricular systolic pressures being reduced secondary to the systemic vascular hypotension. Although nicotine excited intrinsic cardiac neurons similarly before and after raising intracranial pressure, it failed to enhance cardiac liberation of noradrenaline after compared to before raising intracranial pressure. Nicotine-induced ventricular augmentation was obtunded after brain death despite the fact that ventricular myocytes underwent no detectable histological changes. In contrast, nicotine induced similar cardiac augmentation before and after raising intracranial pressure when intrathoracic autonomic neurons or when intrathoracic sympathetic, not parasympathetic neurons, were decentralized. CONCLUSION: Cardiac sympathetic efferent neuronal function is obtained by acutely raising intracranial pressure.

The impact of illness disclosure and custody plans on adolescents whose parents live with AIDS.

OBJECTIVES: To describe the disclosure and custody planning of parents living with AIDS and the impact of these on their adolescents' adjustment. METHODS: An examination of the association of multiple behaviour problems in children and the illness disclosure and custody plans of their parents living with AIDS. RESULTS: Both mothers (87%) and fathers were significantly more likely to disclose their HIV serostatus to adolescents (73%), compared with younger children (23%); only 44% disclosed their illness to all their children; 11% disclosed to none. Most parents (80%) living with AIDS had discussed their custody plans. However, only 30% initiated legal plans, typically for younger children. Adolescents who were informed of their parents' serostatus engaged in more sexual risk acts, smoked more cigarettes, and reported more severe substance use and greater emotional distress than uninformed adolescents. Legal custody arrangements were not associated with adolescent adjustment at recruitment or follow-up. CONCLUSIONS: A longitudinal analysis of the impact on adolescents of the behaviours of parents living with AIDS is needed.

AIDS/HIV risk behavior among the chronic mentally ill.

OBJECTIVE: There is growing concern that chronic mentally ill adults living in the community have a high risk for HIV infection. The purpose of this study was to identify risk knowledge, high-risk behaviors, and risk-related encounters of chronic psychiatric outpatients. METHOD: Detailed information on high-risk behaviors and risk-related situations during the past 12 months was collected from 60 outpatients appearing for regular visits at inner-city community mental health clinics. RESULTS: Of the 60 outpatients, 37 (62%) had been sexually active during the past year, and 42% of the men and 19% of the women reported multiple sexual contacts and infrequent use of condoms during intercourse. Assessments of the patients' knowledge of AIDS risks revealed substantial deficits in their practical understanding of AIDS and risk reduction measures. Although use of intravenous drugs was uncommon in this group, many subjects reported histories of 1) trading sex for money, drugs, or a place to stay, 2) coercion to engage in unwanted sex, 3) causal sexual encounters, and 4) sexual activity after use of drugs or intoxicants. Twenty percent of the subjects had met their sexual partners on the streets, in parks, or in other public places. One-third had been treated for sexually transmitted diseases other than AIDS. CONCLUSIONS: These findings underscore the need for AIDS risk assessment, counseling, and prevention programs for the chronic mentally ill.

Outcome of cognitive-behavioral and support group brief therapies for depressed, HIV-infected persons.

OBJECTIVE: Although many studies have documented patterns of emotional distress in persons with HIV disease, there have been few controlled evaluations of therapy outcomes with these individuals. This research evaluated the effects of brief cognitive-behavioral or social support group therapy with this population. METHOD: Sixty-eight depressed men with HIV infection were randomly assigned to one of three conditions: eight-session cognitive-behavioral groups, eight-session social support groups, or a comparison condition. Before and after intervention and at 3-month follow-up, all participants were individually assessed by using measures of symptoms of distress as well as substance use and sexual practices. RESULTS: Relative to the comparison group, both the cognitive-behavioral and social support group therapies produced reductions in depression, hostility, and somatization. The social support intervention also produced reductions in overall psychiatric symptoms and tended to reduce maladaptive interpersonal sensitivity, anxiety, and frequency of unprotected receptive anal intercourse, while the cognitive-behavioral intervention resulted in less frequent illicit drug use during the follow-up period. Tests for clinical significance of change particularly underscored benefits of the social support group intervention both at postintervention and at long-term follow-up. CONCLUSIONS: Brief group therapy for depressed persons with HIV infection produced reductions in symptoms of distress. The two forms of therapy resulted in shared and unique improvements in functioning, although social support groups focused on emotional coping presented greater evidence of clinically significant change. As more persons contract HIV infection and live longer with HIV disease, further research is needed to evaluate outcomes of mental health services with these individuals.

Major histocompatibility complex class I and class II expression by myocytes in cardiac biopsies posttransplantation.

A total of 85 cardiac biopsies from patients 23-265 days posttransplant were studied for the correlation of the rejection grade score with the level of major histocompatibility complex (MHC) class I and class II expression on cardiac myocytes and endothelial cells, the quantitative level of leukocytic infiltrate, and the immunophenotype of the leukocytes. Results indicate a lack of absolute correlation between rejection grade scores and levels of MHC antigen expression. Further, a lack of absolute correlation was also seen with quantitation of leukocytic infiltrates and relative levels of MHC antigen expression. Of great interest was our preliminary finding that as early as 4 weeks prior to a rejection episode scored by routine histological criteria as grade 4, cardiac biopsy from the patient demonstrated high levels of MHC class I and class II expression. Similar increases of MHC antigen expression prior to an increase in histological rejection score grades were also noted in serial biopsies of 2 other patients. These data suggest that it may be quite useful to examine levels of MHC antigens on cardiac biopsies posttransplantation as an additional parameter for monitoring of cardiac rejection episodes.

Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline.

Twenty-two children with attention deficit-hyperactivity disorder underwent a double-blind, placebo-controlled, crossover evaluation of the efficacy of standard methylphenidate twice a day and comparable doses every morning of a sustained-release preparation of methylphenidate (SR-20 Ritalin), a sustained-release form of dextroamphetamine (Dexedrine Spansule), and pemoline. The children were participating in a summer treatment program in which they engaged in recreational and classroom activities. Dependent measures include evaluations of social behavior during group recreational activities, classroom performance, and performance on a continuous performance task. Results revealed generally equivalent and beneficial effects of all four medications. Dexedrine Spansule and pemoline tended to produce the most consistent effects and were recommended for 10 of the 15 children who were responders to medication. The continuous performance task results showed that all four medications had an effect within 2 hours of ingestion, and the effects lasted for 9 hours. The implications of these results for the use of long-acting stimulant medication in children with attention deficit-hyperactivity disorder are discussed.

Anatomy of human extrinsic cardiac nerves and ganglia.

The anatomy of the human extrinsic cardiac nerves and ganglia was reinvestigated because descriptions of human cardiac innervation vary, detailed analyses of subhuman mammalian cardiac innervation reveal considerable similarities among species and the anatomic pattern of cardiac innervation observed in subhuman mammals differs significantly from those described for humans. The presence of a consistent pattern of cardiac innervation in subhuman mammals raised the question as to whether a similar pattern exists in humans. To investigate this, the cervical and thoracic autonomic nerves and ganglia were dissected in 13 embalmed and 10 autopsy cadavers. All major sympathetic cardiopulmonary nerves were found to arise from the stellate ganglia and the caudal halves of the cervical sympathetic trunks below the level of the cricoid cartilage. These sympathetic cardiopulmonary nerves usually consisted of 3 nerves on the right side and 4 on the left. In contrast to widely accepted reports, no sympathetic cardiopulmonary nerves were found to arise from the superior cervical ganglia or the thoracic sympathetic trunks inferior to the stellate ganglia. Parasympathetic cardiopulmonary nerves were found to arise from the recurrent laryngeal nerves and the thoracic vagi immediately distal to them. These nerves interconnected with sympathetic cardiopulmonary nerves anterior and posterior to the main pulmonary artery to form the ventral and dorsal cardiopulmonary plexuses. These plexuses contained relatively large discrete nerves as well as smaller interconnections. Emerging from these plexuses to innervate the ventricles were 3 distinct relatively large cardiac nerves, the right and left coronary cardiac nerves and the left lateral cardiac nerve. In addition to these 3 major nerves, small cardiac nerves arose from the plexuses and the thoracic vagi. Histologic examination of representative dissections confirmed the presence of neural tissue and identified the locations of neuronal cell bodies in these structures. Cell bodies were located in the nodose, superior cervical, middle cervical, stellate and thoracic sympathetic ganglia. The middle cervical ganglia varied in size and number. Neuronal cell bodies were found in the cervical and thoracic sympathetic trunks and in small mediastinal ganglia located along the courses of the cardiopulmonary and cardiac nerves. Marked similarities exist between the anatomy of the cardiopulmonary nerves and ganglia of humans and baboons.

Coronary revascularization in the presence of ascending aortic calcification: use of an internal mammary artery-saphenous vein composite graft.

Complications arising from manipulation of the diseased ascending aorta constitute a significant portion of the morbidity and mortality of coronary revascularization. A case is described in which coronary revascularization was achieved by extension of the left internal mammary artery with a segment of reversed saphenous vein. The major advantage of this technique is that it obviates any instrumentation of the aorta or great vessels.

Continuous warm blood cardioplegia preserves cardiac autonomic function.

We studied in anesthetized dogs, the effects of cardiopulmonary bypass with normothermic whole blood, crossclamping of the aortic root, and continuous warm blood cardioplegia on the ability of the efferent sympathetic nervous system to augment the heart and that of the efferent parasympathetic nervous system to depress the heart. In control states, heart rate, atrial force of contraction, and right and left ventricular wall systolic pressures were augmented by stimulation of the intrathoracic efferent sympathetic nervous system and by administration of isoproterenol into the systemic circulation. After 1 hour of normothermic cardiopulmonary bypass that utilized aortic crossclamping and continuous perfusion of the coronary arteries with normothermic blood (20 mEq/L potassium), cardiac-augmenting effects induced by the efferent sympathetic nervous system and by isoproterenol were similar. Depressive responses elicited by the efferent parasympathetic nervous system were also unaffected by these procedures. Continuous warm blood cardioplegia does not result in impairment of the efferent sympathetic nervous system regulating the heart.

Influences of cardiopulmonary bypass, temperature, cardioplegia, and topical hypothermia on cardiac innervation.

The effects of normothermic and hypothermic cardiopulmonary bypass, crossclamping of the aortic root, cold cardioplegia, as well as epicardial application of iced slush, on the efficacy of the efferent sympathetic nervous system to augment the heart and the efferent parasympathetic nervous system to depress the heart were studied in anesthetized dogs. Cardiac rate and force are augmented by stimulation of the intrathoracic efferent sympathetic nervous system and reduced by stimulation of the intrathoracic efferent parasympathetic nervous system. After cardiopulmonary bypass, which included systemic and topical hypothermia, aortic crossclamping, and crystalloid cardioplegia, the augmentor effects of the efferent sympathetic nervous system were obtunded whereas the depressor effects exerted by the efferent parasympathetic nervous system were not. Direct cardiac myocyte augmentor responses induced by isoproterenol were unaffected by these interventions. Normothermic cardiopulmonary bypass, hypothermic cardiopulmonary bypass, crossclamping of the aorta, or cold cardioplegia did not result in blunting of the efferent sympathetic cardiac nervous system. Significant blunting of cardiac augmentation induced by the efferent sympathetic nervous system occurred after topical application of iced slush alone. These data demonstrate that blunting of the efferent sympathetic, but not parasympathetic, innervation of the heart occurs after cardiopulmonary bypass, which presumably is primarily due to altering the function of subepicardial efferent sympathetic axons by topical hypothermia and not due to altered cardiac myocyte function. These data imply that after cardiopulmonary bypass involving the procedures described, the ability of the efferent sympathetic nervous system to support cardiac rate and force is transiently impaired.

Surgical repair of stenotic ostial lesions of the left main coronary artery.

Fourteen patients with isolated stenosis of the left coronary artery ostium underwent vein patch angioplasty. An anterior approach between the aorta and pulmonary artery to expose the left main coronary ostium was used in 12 of 14 patients. There were no deaths, and postoperative angiograms in 13 of the patients showed normal coronary ostial contour with normal runoff. Two perioperative myocardial infarctions were observed. Four of the 14 patients underwent an urgent operation. Isolated coronary ostial stenosis appears to be a distinct clinical entity occurring in younger patients, mostly female, and often with a short clinical course. Unstable pain and hemodynamics are observed. The common pathologic cause of the stenotic lesion is not clear.

Anomalous origin of left main cononary artery from anterior sinus of Valsalva with myocardial infarction.

The origin of the left main coronary artery, or its branches, from the right or anterior sinus of Valsalva is a recognized congenital anomaly. The origin of the entire left main coronary artery from a separate ostium in the right sinus of Valsalva and its course to the right and behind the ascending aorta, in a living patient without associated congenital heart disease, has not been described. This anomaly was recognized as the cause of an anterior myocardial infarction in a 12-year-old girl, and it is the subject of this case report.