Improved speech and language development after unilateral cochlear implantation in children with a potentially useable contralateral ear.

OBJECTIVES: Increasingly, children are considered for a unilateral cochlear implant (CI), even if the contralateral ear falls outside current audiological guidelines, especially if they are not considered to be reaching their educational potential. Here we present the outcomes of CI in children with potentially useable hearing in the contralateral ear. METHODS: A retrospective case note review was performed for a total of 57 patients. Primary outcome was speech and language (SaL) development, as measured by the Manchester Speech and Language Development Scale (MSLDS) and SaL age equivalent. Secondary outcomes were auditory perception, perceived parental benefit and compliance; respectively measured by Categories of Auditory Performance (CAP), Brief Assessment of Parental Perception (BAPP) and reported use. RESULTS: SaL development improved after CI with a mean pre-operative MSLDS score of 5.8 to a postoperative score of 8.0 (n = 57) and a mean SaL age equivalent of 14 months in a one-year period (n = 14). Furthermore, CAP scores improved from 4.9 to 7.0 (n = 57). Analysis of BAPP scores showed improved quality of life in 18/19 patients (94.7%). With regards to compliance, 50/57 (87.7%) are fulltime users of both their CI and their HA. CONCLUSION: The present study indicates that despite one ear having potentially useable hearing outside national audiological criteria, the majority of participants received benefit from a CI in the poorer hearing ear. We suggest that assessment of each ear separately and treatment with the most appropriate amplification device, has given these children a benefit they may not otherwise have acquired if they only had bilateral HA.

Sox2 is dispensable for primary melanoma and metastasis formation.

Tumor initiation and metastasis formation in many cancers have been associated with emergence of a gene expression program normally active in embryonic or organ-specific stem cells. In particular, the stem cell transcription factor Sox2 is not only expressed in a variety of tumors, but is also required for their formation. Melanoma, the most aggressive skin tumor, derives from melanocytes that during development originate from neural crest stem cells. While neural crest stem cells do not express Sox2, expression of this transcription factor has been reported in melanoma. However, the role of Sox2 in melanoma is controversial. To study the requirement of Sox2 for melanoma formation, we therefore performed CRISPR-Cas9-mediated gene inactivation in human melanoma cells. In addition, we conditionally inactivated Sox2 in a genetically engineered mouse model, in which melanoma spontaneously develops in the context of an intact stroma and immune system. Surprisingly, in both models, loss of Sox2 did neither affect melanoma initiation, nor growth, nor metastasis formation. The lack of a tumorigenic role of Sox2 in melanoma might reflect a distinct stem cell program active in neural crest stem cells and during melanoma formation.

Tissue Expression of Aquaporin 2 Is Correlated to Urine Output and Allograft Function in Sensitized Kidney Transplant Patients.

BACKGROUND: Salt and water disturbances often occur during acute kidney allograft dysfunction that contribute to graft failure, but this condition has been poorly investigated in the alloreactivity setting. We evaluated the tissue expression of aquaporins (AQP1 and AQP2) and the epithelial sodium channel (ENAC) in kidney biopsy specimens from sensitized kidney transplant recipients. METHODS: Eighty-six biopsy specimens from 33 sensitized patients were divided into 3 groups according to clinical context: time-zero (n = 9), protocol (n = 9), and indication (n = 68). The indication biopsy specimens were further divided into 3 subgroups according to the presence of acute tubular necrosis or rejection. Normal kidney tissue samples (n = 6) served as the control specimens. Immmunohistochemical expression of AQP1, AQP2, and ENAC was determined by using image analyzing software. RESULTS: Significantly lower AQP1 expression was observed in the time-zero and indication biopsy specimens with rejection compared with control specimens (P = .03 and P = .04, respectively). AQP2 expression was significantly lower in patients with an indication biopsy specimen compared with control and protocol biopsy specimens (P = .05 and P = .005). For ENAC, a lower expression was noted in the indication biopsy specimens compared with the control specimens (P = .04). Both AQP1 and AQP2 tissue expressions were significantly correlated to urine output (r = 0.45 and r = 0.32; P = .001 and P = .02), and AQP2 was correlated with the glomerular filtration rate estimated by using the Modification of Diet in Renal Disease Study equation at biopsy (r = 0.23; P = .05). CONCLUSIONS: These findings partially confirm previous experimental data showing downregulation of AQP1 expression after ischemia/reperfusion injury and during rejection. AQP2 downregulation seems to be rejection-independent, occurring during deteriorating or poor kidney graft function.

Pre-transplant soluble CD30 in combination with total DSA but not pre-transplant C1q-DSA predicts antibody-mediated graft loss in presensitized high-risk kidney transplant recipients.

Presensitized kidney transplant recipients are at high-risk for early antibody-mediated rejection. We studied the impact of pre- and post-transplant donor-specific human leukocyte antigen (HLA) antibodies (DSA) and T-cell-activation on the occurrence of antibody-mediated rejection episodes (AMR) and graft loss (AMR-GL) in a unique cohort of 80 desensitized high-risk kidney transplant recipients. Patients with pre-transplant DSA demonstrated more AMR episodes than patients without DSA, but did not show a significantly increased rate of AMR-GL. The rates of AMR and AMR-GL were not significantly increased in patients with complement split product (C1q)-binding pre-transplant DSA. Pre-transplant C1q-DSA became undetectable post-transplant in 11 of 13 (85%) patients; 2 (18%) of these 11 patients showed AMR but no AMR-GL. In contrast, the post-transplant presence of C1q-DSA was associated with significantly higher rates of AMR (86 vs 33 vs 0%; P < 0.001) and AMR-GL (86 vs 0 vs 0%; log-rank P < 0.001) compared with post-transplant DSA without C1q-binding or the absence of DSA. Patients with both pre-transplant DSA and evidence of pre-transplant T-cell-activation as indicated by soluble CD30-positivity showed a significantly increased risk for AMR-GL [HR = 11.1, 95% confidence interval (CI) = 1.68-73.4; log-rank P = 0.013]. In these high-risk patients, AMR-GL was associated with total DSA in combination with T-cell-activation pre-transplant, and de novo or persistent C1q-binding DSA post-transplant.

A Single-center Experience on the Value of Pancreas Graft Biopsies and HLA Antibody Monitoring After Simultaneous Pancreas-Kidney Transplantation.

BACKGROUND: In simultaneous pancreas-kidney transplantation (SPKT), monitoring of the pancreas allograft is more complex than the kidney allograft due to difficulties in obtaining pancreas histology and weak clinical evidence supporting the role of donor-specific antibodies (DSA). METHODS: We performed a single-center retrospective analysis of all 17 SPKT recipients who underwent a total of 22 pancreas allograft indication biopsies from October 2009 to September 2012. Fifteen patients had at least 2 DSA measurements: pretransplantation and at the time of biopsy. RESULTS: All 7 patients (100%) with post-transplantation DSA-positivity (de novo: n = 6; persistent: n = 1) at biopsy had at least 1 rejection episode either of the pancreas (n = 4) or the kidney (n = 3), with 3 antibody-mediated rejections (AMR). In contrast, only 4 of 8 patients (50%) without post-transplantation DSA had evidence of rejection, with 1 AMR. Findings during pancreas allograft biopsy procedures led to a change of immunosuppressive therapy in 11 of 15 (73%) patients. Patient survival, graft survival, and function were not adversely affected by the presence of post-transplantation DSA. One major and 2 minor procedure-related complications occurred during the pancreas biopsies. CONCLUSIONS: In this small retrospective analysis, pancreas allograft histology provided the most therapeutically relevant information, rather than the kidney histology or DSA monitoring.

Functional but not structural subgenual prefrontal cortex abnormalities in melancholia.

Major depression is a heterogeneous condition, and the search for neural correlates specific to clinically defined subtypes has been inconclusive. Theoretical considerations implicate frontostriatal, particularly subgenual prefrontal cortex (PFC), dysfunction in the pathophysiology of melancholia--a subtype of depression characterized by anhedonia--but no empirical evidence has been found yet for such a link. To test the hypothesis that melancholic, but not nonmelancholic depression, is associated with the subgenual PFC impairment, concurrent measurement of brain electrical (electroencephalogram, EEG) and metabolic (positron emission tomography, PET) activity were obtained in 38 unmedicated subjects with DSM-IV major depressive disorder (20 melancholic, 18 nonmelancholic subjects), and 18 comparison subjects. EEG data were analyzed with a tomographic source localization method that computed the cortical three-dimensional distribution of current density for standard frequency bands, allowing voxelwise correlations between the EEG and PET data. Voxel-based morphometry analyses of structural magnetic resonance imaging (MRI) data were performed to assess potential structural abnormalities in melancholia. Melancholia was associated with reduced activity in the subgenual PFC (Brodmann area 25), manifested by increased inhibitory delta activity (1.5-6.0 Hz) and decreased glucose metabolism, which themselves were inversely correlated. Following antidepressant treatment, depressed subjects with the largest reductions in depression severity showed the lowest post-treatment subgenual PFC delta activity. Analyses of structural MRI revealed no group differences in the subgenual PFC, but in melancholic subjects, a negative correlation between gray matter density and age emerged. Based on preclinical evidence, we suggest that subgenual PFC dysfunction in melancholia may be associated with blunted hedonic response and exaggerated stress responsiveness.

Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms.

BACKGROUND: Although it has been hypothesized that glucocorticoid hypersecretion in depressed patients leads to neuronal atrophy in the hippocampus, magnetic resonance imaging (MRI) -based morphometry studies of the hippocampus to date have produced mixed results. METHODS: In our MRI study, hippocampal volumes were measured in 25 depressed patients (13 with melancholia and 12 without melancholia) and 15 control subjects. RESULTS: No significant differences in hippocampus volumes were found between any of the subject groups, although within subjects right hippocampal volumes were found to be significantly larger than left hippocampal volumes. Additionally, right and total (left + right) hippocampal volumes in control and depressed subjects were found to be positively correlated with trait anxiety as measured by the state/trait anxiety inventory. CONCLUSIONS: Because our subject group is younger than those in studies reporting hippocampal atrophy, we conclude that longitudinal studies will be necessary for investigation of the lifelong course of hippocampal volumetry.

Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis.

OBJECTIVE: The anterior cingulate cortex has been implicated in depression. Results are best interpreted by considering anatomic and cytoarchitectonic subdivisions. Evidence suggests depression is characterized by hypoactivity in the dorsal anterior cingulate, whereas hyperactivity in the rostral anterior cingulate is associated with good response to treatment. The authors tested the hypothesis that activity in the rostral anterior cingulate during the depressed state has prognostic value for the degree of eventual response to treatment. Whereas prior studies used hemodynamic imaging, this investigation used EEG. METHOD: The authors recorded 28-channel EEG data for 18 unmedicated patients with major depression and 18 matched comparison subjects. Clinical outcome was assessed after nortriptyline treatment. Of the 18 depressed patients, 16 were considered responders 4-6 months after initial assessment. A median split was used to classify response, and the pretreatment EEG data of patients showing better (N=9) and worse (N=9) responses were analyzed with low-resolution electromagnetic tomography, a new method to compute three-dimensional cortical current density for given EEG frequency bands according to a Talairach brain atlas. RESULTS: The patients with better responses showed hyperactivity (higher theta activity) in the rostral anterior cingulate (Brodmann's area 24/32). Follow-up analyses demonstrated the specificity of this finding, which was not confounded by age or pretreatment depression severity. CONCLUSIONS: These results, based on electrophysiological imaging, not only support hemodynamic findings implicating activation of the anterior cingulate as a predictor of response in depression, but they also suggest that differential activity in the rostral anterior cingulate is associated with gradations of response.

Six-month test-retest reliability of MRI-defined PET measures of regional cerebral glucose metabolic rate in selected subcortical structures.

Test-retest reliability of resting regional cerebral metabolic rate of glucose (rCMR) was examined in selected subcortical structures: the amygdala, hippocampus, thalamus, and anterior caudate nucleus. Findings from previous studies examining reliability of rCMR suggest that rCMR in small subcortical structures may be more variable than in larger cortical regions. We chose to study these subcortical regions because of their particular interest to our laboratory in its investigations of the neurocircuitry of emotion and depression. Twelve normal subjects (seven female, mean age = 32.42 years, range 21-48 years) underwent two FDG-PET scans separated by approximately 6 months (mean = 25 weeks, range 17-35 weeks). A region-of-interest approach with PET-MRI coregistration was used for analysis of rCMR reliability. Good test-retest reliability was found in the left amygdala, right and left hippocampus, right and left thalamus, and right and left anterior caudate nucleus. However, rCMR in the right amygdala did not show good test-retest reliability. The implications of these data and their import for studies that include a repeat-test design are considered.

Thalamic metabolic rate predicts EEG alpha power in healthy control subjects but not in depressed patients.

BACKGROUND: EEG alpha power has been demonstrated to be inversely related to mental activity and has subsequently been used as an indirect measure of brain activation. The hypothesis that the thalamus serves as a neuronal oscillator of alpha rhythms has been supported by studies in animals, but only minimally by studies in humans. METHODS: In the current study, PET-derived measures of regional glucose metabolism, EEG, and structural MRI were obtained from each participant to assess the relation between thalamic metabolic activity and alpha power in depressed patients and healthy controls. The thalamus was identified and drawn on each subject's MRI. The MRI was then co-registered to the corresponding PET scan and metabolic activity from the thalamus extracted. Thalamic activity was then correlated with a 30-min aggregated average of alpha EEG power. RESULTS: Robust inverse correlations were observed in the control data, indicating that greater thalamic metabolism is correlated with decreased alpha power. No relation was found in the depressed patient data. CONCLUSIONS: The results are discussed in the context of a possible abnormality in thalamocortical circuitry associated with depression.

Metabolic rate in the right amygdala predicts negative affect in depressed patients.

The role of the amygdala in major depression was investigated. Resting regional cerebral metabolic rate (rCMRglu) was measured with [18F]fluorodeoxyglucose positron emission tomography (PET) in two samples of subjects using two different PET cameras. The samples consisted of 10 and 17 medication-free depressives and 11 and 13 controls, respectively. Using coregistration of PET and magnetic resonance images, regions were individually delineated for the amygdala and thalamus, the latter of which was used as a control region. Within the depressed groups, right amygdalar rCMRglu was positively correlated with negative affect. Thalamic rCMRglu was not related to negative affect, and amygdalar rCMRglu accounted for a significant portion of variance in depressives' negative affect scores over and above the contribution of thalamic rCMRglu.

Relations between PET-derived measures of thalamic glucose metabolism and EEG alpha power.

Electroencephalogram (EEG) alpha power has been demonstrated to be inversely related to mental activity and has subsequently been used as an indirect measure of brain activation. The thalamus has been proposed as an important site for modulation of rhythmic alpha activity. Studies in animals have suggested that cortical alpha rhythms are correlated with alpha rhythms in the thalamus. However, little empirical evidence exists for this relation in humans. In the current study, resting EEG and a fluorodeoxyglucose positron emission tomography scan were measured during the same experimental session. Over a 30-min period, average EEG alpha power across 28 electrodes from 27 participants was robustly inversely correlated with glucose metabolic activity in the thalamus. These data provide the first evidence for a relation between alpha EEG power and thalamic activity in humans.

Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.

BACKGROUND AND METHODS: The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter, documented coronary artery disease, and a family history of vascular disease, 120 completed the 2 1/2-year double-blind study, which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice a day) and colestipol (10 g three times a day); niacin (1 g four times a day) and colestipol (10 g three times a day); or conventional therapy with placebo (or colestipol if the low-density lipoprotein [LDL] cholesterol level was elevated). RESULTS: The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes, -7 and +5 percent, respectively), but more substantially among patients treated with lovastatin and colestipol (-46 and +15 percent) or niacin and colestipol (-32 and +43 percent). In the conventional-therapy group, 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent. By comparison, progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent), and regression was more frequent (lovastatin and colestipol, 32 percent; niacin and colestipol, 39 percent; P less than 0.005). Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure, and an increase in HDL cholesterol correlated independently with regression of coronary lesions. Clinical events (death, myocardial infarction, or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy, as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment, 0.27; 95 percent confidence interval, 0.10 to 0.77). CONCLUSIONS: In men with coronary artery disease who were at high risk for cardiovascular events, intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions, increased the frequency of regression, and reduced the incidence of cardiovascular events.

Hospice: social work's response to a new form of social caring.

Social work's response to hospice, as a new form of social caring, is portrayed by a social work process paradigm, conceptualized from the practice and research experiences of the authors. Guidelines are suggested for working with patients, families, care providers, and other concerned persons through the four phases of hospice care. As changes occur in the patient and the hospice settings, the participants join together to bring about a satisfactory fit between the person needing care and the environment. By anticipating the needs and reactions of the terminally ill patient to each transition in the care process, the social worker assists in orchestrating proactive interventions through the continuum of hospice care. Future research studies are recommended for determining what difference social work actions make toward ensuring a "safe passage."

"Safe passage": social work roles and functions in hospice care.

What are social work's unique roles and functions in behalf of patients and their families in hospice care? The question is answered in the first phase of a Joint Research Project of social work faculty, hospice social workers and graduate social work students. The special roles, illustrative functions and potential outcomes of social work in hospice are identified. Case examples are utilized to illustrate social work's response to patients, families, staff and the service network. The authors hypothesize that social workers in hospice and other health care settings are instrumental in charting and facilitating within a nurturing environment a "safe passage" for the person-in-transition.