Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

The gut microbiota is associated with psychiatric symptom severity and treatment outcome among individuals with serious mental illness.

BACKGROUND: Emerging evidence implicates the gut microbiota in central nervous system functioning via its effects on inflammation, the hypothalamic-pituitary axis, and/or neurotransmission. Our understanding of the cellular underpinnings of the brain-gut relationship is based almost exclusively on animal models with some small-scale human studies. This study examined the relationship between the gut microbiota and psychiatric symptom severity and treatment response among inpatients with serious mental illness. METHOD: We collected data from adult inpatients (N = 111). Measures of diagnoses, suicide severity, trauma, depression, and anxiety were collected shortly after admission, while self-collected fecal swabs were collected early in the course of hospitalization and processed using 16S rRNA gene sequencing and whole genome shotgun sequencing methods. RESULTS: Results indicate that depression and anxiety severity shortly after admission were negatively associated with bacterial richness and alpha diversity. Additional analyses revealed a number of bacterial taxa associated with depression and anxiety severity. Gut microbiota richness and alpha diversity early in the course of hospitalization was a significant predictor of depression remission at discharge. CONCLUSIONS: This study is among the first to demonstrate a gut microbiota relationship with symptom severity among psychiatric inpatients as well as a relationship to remission of depression post-treatment. These findings are consistent with animal models and limited human studies as well as with the broader literature implicating inflammation in the pathophysiology of depression. These findings offer the foundation for further studies of novel therapeutic approaches to the treatment, prevention of, or recurrence of serious mental illness.

Classifying suicidal behavior with resting-state functional connectivity and structural neuroimaging.

OBJECTIVE: About 80% of patients who commit suicide do not report suicidal ideation the last time they speak to their mental health provider, highlighting the need to identify biomarkers of suicidal behavior. Our goal is to identify suicidal behavior neural biomarkers to classify suicidal psychiatric inpatients. METHODS: Eighty percent of our sample [suicidal (n = 63) and non-suicidal psychiatric inpatients (n = 65)] was used to determine significant differences in structural and resting-state functional connectivity measures throughout the brain. These measures were used in a random forest classification model on 80% of the sample for training the model. RESULTS: The model built on 80% of the patients had sensitivity = 79.4% and specificity = 72.3%. This model was tested on an independent sample (20%; n = 32) with sensitivity = 81.3% and specificity = 75.0% for confirming the generalizability of the model. Altered resting-state functional connectivity features from frontal and middle temporal regions, as well as the amygdala, parahippocampus, putamen, and vermis were found to generalize best. CONCLUSION: This work demonstrates neuroimaging (an unbiased biomarker) can be used to classify suicidal behavior in psychiatric inpatients without observing any clinical features.

Insula and amygdala resting-state functional connectivity differentiate bipolar from unipolar depression.

OBJECTIVE: Distinguishing depressive episodes due to bipolar disorder (BD) or major depressive disorder (MDD) solely on clinical grounds is challenging. We aimed at comparing resting-state functional connectivity (rsFC) of regions subserving emotional regulation in similarly depressed BD and MDD. METHOD: We enrolled 76 in-patients (BD, n = 36; MDD, n = 40) and 40 healthy controls (HC). A seed-based approach was used to identify regions showing different rsFC with the insula and the amygdala. Insular and amygdalar parcellations were then performed along with diagnostic accuracy of the main findings. RESULTS: Lower rsFC between the left insula and the left mid-dorsolateral prefrontal cortex and between bilateral insula and right frontopolar prefrontal cortex (FPPFC) was observed in BD compared to MDD and HC. These results were driven by the dorsal anterior and posterior insula (PI). Lower rsFC between the right amygdala and the left anterior hippocampus was observed in MDD compared to BD and HC. These results were driven by the centromedial and laterobasal amygdala. Left PI/right FPPC rsFC showed 78% accuracy differentiating BD and MDD. CONCLUSION: rsFC of amygdala and insula distinguished between depressed BD and MDD. The observed differences suggest the possibility of differential pathophysiological mechanisms of emotional dysfunction in bipolar and unipolar depression.

Time-dependent changes in nicotine behavioral responsivity during early withdrawal from chronic cocaine administration and attenuation of cocaine sensitization by mecamylamine.

Cocaine abuse is associated with a high prevalence of nicotine dependence. In animals, nicotinic antagonists have been reported to block the development of cocaine behavioral sensitization and to attenuate cocaine place preference or self-administration. In the present study, we have determined: (1) changes in the locomotor responses to nicotine challenge during the first week of withdrawal from daily cocaine pretreatment; and (2) effects of the non-selective nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine given during the first 5 days of cocaine withdrawal on the maintenance of cocaine behavioral sensitization. Male Sprague-Dawley rats were pretreated with daily saline (SI) or cocaine (CI) injections for 14 days. In Experiment 1, separate animals in the SI and CI groups received a single nicotine challenge on day 1, 3, or 7 of withdrawal from their respective pretreatments. The CI group displayed enhanced locomotor responses to nicotine as compared to SI controls on days 3 and 7 of withdrawal, but not day 1. In Experiment 2, SI and CI animals were treated once a day with either saline or mecamylamine during the first 5 days of withdrawal, and were subsequently challenged with single cocaine injections on both withdrawal days 7 and 14. Mecamylamine treatment significantly attenuated expression of cocaine behavioral sensitization on both withdrawal days 7 and 14. Time-dependent changes in nicotinic responses occur during the first week of cocaine withdrawal, and intact nAChR neurotransmission during this period may be necessary for maintenance of cocaine behavioral sensitization.

A qualitative and quantitative assessment of the impact of three processing algorithms with halving of study count statistics in myocardial perfusion imaging: filtered backprojection, maximal likelihood expectation maximisation and ordered subset expectation maximisation with resolution recovery.

INTRODUCTION: Ordered subset expectation maximisation with depth-dependent resolution recovery (OSEM-RR) is a processing algorithm reported to improve images with halved tracer activity in myocardial perfusion scintigraphy (MPS) compared to filtered backprojection (FBP) using conventional activities. OSEM-RR has not yet been compared with maximal likelihood expectation maximisation (MLEM). METHODS: 39 patients undergoing MPS and two anthropomorphic phantoms (one with, one without an inferior wall insert) had full-time (FT) and half-time (HT) SPECT datasets acquired simultaneously and processed by FBP, MLEM and OSEM-RR. Two experienced reporters scored images of all clinical studies (n=234) for conspicuity of a perfusion defect, with results being compared using Wilcoxon paired and Kappa tests. A quantitative assessment based on mean segmental pixel counts taken from numbers automatically displayed over the 20 segments of Cedars Sinai Autoquant QPS image were compared using Pearson's correlation and Bland Altman analysis. RESULTS: A small but consistent superior concurrence between FT and HT datasets for OSEM-RR compared to FBP and MLEM was observed for both qualitative and quantitative analyses. OSEM-RR resulted in better definition of the inferior wall defect on the phantom study. CONCLUSION: OSEM-RR appears superior to both FBP and MLEM in terms of handling reduced count statistics.

A pilot study of dual-isotope lymphoscintigraphy for breast sentinel node biopsy comparing intradermal and intraparenchymal injection.

AIMS: Identification of sentinel lymph nodes (SLN) may depend on the tissue plane of tracer injection. To explore this, we developed a dual-isotope technique to compare the lymphatic drainage basins accessed by intradermal and parenchymal injections. METHODS: Fifteen breast cancer patients had simultaneous parenchymal and intradermal injections of (99m)Tc-labelled human immunoglobulin G (HIG) and (111)In-HIG, respectively, 2-4h before axillary lymph node clearance surgery. All 228 freshly dissected nodes were assayed by well counting and examined for metastatic disease by haematoxylin/eosin staining and immuno-histochemistry. RESULTS: Total nodal uptake following intradermal injection was 10 times more than after parenchymal injection. Tracer uptake within the first three draining nodes divided patients into three groups; four (group 1) had identical 1st, 2nd and 3rd echelon nodes, six (group 2) had identical 1st and 2nd echelon nodes and five (group 3) had different 1st echelon nodes. With respect to the first, second and third groups, there was close, moderate and poor correlation (Pearson), respectively, between individual nodal counts accumulated from the two injection sites. Of eight patients with nodal disease, the SLN identified by intradermal and parenchymal injections contained disease in seven and four patients, respectively. CONCLUSIONS: Comparison of nodal tracer distributions from the two injection planes allows a functional model to be developed with two possible routes of drainage from the parenchymal plane, one joining the tract from the areolar plexus and the other passing independently to the axilla which builds upon Sappey's original anatomical model. This may explain the variable uptake, discordance and false negative SLN identification.

A simple processing method allowing comparison of renal enhancing volumes derived from standard portal venous phase contrast-enhanced multidetector CT images to derive a CT estimate of differential renal function with equivalent results to nuclear medicine quantification.

As iodinated contrast medium is cleared by glomerular filtration, it should be possible to apply the same principles utilized in radionuclide studies to derive differential renal function by comparison of enhancing renal volumes derived from contrast enhanced multidetector CT (CEMDCT). Having established a technique iteratively which appeared successful, a retrospective study was performed using 25 consecutive patients with a wide range of urological conditions who had undergone both CEMDCT, including the renal area in the portal venous phase, and nuclear medicine (NM) assessment of renal function with no urological intervention between the studies. Proprietary volume software was used to quantify the volume and attenuation of each kidney, the products of which (after subtraction of soft tissue attenuation derived from a region of interest over psoas) gave right and left enhancing renal volumes. The contribution by each kidney as a percentage of total renal enhancing tissue was derived. Comparison with NM studies resulted in excellent correlation of relative renal function by CEMDCT and NM assessments having a regression of near unity and a Pearson's correlation coefficient of 0.96. Bland Altman and Passing Bablock tests confirmed good agreement between the two methods with no bias. This is a simple, practicable processing technique using standard portal venous phase CEMDCT images to quantify differential function. This technique may allow a one-stop CT assessment of both anatomy and function.

The effect of acute hypoxemia and hypotension on adenosine-mediated depression of evoked hippocampal synaptic transmission.

The present study was designed to investigate the relative contributions of arterial P(O(2)), local cerebral blood flow, and oxygen delivery to the adenosine A(1) receptor-mediated depression of evoked synaptic transmission recorded in the rat hippocampus. Urethane-anesthetized rats were given a unilateral common carotid artery occlusion and then placed in a stereotaxic apparatus for stimulation and recording of bilateral hippocampal field excitatory postsynaptic potentials (fEPSPs). Arterial blood gases, mean arterial blood pressure (MAP), and bilateral hippocampal blood flow (HBF) were also measured. Arterial P(O(2)), HBF, and oxygen delivery were manipulated using normoxic hypotension, hypoxic hypotension, and hypoxic normotension. Both hypoxic hypotension and normoxic hypotension resulted in decreased HBF, decreased oxygen delivery, and a depression of the evoked fEPSP limited to the hippocampus ipsilateral to the occlusion. The enhanced HBF and oxygen delivery associated with increased MAP resulted in a restoration and maintenance of hippocampal fEPSPs despite sustained hypoxemia. The adenosine A(1) receptor-mediated depression of the fEPSP was more strongly correlated with changes in HBF and oxygen delivery than with arterial P(O(2)). We propose that adenosine plays an important role mediating the depression of neuronal activity associated with reduced oxygen delivery characteristically observed in ischemic brain tissue.

Systemic hypoxia and the depression of synaptic transmission in rat hippocampus after carotid artery occlusion.

The relationship between step reductions in inspired oxygen and the amplitude of evoked field excitatory postsynaptic potentials (fEPSPs) recorded from hippocampal CA1 neurons was examined in anaesthetized rats with a unilateral common carotid artery occlusion. The amplitudes of fEPSPs recorded from the hippocampus ipsilateral to the occlusion were significantly more depressed with hypoxia than were the fEPSPs recorded from the contralateral hippocampus. The adenosine A1-selective antagonist, 8-cyclopentyl-1,3-dimethylxanthine (8-CPT), blunted the hypoxic depression of the fEPSP. Tissue partial pressure of oxygen (Ptiss,O2) was measured in the ipsilateral and contralateral hippocampus using glass Clark-style microelectrodes. Ptiss,O2 fell to similar levels as a function of inspired oxygen in the ipsilateral and contralateral hippocampus, and in the ipsilateral hippocampus after administration of 8-CPT. Hippocampal blood flow (HBF) was measured using laser Doppler flowmetry. A decline in HBF was associated with systemic hypoxia in both hippocampi. HBF, as a function of inspired oxygen, fell significantly more in the ipsilateral than in the contralateral hippocampus. We conclude that endogenous adenosine acting at the neuronal A1 receptor plays a major role in the depression of synaptic transmission during hypoxic ischaemia. The greater susceptibility of the fEPSP in the ipsilateral hippocampus to systemic hypoxia cannot be explained entirely by differences in Ptiss,O2 or HBF between the two hemispheres.

Cytokeratin immunophenotyping of an unusual cervical vertebral chordoma with extensive chondroid foci and perilaryngeal recurrence: a case report with review of the literature.

Chordomas are midline, slowly growing, and locally destructive tumors derived from vestigial remnants of the notochord. We present an unusual case of a cervical vertebral chordoma with extensive chondroid change that aggressively recurred in the anterior larynx and surrounding neck structures, and subsequently in the mediastinum, resulting in the death of the patient. Recent literature has investigated and debated the significance of chondroid elements in chordomas as a differential diagnostic and a prognostic indicator. In particular, the use of immunohistochemical stains for cytokeratin and mesenchymal markers in these areas as a means of distinguishing true from pseudocartilage has received much attention. In this study, we used a spectrum of cytokeratin subtypes (CK 7, 20, 5/6, AE1/3) to further characterize these chondroid areas, and observed that they were positive for the majority of the cytokeratin subtypes, suggesting pseudo, rather than true, cartilaginous change. Clinicopathologic features of this lesion and the recent literature are reviewed.

Convergent validity of Rorschach and TAT scales of object relations.

The Rorschach Mutuality of Autonomy Scale (MOA) and the Social Cognition and Object Relations Scale (SCORS) have been shown to be reliable and valid measures of interpersonal functioning. Utilizing a sample of 57 outpatients with a Diagnostic and Statistical Manual of Mental Disorders Axis II diagnosis, this study extends the findings of previous research demonstrating the reliability and convergent validity of each measure. Analyses focused on the convergent validity between the Rorschach MOA Scale and 8 SCORS variables (complexity, affect, emotional investment in relationships, emotional investment in values and morals, understanding of social causality, management of impulses/aggression, self-esteem, identity/coherence of self) ratings of Thematic Apperception Test narratives. The conceptual nature and clinical utility of these findings are discussed in relation to psychological assessment.

The Rorschach Suicide Constellation: assessing various degrees of lethality.

In this article we examine the relation between the Rorschach Comprehensive System's Suicide Constellation (S-CON; Exner, 1993; Exner & Wiley, 1977) and lethality of suicide attempts during the course of patients' hospitalization at the Austen Riggs Center (Stockbridge, MA). Patient records were rated as nonsuicidal (n = 37), parasuicidal (n = 37), or near-lethal (n = 30) based on the presence and lethality of self-destructive acts. Diagnostic efficiency statistics utilizing a cutoff score of 7 or more positive indicators successfully predicted which patients would engage in near-lethal suicidal activity relative to parasuicidal patients (overall correct classification rate [OCC] = .79), nonsuicidal inpatients (OCC = .79), and college students (OCC = .89). Although these predictions were influenced by relatively high base rates in the hospital population (14.5%), base rate estimates were calculated for other hypothetical populations revealing different prediction estimates that should be considered when judging the relative efficacy of the S-CON. Logistic regression analysis revealed that an S-CON score of 7 or more was the sole predictor of near-lethal suicide attempts among 9 psychiatric and demographic variables.

An empirical study of seriously disturbed suicidal patients.

Aspects of unconscious processes in a group of seriously disturbed psychiatric patients are examined in an effort to predict near-lethal suicide attempts and explore psychoanalytic formulations of suicide. The Rorschach Inkblot Test, the most widely used projective measure in suicide research (Bongar 1991), was chosen for its potential to shed light on specific unconscious processes. Psychic states commonly associated with suicide were measured by psychoanalytic Rorschach analog scales and then subjected to a progression of statistical analyses in order to predict future occurrence and lethality of suicide attempts. On the basis of a priori hypotheses, the authors developed a suicide index comprising four psychoanalytic Rorschach signs that predicted, with considerable accuracy, which patients would later make near-lethal suicide attempts. The best predictors were unconscious processes indicative of penetrating affective overstimulation, disturbance in the capacity to maintain adequate ego boundaries, and depressive affective states characterized by a morbid preoccupation with death and inner decay. These findings provide empirical support for several well-known formulations of the unconscious motivations for suicide.

Adenosine induces initial hypoxic-ischemic depression of synaptic transmission in the rat hippocampus in vivo.

The present study was designed to investigate the role of adenosine in the hypoxic depression of synaptic transmission in rat hippocampus. An in vivo model of hypoxic synaptic depression was developed in which the common carotid artery was occluded on one side in the urethane-anesthetized rat. Inspired oxygen levels were controlled through a tracheal cannula. Rats were placed in a stereotaxic apparatus for stimulation and recording of bilateral hippocampal field excitatory postsynaptic potentials. The percent inspired oxygen could be reduced to levels that produced a reversible and repeatable depression of evoked synaptic transmission restricted to the hippocampus ipsilateral to the occlusion. Further reduction in the level of inspired oxygen depressed synaptic transmission recorded from both hippocampi. The adenosine nonselective antagonist caffeine and the A(1) selective antagonist 8-cyclopentyltheophylline prevented the initial depression in synaptic transmission. We conclude that the initial depression of synaptic transmission observed in the rat hippocampus in vivo is due to endogenous adenosine acting at neuronal adenosine A(1) receptors.

Predicting DMS-IV cluster B personality disorder criteria from MMPI-2 and Rorschach data: a test of incremental validity.

Despite their frequent conjoint clinical use, the incremental validity of Rorschach (Rorschach, 1921/1942) and MMPI (Hathaway & McKinley, 1943) data has not been adequately established, nor has any study to date explored the incremental validity of these tests for predicting Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM-IV]; American Psychiatric Association, 1994) personality disorders (PDs). In a reanalysis of existing data, we used select Rorschach variables and the MMPI PD scales to predict DSM-IV antisocial, borderline, histrionic, and narcissistic PD criteria in a sample of treatment-seeking outpatients. The correlational findings revealed alimited relation between Rorschach and MMPI-2 (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) variables, with only 5 of 30 correlations reaching significance (p <.05). Hierarchical regression analyses showed that both the MMPI and Rorschach data add incrementally in the prediction of DSM-IV borderline and narcissistic PD total criteria scores. The findings were less clear for the incremental value of Rorschach and MMPI-2 data in predicting the total number of DSM-IV histrionic PD criteria, which were best predicted by Rorschach data, and antisocial PD criteria, which were best predicted by MMPI-2 data. In addition to providing evidence of the incremental validity of Rorschach data, these findings also shed light on the psychological characteristics of the DSM-IV Cluster B PDs.

Interpersonal dependency and personality pathology: variations in Rorschach Oral Dependency scores across Axis II diagnoses.

Although several investigations have examined the relationship of Rorschach Oral Dependency (ROD; Masling, Rabie, & Blondheim, 1967) scores to Axis I diagnosis, there has been very little research assessing variations in ROD scores across Axis II personality disorders (PDs). In this study, ROD scores were compared in 5 PD groups (borderline PD inpatients, borderline PD outpatients, avoidant-dependent PD outpatients, narcissistic PD outpatients, and antisocial PD outpatients), and 2 non-PD comparison groups (psychotic disorder inpatients and college students). Borderline PD inpatients had significantly higher ROD scores than borderline PD outpatients, antisocial PD outpatients, and college students; no other between-group differences were found. We discuss implications of these results for research on dependency and Axis II psychopathology and offer suggestions for future studies.

Polymorphism of human mucin genes in chest disease: possible significance of MUC2.

Most of the genes that encode epithelial mucins are highly polymorphic due to variations in the length of domains of tandemly repeated (TR) coding sequence, the part of the apomucin that is heavily glycosylated. We report here for the first time a difference in the distribution of MUC TR length alleles in chest disease. We examined the distribution of the length alleles of those MUC genes whose expression we have confirmed in the bronchial tree in an age- and sex-matched series of 50 pairs of atopic patients with and without asthma. There was no significant difference in the distribution of alleles of MUC1, MUC4, MUC5AC, and MUC5B. MUC2, however, showed a highly significant difference in distribution. The atopic, nonasthmatic individuals showed an allele distribution that was very different from all our other patient and control groups, this group showing a longer mean allele length. The observations suggest that longer MUC2 alleles may help protect atopic individuals from developing asthma, though the effect may be due to a linked gene. The biological significance of this variation with respect to susceptibility to asthma will merit further investigation, and it will also be important to substantiate this finding on an independent data set.

Exploring the inner world of self-mutilating borderline patients: a Rorschach investigation.

Psychiatric patients who engage in self-destructive behavior by cutting, burning, or abrading their skin are currently one of the most difficult-to-treat groups in both inpatient and outpatient settings. The complexities of treating these patients, the risk factors associated with this symptom, and the rise in the prevalence of self-mutilation in America's adolescents and young adults provided the impetus for the current study. This article explores aspects of aggression, dependency, object relations, defensive structure, and psychic boundary integrity that may contribute to the genesis and maintenance of self-mutilation. Rorschach protocols from 90 borderline personality-disordered inpatients (48 self-mutilators and 42 non-self-mutilators) were scored using five psychoanalytic content scales. Results indicate that self-mutilating patients exhibit greater incidence of primary process aggression, severe boundary disturbance, pathological object representations, defensive idealization, devaluation, and splitting than did a matched group of non-self-mutilating borderline patients. Clinical theory and technical recommendations are considered in light of the current empirical findings.