Practitioner Review: Neurobiological consequences of childhood maltreatment - clinical and therapeutic implications for practitioners.

BACKGROUND: Childhood maltreatment is one of the most important preventable risk factors for a wide variety of psychiatric disorders. Further, when psychiatric disorders emerge in maltreated individuals they typically do so at younger ages, with greater severity, more psychiatric comorbid conditions, and poorer response to established treatments, resulting in a more pernicious course with an increased risk for suicide. Practitioners treating children, adolescents, and young adults with psychiatric disorders will likely encounter the highest prevalence of clients with early-onset maltreatment-associated psychiatric disorders. These may be some of their most challenging cases. METHOD: In this report, we explore key validated alterations in brain structure, function, and connectivity associated with exposure to childhood maltreatment as potential mechanisms behind their patients' clinical presentations. RESULTS: We then summarize key behavioral presentations likely associated with neurobiological alterations and propose a toolkit of established trauma and skills-based strategies that may help diminish symptoms and foster recovery. We also discuss how some of these alterations may serve as latent vulnerability factors for the possible development of future psychopathology. CONCLUSIONS: Research on the neurobiological consequences of childhood adversity provides a vastly enriched biopsychosocial understanding of the developmental origins of health and pathology that will hopefully lead to fundamental advances in clinical psychology and psychiatry.

The effects of bovine colostrum supplementation on in vivo immunity following prolonged exercise: a randomised controlled trial.

BACKGROUND: Bovine colostrum (COL) has been advocated as a nutritional countermeasure to exercise-induced immune dysfunction, but there is a lack of research with clinically relevant in vivo measures. AIM: To investigate the effects of COL supplementation on in vivo immunity following prolonged exercise using experimental contact hypersensitivity (CHS) with the novel antigen diphenylcyclopropenone (DPCP). METHODS: In a double-blind design, 31 men were randomly assigned to COL (20 g/day) or placebo (PLA) for 58 days. Participants ran for 2 h at 60% maximal aerobic capacity on day 28 and received a primary DPCP exposure (sensitisation) 20 min after. On day 56, participants received a low-dose-series DPCP challenge to elicit recall of in vivo immune-specific memory (quantified by skinfold thickness 24 and 48 h later). Analysis of the dose-response curves allowed determination of the minimum dose required to elicit a positive response (i.e., sensitivity). RESULTS: There was no difference in summed skinfold thickness responses between COL and PLA at 24 h (p = 0.124) and 48 h (p = 0.405). However, sensitivity of in vivo immune responsiveness was greater with COL at 24 h (p < 0.001) and 48 h (p = 0.023) with doses ~ twofold greater required to elicit a positive response in PLA. CONCLUSIONS: COL blunts the prolonged exercise-induced decrease in clinically relevant in vivo immune responsiveness to a novel antigen, which may be a mechanism for reduced illness reports observed in the previous studies. These findings also suggest that CHS sensitivity is highly relevant to host defence.

Influence of 4 weeks of bovine colostrum supplementation on neutrophil and mucosal immune responses to prolonged cycling.

Bovine colostrum (COL) has been advocated as a nutritional countermeasure to exercise-induced immune dysfunction. The aims of this study were to identify the effects of 4 weeks of COL supplementation on neutrophil responses and mucosal immunity following prolonged exercise. In a randomized double-blind, parallel group design, participants [age 28 ± 8 years; body mass 79 ± 7 kg; height 182 ± 6 cm; maximal oxygen uptake (V̇O2max) 55 ± 9 mL/kg/min] were assigned to 20 g per day of COL (n = 10) or an isoenergetic/isomacronutrient placebo (PLA; n = 10) for 4 weeks. Venous blood and unstimulated saliva samples were obtained before and after 2.5 h of cycling at 15% Δ (∼55-60% V̇O2max). A significantly greater formyl-methionyl-leucyl phenylalanine-stimulated oxidative burst was observed in the COL group compared with PLA group (P < 0.05) and a trend toward a time × group interaction (P = 0.06). However, there was no effect of COL on leukocyte trafficking, phorbol-12-myristate-13-acetate-stimulated oxidative burst, bacterial-stimulated neutrophil degranulation, salivary secretory IgA, lactoferrin or lysozyme (P > 0.05). These findings provide further evidence of the beneficial effects of COL on receptor-mediated stimulation of neutrophil oxidative burst in a model of exercise-induced immune dysfunction.

Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies.

Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.

A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence.

BACKGROUND: Of the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy. METHODS: This was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19-9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1-21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)-time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting. RESULTS: Forty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36-81), 53% male, 73% node positive, 49% elevated CA 19-9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9-36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46-1.87, p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46-2.05, p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms. CONCLUSIONS: Treatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy.

Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice.

Neonatal hyperoxia impairs vascular and alveolar growth in mice and decreases endothelial progenitor cells. To determine the role of bone marrow-derived cells in restoration of neonatal lung structure after injury, we studied a novel bone marrow myeloid progenitor cell population from Tie2-green fluorescent protein (GFP) transgenic mice (bone marrow-derived angiogenic cells; BMDAC). We hypothesized that treatment with BMDAC would restore normal lung structure in infant mice during recovery from neonatal hyperoxia. Neonatal mice (1-day-old) were exposed to 80% oxygen for 10 days. BMDACs (1 x 10(5)), embryonic endothelial progenitor cells, mouse embryonic fibroblasts (control), or saline were then injected into the pulmonary circulation. At 21 days of age, saline-treated mice had enlarged alveoli, reduced septation, and a reduction in vascular density. In contrast, mice treated with BMDAC had complete restoration of lung structure that was indistinguishable from room air controls. BMDAC comprised 12% of distal lung cells localized to pulmonary vessels or alveolar type II (AT2) cells and persist (8.8%) for 8 wk postinjection. Coculture of AT2 cells or lung endothelial cells (luEC) with BMDAC augmented AT2 and luEC cell growth in vitro. We conclude that treatment with BMDAC after neonatal hyperoxia restores lung structure in this model of bronchopulmonary dysplasia.

Human cerebral hemispheres develop at different rates and ages.

The development of the cerebral hemispheres was assessed by using measures of electroencephalographic coherence and phase in 577 children ranging in age from 2 months to early adulthood. Two categories of age-dependent change in electroencephalographic coherence and phase were noted: continuous growth processes that were described best by an exponential growth function, and discrete growth spurts that appeared in specific anatomical locations at specific postnatal periods. The left and right hemispheres developed at different rates and with different postnatal onset times with the timing of growth spurts overlapping the timing of the major developmental stages described by Piaget.

Carbon-nitrogen cycling through microbial formamide metabolism.

A microbially mediated carbon-nitrogen cycle involving a newly isolated facultatively methylotrophic pseudomonad is described. The new isolate utilizes formamide as its sole carbon, nitrogen, and energy source. Other organisms involved in the proposed cycle are cyanogenic plants; phytopathogenic fungi, which convert cyanogenic glycosides to formamide; and nitrifying microorganisms. This cycle may be quantitatively important in view of the large variety of cyanogenic plants known to exist.

Intelligence and EEG phase reset: a two compartmental model of phase shift and lock.

OBJECTIVES: The purpose of this study was to explore the relationship between EEG phase reset and performance on the Wechsler Intelligence test. METHODS: The electroencephalogram (EEG) was recorded from 19 scalp locations from 378 subjects ranging in age from 5 years to 17.6 years. The Wechsler Intelligence test (WISC-R) was administered to the same subjects on the same day but not while the EEG was recorded. Complex demodulation was used to compute instantaneous EEG phase differences between pairs of electrodes and the 1st and 2nd derivatives were used to measure phase reset by phase shift duration and phase lock duration. The dependent variable was full scale I.Q. and the independent variables were phase shift duration (SD) and phase lock duration (LD) with age as a covariate. RESULTS: Phase shift duration (40-90 ms) was positively related to intelligence (P<.00001) and the phase lock duration (100-800 ms) was negatively related to intelligence (P<.00001). Phase reset in short interelectrode distances (6 cm) was more highly correlated to I.Q. (P<.0001) than in long distances (>12 cm). CONCLUSIONS: The duration of unstable phase dynamics and phase locking represent a bounded optimization process, for example, too long a duration of phase locking then less flexibility and too short of a phase shift then reduced neural resources. A two compartmental model of local field coupling and neuron synchrony to a preferred phase was developed to explain the findings.

Intelligence and eeg measures of information flow: efficiency and homeostatic neuroplasticity.

The purpose of this study was to explore the relationship between the magnitude of EEG information flow and intelligence. The electroencephalogram (EEG) was recorded from 19 scalp locations from 371 subjects ranging in age from 5 years to 17.6 years. The Wechler Intelligence Scale for Children (WISC-R) was administered for individuals between 5 years of age and 16 years and the Weschler Adult Intelligence Scale revised (WAIS-R) was administered to subjects older than 16 years to estimate I.Q. The phase slope index estimated the magnitude of information flow between all electrode combinations for difference frequency bands. Discriminant analyses were performed between high I.Q. (>120) and low I.Q. groups (<90). The magnitude of information flow was inversely related to I.Q. especially in the alpha and beta frequency bands. Long distance inter-electrode distances exhibited greater information flow than short inter-electrode distances. Frontal-parietal correlations were the most significant. It is concluded that higher I.Q. is related to increased efficiency of local information processing and reduced long distance compensatory dynamics that supports a small-world model of intelligence.

CD30+ Cutaneous T Cell Lymphoma: Response to Rotational Total Skin Electron Irradiation.

INTRODUCTION: Rotational total skin electron irradiation (RTSEI) is an effective therapy for cutaneous T cell lymphoma (CTCL). CD30 expression has been identified as a prognostic factor in CTCL. Therefore, we investigated CD30 status, treatment response, and survival in our cohort of patients with CTCL treated with RTSEI. METHODS: Patients with CTCL treated with RTSEI (≥30 Gy) between 2000 and 2013 at our institution were identified, and clinical and pathologic data were retrospectively reviewed. Primary outcomes were complete clinical response (CCR; >90% reduction of skin disease burden), relapse-free survival (RFS), and overall survival (OS). RESULTS: Sixty-eight patients with CTCL treated with RTSEI were identified. Median age at diagnosis was 51 years with median follow-up of 61 months. Median OS was 76 months and median RFS was 11 months. Thirteen patients (19%) had CD30+ lymphocytes on initial pathology. In the CD30+ cohort, there were no T2, eight T3, and five T4 cases. In comparison, in the CD30- cohort, there were 18 T2, 29 T3, and 8 T4 cases (P = 0.01). Six weeks post-RTSEI, CCR was 85% in CD30+ and 81% in CD30- cases (P = 1). Six months post-RTSEI, CCR was 23% in CD30+ and 50% in CD30- cases (P = 0.083). CONCLUSION: RTSEI resulted in excellent CCR at 6 weeks in our cohort of patients with CTCL, with a median RFS of 11 months. We found CD30+ patients presented with significantly higher T stage at time of RTSEI and trended towards decreased CCR at 6 months post-RTSEI compared with the CD30- group.

EEG and intelligence: relations between EEG coherence, EEG phase delay and power.

OBJECTIVE: There are two inter-related categories of EEG measurement: 1, EEG currents or power and; 2, EEG network properties such as coherence and phase delays. The purpose of this study was to compare the ability of these two different categories of EEG measurement to predict performance on the Weschler Intelligence test (WISC-R). METHODS: Resting eyes closed EEG was recorded from 19 scalp locations with a linked ears reference from 442 subjects aged 5-52 years. The Weschler Intelligence test was administered to the same subjects but not while the EEG was recorded. Subjects were divided into high IQ (> or = 120) and low IQ (< or = 90) groups. EEG variables at P<.05 were entered into a factor analysis and then the single highest loading variable on each factor was entered into a discriminant analysis where groups were high IQ vs. low.Q. RESULTS: Discriminant analysis of high vs. low IQ was 92.81-97.14% accurate. Discriminant scores of intermediate IQ subjects (i.e. 90 < IQ < 120) were intermediate between the high and low IQ groups. Linear regression predictions of IQ significantly correlated with the discriminant scores (r = 0.818-0.825, P < 10(-6)). The ranking of effect size was EEG phase > EEG coherence > EEG amplitude asymmetry > absolute power > relative power and power ratios. The strongest correlations to IQ were short EEG phase delays in the frontal lobes and long phase delays in the posterior cortical regions, reduced coherence and increased absolute power. CONCLUSIONS: The findings are consistent with increased neural efficiency and increased brain complexity as positively related to intelligence, and with frontal lobe synchronization of neural resources as a significant contributing factor to EEG and intelligence correlations. SIGNIFICANCE: Quantitative EEG predictions of intelligence provide medium to strong effect size estimates of cognitive functioning while simultaneously revealing a deeper understanding of the neurophysiological substrates of intelligence.

Total skin electron therapy for cutaneous T-cell lymphoma using a modern dual-field rotational technique.

PURPOSE: To report our experience with rotational total skin electron irradiation (RTSEI) in cutaneous T-cell lymphoma (CTCL), and to examine response by disease stage and race. METHODS AND MATERIALS: We reviewed our outcomes for 68 CTCL patients who received RTSEI (≥ 30 Gy) from 2000 to 2013. Primary outcomes were complete clinical response (CCR), recurrence-free survival (RFS), and overall survival (OS). Using log-rank tests and Cox proportional hazards, OS and RFS were compared across tumor stages at time of RTSEI with further racial subgroup analysis. RESULTS: Median age at diagnosis and at time of radiation was 52 and 56 years, respectively. Median follow-up was 5.1 years, 49% were African American, and 49% were female. At time of treatment, 18, 37, and 13 patients were T stage 2, 3, and 4, respectively. At 6 weeks after RTSEI, overall CCR was 82% (88%, 83%, and 69% for T2, T3, and T4, respectively). Median RFS was 11 months for all patients and 14, 10, and 12 months for stage T2, T3, and T4, respectively. Tumor stage was not associated with RFS or CCR. Maintenance therapy after RTSEI was associated with improved RFS in both crude and multivariable analysis, controlling for T stage. Median OS was 76 months (91 and 59 months for T3 and T4, respectively). With the exception of improved OS in African Americans compared with whites at stage T2, race was not associated with CCR, RFS, or OS. CONCLUSIONS: These results represent the largest RTSEI clinical outcomes study in the modern era using a dual-field rotational technique. Our observed response rates match or improve upon the standard set by previous outcome studies using conventional TSEI techniques, despite a large percentage of advanced CTCL lesions in our cohort. We found that clinical response after RTSEI did not seem to be affected by T stage or race.

Cortical sensorimotor reorganization after spinal cord injury: an electroencephalographic study.

The aim of this study was to determine if cortical motor representation and generators change after partial or complete paralysis after spinal cord injury (SCI). Previously reported evidence for a change in cortical motor function after SCI was derived from transcranial magnetic stimulation. These studies inferred a reorganization of the cortical motor system. We applied the new technique of high-resolution EEG to measure changes in cortical motor representation directly. We recorded and mapped the motor potential (MP) of the movement-related cortical potentials in 12 SCI patients and 11 control subjects. Results were analyzed using a distance metric to compare MP locations between patients and control subjects. EEG was coregistered with subject-specific MR images and a boundary element model created for dipole source analysis (DSA). When compared with normal control subjects, seven quadriparetics had posteriorly located MPs with finger movements. One paraparetic had a posterior MP with toe movements, but three who could not move the toes had normally located MPs on attempts to move. DSA confirmed the electrical field map distributions of the MPs. We are reporting a reorganization of cortical motor activity to a posterior location after SCI. These results suggest an important role of the somatosensory cortex (S1) in the recovery process after SCI.

Cortical motor reorganization after paraplegia: an EEG study.

OBJECTIVE: To determine whether a previously identified posterior reorganization of the cortical motor network after spinal cord injury (SCI) is correlated with prognosis and outcome. METHODS: We applied the techniques of high-resolution EEG and dipole source analysis to record and map the motor potentials (MPs) of the movement-related cortical potentials in 44 patients after SCI. Twenty normal controls were also tested. Results were analyzed using a distance metric to compare MP locations. EEG was coregistered with individual specific MR images and a boundary element model created for dipole source analysis. RESULTS: MPs with finger movements were mapped to a posterior location in 20 of 24 tetraplegics compared with normal controls. Two patients, one studied 4 and one 6 weeks after injury, initially had posterior MPs that, on serial testing, moved to an anterior position with recovery. Dipole source localization of the MP generators confirmed these results. Nine of 20 paraplegics had a posterior MP location with actual or attempted toe movements. All 5 patients who could move their toes had posterior MPs. The MP was posterior in 4 of the 15 paralyzed patients. This is a significant difference in proportions. The only patient with paraparesis whose testing was repeated had an MP that moved to an anterior position with recovery. CONCLUSIONS: Posterior reorganization has a significant relationship to prognosis in paraplegia and is reversed in some SCI patients who recover function. Posterior reorganization may result from a preferential survival of axons that originate in somatosensory cortex and contribute to the corticospinal tract. These preliminary results should be verified by a larger prospective study.

Quantitative MRI of the gray-white matter distribution in traumatic brain injury.

Quantitative analyses were performed on magnetic resonance images (MRIs) obtained from the brains of 31 traumatic brain-injured (TBI) patients and 25 normal control subjects. The quantitative analyses involved comparisons of the shapes of proton density gray scale pixel histograms obtained from both 3-mm and 5-mm slice thickness. Image segmentation was accomplished by a multispectral fuzzy C-means and/or k-nearest-neighbor (kNN) algorithms and manual classification was used to label segmented classes into CSF, white matter, and other. Shape descriptors were derived from the pixel intensity histograms of the combined gray matter and white matter classes for each MRI slice. Statistical analyses revealed significant differences in pixel intensity distributions between TBI and control subjects. Normal control subjects tended to exhibit bimodal gray matter-white matter histograms, whereas, TBI patients tended to exhibit unimodal gray matter-white matter histograms. In the control subjects the pixels intermediate in intensity between gray and white matter were located primarily at the border between the gray and white matter, whereas TBI patients exhibited a thickening of the number of intermediate pixels at the border as well as an increase in intermediate pixels in the middle of the gray and white matter. The greater the severity of TBI, then the larger the number of intermediate intensity pixels within and between gray and white matter. Further analyses demonstrated shifts in magnetic resonance relaxation times in gray and white matter in TBI patients, which suggested that the tendency toward unimodality in TBI patients represents a pathological reduction in brain differentiation due to measurable biophysical change.

Conjunctival impression cytology.

A new technique is presented using impression of the conjunctiva with a plastic device to study the conjunctival response in various conjunctival disease states. When used with a rapid acting stain the impression technique proved to be accurate, reproducible, and nondestructive when compared to the standard spatula scraping of the conjunctiva using Giemsa stain.

Comprehensive predictions of outcome in closed head-injured patients. The development of prognostic equations.

A comprehensive diagnostic evaluation was administered to 162 closed head-injured patients within 1 to 21 days (mean, 7.5 days) after injury. Each evaluation consisted of (1) power spectral analyses of electroencephalogram (EEG) recorded from 19 scalp locations referenced to age-matched norms, (2) brainstem auditory evoked potentials, (3) computed tomography (CT)-scan, and (4) Glasgow Coma Score (GCS) at time of admission (GCS-A) and at time of EEG test (GCS-T). Functional outcome at one year following injury was assessed using the Rappaport Disability Rating Scale (DRS), which measures the level of disability in the six diagnostic categories of (1) eye opening, (2) best verbal response, (3) best motor response, (4) self-care ability for feeding, grooming, and toileting, (5) level of cognitive functioning, and (6) employability. The ability of the different diagnostic measures to predict outcome at one year following injury was assessed using stepwise discriminant analyses to identify patients in the extreme outcome categories of complete recovery versus death and multivariate regression analyses to predict patients with intermediate outcome scores. The best combination of predictor variables was EEG and GCS-T, which accounted for 74.6% of the variance in the multivariate regression analysis of intermediate outcome scores and 95.8% discriminant accuracy between good outcome and death. The best single predictors of outcome in both the discriminant analyses and the regression analyses were EEG coherence and phase. A gradient of prognostic strength of diagnostic measures was EEG phase greater than EEG coherence greater than GCS-T greater than CT-scan greater than EEG relative power. The value of EEG coherence and phase in the assessment of diffuse axonal injury was discussed.