Rhesus infant nervous temperament predicts peri-adolescent central amygdala metabolism & behavioral inhibition measured by a machine-learning approach.

Anxiety disorders affect millions of people worldwide and impair health, happiness, and productivity on a massive scale. Developmental research points to a connection between early-life behavioral inhibition and the eventual development of these disorders. Our group has previously shown that measures of behavioral inhibition in young rhesus monkeys (Macaca mulatta) predict anxiety-like behavior later in life. In recent years, clinical and basic researchers have implicated the central extended amygdala (EAc)-a neuroanatomical concept that includes the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST)-as a key neural substrate for the expression of anxious and inhibited behavior. An improved understanding of how early-life behavioral inhibition relates to an increased lifetime risk of anxiety disorders-and how this relationship is mediated by alterations in the EAc-could lead to improved treatments and preventive strategies. In this study, we explored the relationships between infant behavioral inhibition and peri-adolescent defensive behavior and brain metabolism in 18 female rhesus monkeys. We coupled a mildly threatening behavioral assay with concurrent multimodal neuroimaging, and related those findings to various measures of infant temperament. To score the behavioral assay, we developed and validated UC-Freeze, a semi-automated machine-learning (ML) tool that uses unsupervised clustering to quantify freezing. Consistent with previous work, we found that heightened Ce metabolism predicted elevated defensive behavior (i.e., more freezing) in the presence of an unfamiliar human intruder. Although we found no link between infant-inhibited temperament and peri-adolescent EAc metabolism or defensive behavior, we did identify infant nervous temperament as a significant predictor of peri-adolescent defensive behavior. Our findings suggest a connection between infant nervous temperament and the eventual development of anxiety and depressive disorders. Moreover, our approach highlights the potential for ML tools to augment existing behavioral neuroscience methods.

System Xc- Antiporter Inhibitors: Azo-Linked Amino-Naphthyl-Sulfonate Analogues of Sulfasalazine.

The cystine/glutamate antiporter system Xc- (SXc-) mediates the exchange of intracellular L-glutamate (L-Glu) with extracellular L-cystine (L-Cys2). Both the import of L-Cys2 and the export of L-Glu take on added significance in CNS cells, especially astrocytes. When the relative activity of SXc- overwhelms the regulatory capacity of the EAATs, the efflux of L-Glu through the antiporter can be significant enough to trigger excitotoxic pathology, as is thought to occur in glioblastoma. This has prompted considerable interest in the pharmacological specificity of SXc- and the development of inhibitors. The present study explores a series of analogues that are structurally related to sulfasalazine, a widely employed inhibitor of SXc-. We identify a number of novel aryl-substituted amino-naphthylsulfonate analogues that inhibit SXc- more potently than sulfasalazine. Interestingly, the inhibitors switch from a competitive to noncompetitive mechanism with increased length and lipophilic substitutions, a structure-activity relationship that was previously observed with aryl-substituted isoxazole. These results suggest that the two classes of inhibitors may interact with some of the same domains on the antiporter protein and that the substrate and inhibitor binding sites may be in close proximity to one another. Molecular modeling is used to explore this possibility.

Restoring ADL function after wrist surgery in children with cerebral palsy: a novel Bilateral robot system design.

Cerebral palsy is a leading cause of disability in children and reducing its effects on arm function will improve quality of life. Our goal is to train children with CP after wrist tendon transfer surgery using a robotic therapy system consisting of two robot arms and wrist robots. The therapeutic goal is to determine if the robot training combined with surgery intervention improved functional outcomes significantly more than surgery alone. To accomplish this long-term goal we have developed a Bilateral ADL Exercise Robot, BiADLER aimed at training children with CP in reach to grasp coordination on ADLs. Specifically, the robot will provide active training using an assist-as-needed. This paper presents the design concepts.

Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency.

OBJECTIVE: To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity. METHODS: A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency. RESULTS: Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52). CONCLUSIONS: These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.

Opportunity of detecting pre-hypertension: worldwide data on blood pressure overswinging.

Overswinging or CHAT (brief for Circadian Hyper-Amplitude-Tension), that is an excessive circadian variation in blood pressure (BP), has been associated with a large increase in cardiovascular disease risk, present even in the absence of an elevated BP itself. This usually asymptomatic condition is usually overlooked by current practice based on spot-checks, because to be diagnosed, measurements need to be taken around-the-clock, preferably for 7 days at the outset. Once diagnosed, however, a usual circadian BP pattern can be restored by means of certain non-pharmacologic or pharmacologic interventions timed appropriately. Thereby, it is possible to reduce the risk of cardiovascular morbidity and mortality, cerebral ischemic events and nephropathy in particular. For the preparation of guidelines regarding the diagnosis of BP disorders and for the institution of primary as well as secondary preventive measures, it is important to know what the incidence of CHAT is on a global basis. We found 191 cases of CHAT among 1602 mostly 7-day/24-h BP profiles, obtained from several centers in different countries participating in an ongoing project on the BIOsphere and the COSmos (BIOCOS). CHAT incidence is about the same between men and women, but it is diagnosed more often among patients with borderline hypertension or with glucose intolerance. It is also more common among MESOR-hypertensive than among MESOR-normotensive individuals. Priority should be given to the development of an unobtrusive and affordable device to automatically monitor BP and to analyze the data as-one-goes, so that cardiovascular disease risk can be prevented.

Circadian and circaseptan (about-weekly) aspects of immigrant Indians' blood pressure and heart rate in California, USA.

Time structurally (chronomically) interpreted half-hourly monitoring of blood pressure (BP) and heart rate (HR) for at least 7 days and preferably for 17 days is recommended, separately for a diagnosis of BP disorders and when necessary again for the same or longer spans for treatment, whenever a positive diagnosis of a disorder is made. In this study, 30 clinically healthy subjects underwent 7-day monitoring and provided a series of findings, including the detection of Circadian Hyper-Amplitude-Tension (CHAT), that is blood pressure overswinging, which carries a high risk of hard cardiovascular events. The results specifically bear upon south-east Asian-Indian immigrants. They show that cardiovascular disease risk increases with age, with a positive family history of hypertension and/or other cardiovascular diseases and even with the duration of stay in the USA. A relation to body mass index is also shown. Such monitoring for prehabilitation may eventually reduce the need for rehabilitation.

Oil-in-water microemulsions stabilized by charged diblock copolymers.

We present here oil-in-water microemulsions stabilized by charged diblock copolymers alone, along with their structural characterization by small-angle neutron scattering measurements. They consist of swollen spherical micelles containing small amounts of oil in their core, which is surrounded by a corona of stretched polyelectrolyte chains. Structural changes, including core size variations, are evidenced when using a cosurfactant, or upon addition of salt, through a contraction of the charged corona. Attempts to relate the micellar structure to the individual copolymer characteristics are also presented, and show that the size of the hydrophobic block mainly determines that of the micelles.

Chronic centrifugation (hypergravity) disrupts the circadian system of the rat.

The present study was conducted to evaluate the response of rat deep body temperature (DBT) and gross locomotor activity (LMA) circadian rhythms to acute hypergravity onset and adaptation to chronic (14 day) hypergravity exposure over three gravity intensities (1.25, 1.5, and 2 G). Centrifugation of unanesthetized naive animals resulted in a dramatic acute decrease in DBT (-1.45, -2.40, and -3.09 degrees C for the 1.25, 1.5, and 2.0 G groups, respectively). LMA was suppressed for the duration of centrifugation (vs. control period); the percent decrease for each group on days 12-14, respectively, was 1.0 G, -15.2%, P = not significant; 1.25 G, -26.9%, P < 0.02; 1.5 G, -44.5%, P < 0.01; and 2.0 G, -63.1%, P < 0.002. The time required for DBT and LMA circadian rhythmic adaptation and stabilization to hypergravity onset increased from 1.25 to 2.0 G in all circadian metrics except daily means. Periodicity analysis detected the phenomenon of circadian rhythm splitting, which has not been reported previously in response to chronic hypergravity exposure. Our analysis documents the disruptive and dose-dependent effects of hypergravity on circadian rhythmicity and the time course of adaptation to 14-day chronic centrifugation exposure.

Light-emitting diodes and cool white fluorescent light similarly suppress pineal gland melatonin and maintain retinal function and morphology in the rat.

BACKGROUND AND PURPOSE: A novel light-emitting diode (LED) light source for use in animal-habitat lighting was evaluated. METHODS: The LED was evaluated by comparing its effectiveness with that of cool white fluorescent light (CWF) in suppressing pineal gland melatonin content and maintaining normal retinal physiology, as evaluated by use of electroretinography (ERG), and morphology. RESULTS: Pineal melatonin concentration was equally suppressed by LED and CWF light at five light illuminances (100, 40, 10, 1, and 0.1 lux). There were no significant differences in melatonin suppression between LED and CWF light, compared with values for unexposed controls. There were no differences in ERG a-wave implicit times and amplitudes or b-wave implicit times and amplitudes between 100-lux LED-exposed rats and 100-lux CWF-exposed rats. Results of retinal histologic examination indicated no differences in retinal thickness, rod outer segment length, and number of rod nuclei between rats exposed to 100-lux LED and 100-lux CWF for 14 days. Furthermore, in all eyes, the retinal pigmented epithelium was intact and not vacuolated, whereas rod outer segments were of normal thickness. CONCLUSION: LED light does not cause retinal damage and can suppress pineal melatonin content at intensities similar to CWF light intensities.

Leg intramuscular pressures during locomotion in humans.

To assess the usefulness of intramuscular pressure (IMP) measurement for studying muscle function during gait, IMP was recorded in the soleus and tibialis anterior muscles of 10 volunteers during treadmill walking and running by using transducer-tipped catheters. Soleus IMP exhibited single peaks during late-stance phase of walking [181 +/- 69 (SE) mmHg] and running (269 +/- 95 mmHg). Tibialis anterior IMP showed a biphasic response, with the largest peak (90 +/- 15 mmHg during walking and 151 +/- 25 mmHg during running) occurring shortly after heel strike. IMP magnitude increased with gait speed in both muscles. Linear regression of soleus IMP against ankle joint torque obtained by a dynamometer produced linear relationships (n = 2, r = 0.97 for both). Application of these relationships to IMP data yielded estimated peak soleus moment contributions of 0.95-1.65 N . m/kg during walking, and 1.43-2.70 N . m/kg during running. Phasic elevations of IMP during exercise are probably generated by local muscle tissue deformations due to muscle force development. Thus profiles of IMP provide a direct, reproducible index of muscle function during locomotion in humans.

Circadian performance of suprachiasmatic nuclei (SCN)-lesioned antelope ground squirrels in a desert enclosure.

Circadian activity parameters of 53 white-tailed antelope ground squirrels, Ammospermophilus leucurus, were measured to determine the role of the suprachiasmatic nuclei (SCN) pacemaker in their health and survival. Wheel-running activity was monitored in the laboratory with 44 individuals to document the presence of free-running circadian rhythms and ability to entrain to light-dark cycles. Twenty-two individuals were returned to the desert site of origin, including 12 intact control animals and 10 animals whose circadian timing had been disrupted by SCN-lesioning. Time of activity was recorded continuously for 15 days in a large outdoor enclosure by a motion detector, a microchip transponder detector, and video surveillance. An unplanned nighttime attack by a feral cat resulted in the death of 60% of the SCN-lesioned animals and 29% of the control animals in the enclosure. Surface activity of SCN-lesioned animals at the food cache occurred both in daytime and at night, ranging from 16.0% nighttime activity for one partially lesioned individual to 52.1% for one completely lesioned animal. Controls were strongly day-active, with nighttime surface trips constituting only 0-1.3% of all excursions to the cache. Nine wild free-ranging individuals, including one with a radiotransmitter collar, were exclusively day-active. One of the functions of the SCN in mammals may be to reduce activity of animals during times that are unfavorable for activity.

Effect of age on the fatty acid composition of phospholipids in human lymphocytes.

We have examined the fatty acid composition of phospholipids of unstimulated and PHA-stimulated T cells from young and old donors. Our results demonstrate that aging is accompanied by decreases in the saturated fatty acids, myristic acid, and palmitic acid, and a concomitant increase in the unsaturated arachidonic acid. Following activation with PHA for 24 h, age-associated differences in fatty acids could no longer be detected. In contrast to the lymphocyte, aging did not affect the fatty acid composition of either serum or neutrophil phospholipids. Exposure of lymphocytes from old donors to myristic acid complexed medium increased the levels of myristate in the phospholipids to levels similar to that seen in lymphocytes from young donors. We conclude from these studies that aging is accompanied by an alteration in the fatty acid profiles of phospholipids, and that incubation in myristic acid complexed medium modulates these profiles. These alterations are unique to lymphocytes and may contribute to the age-related declines in lymphocyte function.

Diagnosis and management of fetal cardiac tumors: a multicenter experience and review of published reports.

OBJECTIVES: We sought to determine the prevalence and natural history of cardiac tumors in patients referred for fetal echocardiography. BACKGROUND: Cardiac tumors are rare; the prevalence, reported from autopsy studies of patients of all ages, varies from 0.0017% to 0.28%. Despite many case reports, the prevalence and natural history of fetal cardiac tumors are unclear. METHODS: Fourteen thousand fetal echocardiograms recorded over an 8-year period in seven centers were available for retrospective review. Medical records and echocardiograms were studied to determine the reason for referral, family history of tuberous sclerosis, prenatal and postnatal course and tumor description and type. RESULTS: Cardiac tumors were present in 19 pregnancies (0.14%). Gestational age at diagnosis ranged from 21 to 38 weeks. The most common indication for referral was a mass on an obstetric ultrasound study. The tumors were singular in 10 patients and multiple in 9. Tumor size ranged from 0.4 x 0.4 to 3.5 x 4 cm, and the majority of tumors were not hemodynamically significant. There were 17 patients with rhabdomyomas, 1 with a fibroma and 1 with an atrial hemangioma. Tuberous sclerosis complex was diagnosed in 10 patients. Partial or complete tumor regression was seen in eight patients; tumors were unchanged in five; and three required operation. CONCLUSIONS: Fetal cardiac tumors, a rare condition, are often benign. The majority of tumors are rhabdomyomas, but not all fetuses with rhabdomyoma have tuberous sclerosis.

Biliary sludging in critically ill trauma patients.

We used serial weekly ultrasonography to prospectively screen 19 critically ill trauma victims for the development of biliary sludge. Fourteen patients had sludge formation during their hospitalization. Sludge development was positively associated with increased transfusion requirements, but not with any other laboratory or clinical findings, including injury severity scores. The enteral feedings administered to most patients did not prevent sludge formation in the majority of cases; all five patients receiving total parenteral nutrition had sludge. Three patients had complications that could possibly be attributed to the sludge (one case of acalculous cholecystitis and two cases of mild pancreatitis). No such problems occurred in the five patients who did not have sludge. No long-term clinical problems related to sludge have occurred. We conclude that gallbladder sludge frequently develops in critically ill trauma patients and that sludge may be associated with pancreatobiliary complications.

The ramifications of immediate reconstruction in the management of breast cancer.

A retrospective review of 50 patients who underwent immediate postmastectomy breast reconstruction was performed to determine the effect of reconstruction on the treatment of these patients. The overall complication rate was 50% (25 of 50). Smoking statistically correlated with an increased rate of wound complications (0 = 0.0001). Obese patients had nearly twice as many wound complications; however, this finding was not statistically significant (P = 0.261). Eleven of the 50 patients underwent reconstruction with a prosthesis, with an overall complication rate of 64% (seven of 11) and a 55% (six of 11) rate of prosthesis loss. Thirty-nine of the 50 patients underwent reconstruction with autologous tissue. Forty-six per cent (18 of 39) of the patients in the autologous group developed complications, and eight required emergent reoperation to prevent flap loss. The wound complication rate was significantly lower for bipedicled transverse rectus abdominis muscle (TRAM) flap reconstructions than for other forms of autologous reconstruction (P = 0.040). total operative time (including mastectomy) was 3.11 hours (range, 2-4 hours) for the prosthetic group and 9.4 hours (range, 5-15 hours) for the autologous group. All but two patients undergoing autologous tissue reconstruction required blood transfusions; an average of 2.4 U of blood was transfused per patient (range, 0-7 U). Only two patients in the prosthetic group required a transfusion. The average hospital stay was 5 days (range, 2-7 days) for the prosthetic group and 8.3 days (range, 5-19 days) for the autologous tissue group.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro cytolytic activity of lymphocytes from tumor-draining lymph nodes is associated with increased numbers of CD8+ cells and increased cytokine production.

A murine footpad tumor model was used to determine the cytotoxic activity, tumor specificity, phenotypic profile, and cytokine production of stimulated cells from draining lymph nodes (DLN). Popliteal DLN from 5-day-old P-815 footpad tumors were stimulated with 10(-7) M phorbol 12, 13-dibutyrate +5 x 10(-7) M ionomycin for 16 hr and cultured in IL-2 (20 units/ml) for 7 or 14 days without autologous tumor. Most cells in both groups were CD3+ (93% at Day 7, 99% at Day 14); however, the percentage of CD8+ cells increased as the cell population matured in the presence of low-dose IL-2. On Day 7, the phenotypic profile was 62% CD4+ and 29% CD8+, whereas on Day 14 it was 16% CD4+ and 81% CD8+. Similarly, in vitro cytokine production increased with time in culture. After 7 days, the level of tumor necrosis factor-alpha (TNF-alpha) was 220 pg/mL and the interferon-gamma (IF-gamma) production was 150 pg/ml. At Day 14 the TNF level had increased to 500 pg/ml, and IF production had increased to 350 pg/ml. These increases in the CD8+ population and in cytokine production correlated with the increase in the percentage of target cells killed by the DLN cells. Cytolytic activity against P-815 was only 13% on Day 7 but 39% on Day 14. Neither group of effector cells (Day 7 or Day 14) had any cytolytic activity against the syngeneic tumor cell line L-1210, demonstrating the tumor specificity of the DLN cells. We describe a model for generating tumor-specific cytotoxic T-cells that have significant cytokine production, which may account for previously described in vivo activity.

Use of the tram and latissimus dorsi flaps in autogenous breast reconstruction.

Breast cancer has reached near epidemic proportions in this country. It is a devastating blow to the patient and her family. Refinements in breast reconstruction have aided greatly in alleviating this harsh attack on the patient's well being and femininity. Many modalities have been used in the past to achieve breast reconstruction but the use of autogenous tissue and immediate reconstruction have permitted the plastic surgeon the opportunity to regain the normal shape of the breast and at times even obtain an improved aesthetic result. We are still not able to obtain a reconstructed breast that has normal sensation and erogenous stimulation. Patients, however, are demanding more and more of their surgeons as they try to better adapt to their conditions. It is hoped that with the advent of new health care reform these patients will not be deprived of the meaningful advances that have been made to date in this field. To paraphrase a saying attributed to Tagliacozzi: "Our objective is not merely to stamp out disease but it is also to buoy the spirit of the afflicted."

Effects of housing density on mouse physiology and behavior in the NASA Animal Enclosure Module simulators.

Space flight studies using the Animal Enclosure Module (AEM) make it possible to investigate the role of microgravity on animal physiology and behavior. In this study, we compared the health and well-being of mice housed at different densities in AEM simulators (AEMS), to vivarium shoebox (control) cages (VSBC). A stress assessment battery (SAB) of measures was developed to evaluate mouse health and well-being, and to determine if any of the population sizes resulted in a stressful environment. The SAB was based, in part, on recommendations of a NASA Workshop on Rodent Cage Sizing. It includes: 1) General assessment of appearance, 2) Behavioral assessment (video), 3) Food and water consumption, 4) Body weight changes, 5) Thymus, adrenal, spleen, heart and kidney weights, 6) Plasma corticosterone concentration, 7) Total plasma protein concentration, 8) Total blood leukocyte count, 9) Differential leukocyte count: neutrophil/lymphocyte ratio; eosinophil count, 10) Gastric histology.

Mechanisms of change in cardiac performance in infants undergoing extracorporeal membrane oxygenation.

OBJECTIVE: To determine whether changes in cardiac performance observed in infants early during extracorporeal membrane oxygenation are due to the underlying disease process, the partial bypass procedure, changes in cardiac loading conditions, or due to a direct myocardial effect of hypoxia-reoxygenation. DESIGN: Consecutive case series. PATIENTS: Infants with meconium aspiration syndrome were studied at the end of their extracorporeal membrane oxygenation course (veno-arterial, n = 12; veno-venous, n = 8), after lung compliance and pulmonary arterial pressure returned toward normal and they were ready to have extracorporeal membrane oxygenation discontinued. INTERVENTIONS: Heart rate, mean arterial blood pressure, and load-dependent indices, and a load-independent index of cardiac performance were measured at increasing bypass flow rates (25, 50, 75, 100, 125 mL/kg/min). MEASUREMENTS AND MAIN RESULTS: Heart rate, mean arterial blood pressure, and load-dependent indices of cardiac performance (left ventricular shortening fraction and stroke volume) were normal at 25 mL/kg/min bypass flow rate and did not change significantly with increasing bypass flow rates. The load-independent index of performance was within the normal range for infants and did not change significantly with increasing bypass flow rates. CONCLUSIONS: The previously described decreases in cardiac performance during extracorporeal membrane oxygenation are not due to the underlying disease process or the bypass procedure but are due to changes in loading conditions during partial bypass.

Proliferation-associated nucleolar antigen P120: a prognostic marker in node-negative breast cancer.

BACKGROUND: P120 is a nucleolar proliferation antigen found in rapidly dividing cells and in a variety of malignancies. METHODS: Our purpose was to determine whether P120 expression is a prognostic factor for patients with node-negative breast cancer by testing pathologic material from 90 patients for P120 immunoreactivity, histologic grade, and estrogen receptors. RESULTS: P120 was detected in 52 of the 90 specimens (58%). Node-negative cancer patients with tumors that did not express the P120 antigen had a significantly better overall survival rate than node-negative cancer patients with tumors that did express P120 (92% vs 69%; p = 0.035). Histologic studies indicated that 36 tumors were grade I, 28 were grade II, and 26 were grade III. The presence of P120 correlated significantly with the nuclear grade of the tumor: 73% of grade III tumors, 64% of grade II tumors, and 42% of grade I tumors stained positive for P120 (p = 0.033). The correlation between nuclear grade and overall survival rate was also significant (grade 1, 94%; grade II, 79%; grade III, 58%); (p = 0.003). No significant correlation was found between P120 expression and estrogen receptors. Multivariate analysis shows that P120 expression and histologic grade together are the strongest predictors of survival. CONCLUSIONS: The biologic marker P120 may play an important role in determining which patients with node-negative cancer will benefit most from adjuvant therapy.