Axis II psychopathology in individuals with traumatic brain injury.

PRIMARY OBJECTIVES: To determine the frequency and nature of post-TBI personality disorders (PDs) in a community-based sample of individuals with TBI. RESEARCH DESIGN: One hundred individuals with TBI were administered a structural clinical interview to determine Axis II psychopathology. METHODS OF PROCEDURES: The Structured Clinical Interview for DSM-IV Personality Disorders, Clinician Version (SCID II) was used to determine 12 Axis II personality disorders. SCID II questions were modified so that symptom onset could be rated as occurring pre-injury vs. post-TBI. Data were analysed using student T-tests, chi-square analysis and one way analyses of variance. OUTCOMES AND RESULTS: Pre-TBI PDs were diagnosed in 24% of the sample; antisocial PD and obsessive-compulsive PD were the most common diagnoses. Post-TBI, 66% of the sample met criteria for at least one PD, with PDs independent of TBI severity, age at injury, and time since injury. The most common post-TBI PDs were: borderline, avoidant, paranoid, obsessive-compulsive and narcissistic. Men were more likely to be diagnosed with antisocial PD and narcissistic PD. Individuals with pre-TBI PDs were at greater risk of acquiring additional psychopathology post-TBI. Personality traits endorsed by more than 30% of the sample post-TBI reflected loss of self-confidence, attempts to cope with cognitive and interpersonal failures and negative affect. CONCLUSION: These findings argue against a specific TBI personality syndrome, but rather a diversity of personality disorders reflective of the persistent challenges and compensatory coping strategies developed by individuals post-TBI. Prospective need for clinical assessment, pro-active education and focused treatment approaches are discussed.

Axis I psychopathology in individuals with traumatic brain injury.

OBJECTIVES: To assess the incidence, comorbidity, and patterns of resolution of DSM-IV mood, anxiety, and substance use disorders in individuals with traumatic brain injury (TBI). DESIGN: The Structured Clinical Interview for DSM-IV Diagnoses (SCID) was utilized. Diagnoses were determined for three onset points relative to TBI onset: pre-TBI, post-TBI, and current diagnosis. Contrasts of prevalence rates with community-based samples, as well as chi-square analysis and analysis of variance were used. Demographics considered in analyses included gender, marital status, severity of injury, and years since TBI onset. SETTING: Urban, suburban, and rural New York state. PARTICIPANTS: 100 adults with TBI who were between the ages of 18 and 65 years and who were, on average, 8 years post onset at time of interview. MAIN OUTCOME MEASURES: SCID Axis I mood diagnoses of major depression, dysthymia, and bipolar disorder; anxiety diagnoses of panic disorder, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and phobia; and substance use disorders. RESULTS: Prior to TBI, a significant percentage of individuals presented with substance use disorders. After TBI, the most frequent Axis I diagnoses were major depression and select anxiety disorders (ie, PTSD, OCD, and panic disorder). Comorbidity was high, with 44% of individuals presenting with two or more Axis I diagnoses post TBI. Individuals without a pre-TBI Axis I disorder were more likely to develop post-TBI major depression and substance use disorders. Rates of resolution were similar for individuals regardless of previous psychiatric histories. Major depression and substance use disorders were more likely than were anxiety disorders to remit. CONCLUSION: TBI is a risk factor for subsequent psychiatric disabilities. The need for proactive psychiatric assessment and timely interventions in individuals post TBI is indicated.

The Beck Depression Inventory: is it a suitable measure of depression for individuals with traumatic brain injury?

OBJECTIVE: This study examined the relationship between Beck Depression Inventory (BDI) scores and current diagnosis of depression, based on The Structured Clinical Interview for DSM-IV Diagnosis (SCID). DESIGN: Correlation. SETTING: Community-based sample. PARTICIPANTS: 100 individuals with traumatic brain injury (TBI) participated in this study, 25 of whom were diagnosed as depressed and 75 as not depressed at the time of interview. MAIN OUTCOME MEASURES: BDI scores, number of symptoms reported on a symptom checklist and DSM-IV diagnosis of depression. RESULTS: BDI symptoms correlated significantly with the SCID diagnosis of depression (r = .30) but were more strongly related (r = .67) to the number of non-depression-related problems reported, using the TIRR Symptom Checklist, a list of symptoms frequently found post TBI. The BDI had low sensitivity for discriminating depressed from nondepressed individuals (sensitivity = 36% when specificity was set at 80%). These results suggest that for individuals with TBI, high BDI scores may reflect hyperreactivity to post-TBI symptoms to a greater extent than clinical depression. CONCLUSIONS: Further study is needed to (1) understand the physiological, functional, and psychosocial factors that are associated with depression in individuals with TBI; (2) provide the basis for developing better measures of depression; and (3) understand how depression is experienced after TBI.

Increased numbers of mast cells in human middle ear cholesteatomas: implications for treatment.

HYPOTHESIS: Because many of the biologic phenomena in which mast cells are involved also are observed in human cholesteatoma pathology, the authors hypothesized that mast cells may play a role in this disease. The first test of this hypothesis is to determine whether there are an increased number of mast cells associated with cholesteatomas. BACKGROUND: The molecular and cellular defects that result in the pathologic features observed in acquired and congenital cholesteatomas are unknown. One common feature of cholesteatoma pathogenesis is the presence of bacteria and a numerous inflammatory cytokines expressed by host inflammatory cells. The interactions between inflammatory cells and cholesteatoma epithelium could result in the induction of other aberrant biologic features of cholesteatomas. Thus, it is critical to the understanding of the pathogenesis of cholesteatomas to define the specific role of each cell type involved in this disease. Connective tissue mast cells have a complex retinue of functions mediated via the secretion of a variety of cytokines and proteinases, and many of the biologic phenomena in which mast cells are involved also are observed in cholesteatoma pathology. METHODS: The authors evaluated by immunohistochemistry 36 cholesteatomas of all types (e.g., primary and secondary acquired, recurrent, and congenital) and 23 specimens of normal tissues (e.g., tympanic membrane, canal wall skin, and postauricular skin) for the expression of tryptase, a mast cell-specific protease. RESULTS: Cholesteatomas showed approximately threefold to sevenfold increase in the concentration of mast cells when compared with that of normal tissues. In addition, 19-34% of the mast cells were found within the suprabasal layers of the squamous epithelium of cholesteatoma subgroups, a phenomenon observed only in grossly inflamed tympanic membrane specimens, but not in other control tissues including minimally inflamed tympanic membranes. CONCLUSIONS: The authors conclude from these data that mast cells may represent a previously unrecognized host inflammatory cell, which plays an important role in the development of one or more traits of cholesteatoma pathology.

Expression of p53 protein in human middle ear cholesteatomas: pathogenetic implications.

BACKGROUND: Cholesteatoma is a destructive lesion of the middle ear or mastoid process or both. The molecular and cellular defects that result in the clinical hallmarks of acquired and congenital cholesteatomas, namely invasion, migration, uncoordinated proliferation, altered differentiation, aggressiveness, and recidivism, are unknown. Determining the existence of defects in the normal biology, biochemistry, and genetic complement of the major cellular constituents comprising a cholesteatoma (i.e., fibroblasts and keratinocytes) is critical to the understanding of the pathogenesis of cholesteatomas. It has been speculated that the development of human cholesteatomas is due, in part, to the altered control of cellular proliferation, which tilts the balance toward the aggressive, invasive growth of squamous epithelium within the middle ear. However, whether this altered control is due to defects in the mechanisms and underlying genes that control proliferation, or to cytokines released from infiltrating inflammatory cells, or to some other mechanism is unknown. The nuclear phosphoprotein p53 tumor suppressor gene plays a critical regulatory role in cell cycle control and apoptosis. In the current article, the authors have analyzed congenital, primary and secondary acquired, and recurrent cholesteatomas for the altered expression of p53 and Ki-67, a marker of active proliferation. METHODS: p53 and Ki-67 expression was determined by immunohistochemical assays using specific monoclonal antibodies. RESULTS: The authors' results indicate that p53 is elevated 9- to 20-fold in all cholesteatomas when compared to the expression of p53 in normal postauricular skin or tympanic membrane. However, there is no concomitant increase in Ki-67 expression in cholesteatomas. CONCLUSIONS: These data indicate a defect in cholesteatomas in the mechanisms that p53 engages (i.e., cell cycle control or apoptosis or both). In addition, these data further suggest that there is no intrinsic difference between any clinicopathologic group of cholesteatomas, at least with respect to p53-expression and, presumably, p53 function.

Expression of the mast cell growth factor interleukin-3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: implications for melanoma progression.

The molecular events responsible for tumor progression in human cutaneous malignant melanoma remain unclear; however, critical to the process is the dysregulated proliferation of tumor cells and the development of new vascular channels which allow further growth and dissemination. Connective tissue mast cells (MC) have been implicated in tumor progression because they concentrate around tumors (including melanomas) prior to the formation of new blood vessels, and because they contain many chemical mediators, including basic fibroblast growth factor (bFGF), known to have mitogenic and angiogenic effects. Several MC chemotactic and mitogenic factors have been described including interleukin-3 (IL-3). In order to determine whether there is a differential expression of this MC chemotactic/mitogenic factor with tumor progression in vivo, we evaluated by immunohistochemistry 85 melanocytic lesions including primary invasive malignant melanoma (PIMM), melanoma in situ (MMIS), and ordinary intradermal benign melanocytic nevi (BMN) for expression of IL-3. Nucleic acid in situ hybridization also was used to evaluate the melanocytic lesions for IL-3-specific mRNA transcripts. Intracellular IL-3 protein was detected in 29/33 (88%) PIMM and 15/25 (60%) MMIS, but was not detected in any (0/27; 0%) BMN (p < 0.0001). IL-3-specific mRNA transcripts were present in 3/4 PIMM and 2/10 MMIS in which IL-3 protein was not identified, but were not detected in any BMN. IL-3 mRNA or protein was not detected in normal melanocytes present in the perilesional epidermis of any of the specimens studied. Immunohistochemistry also was used to confirm the presence of IL-3 alpha-specific receptors on human cutaneous MC. As demonstrated by others, a significantly increased number of MC was present in the perilesional stroma of PIMM and MMIS vis a vis BMN (p < 0.0001). The results suggest that melanoma cells may attract MC in vivo by producing MC chemotactic/mitogenic factors such as IL-3. The recruitment of MC and the subsequent release of their potent mitogenic and angiogenic factors such as bFGF may thus represent a tumor-host interaction which favors tumor progression. Reed JA, McNutt NS, Bogdany JK, Albino AP. Expression of the mast cell growth factor interleukin-3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: implications for melanoma progression.

Differential expression of CD44 in malignant cutaneous epithelial neoplasms.

The CD44 antigen (ECMRIII, Hermes antigen) is a highly glycosylated cell-surface polypeptide involved in diverse cellular functions, including cell adhesion and lymphocyte-homing receptor activity. CD44 is also expressed in vivo by several tumors, including astrocytomas, meningiomas, and colonic adenocarcinomas. In addition, it has been shown that expression of CD44 appears to confer metastatic potential to cell lines derived from certain adenocarcinomas. In the skin, CD44 is normally expressed in epidermal keratinocytes and hair follicular, sebaceous, and eccrine epithelial cells. However, there have been few data with regard to the expression in vivo of CD44 in primary cutaneous neoplasms. Furthermore, there have not been studies in vivo of the possible differential expression of CD44 in primary versus metastatic tumors in the skin. We have examined by immunohistochemistry the expression of CD44 in cutaneous invasive and metastatic squamous cell carcinomas, metastatic adenocarcinomas, and basal cell carcinomas. All invasive and metastatic squamous cell carcinomas, as well as metastatic adenocarcinomas, strongly expressed CD44; however, basal cell carcinomas were nonreactive or showed only focal, minimal reactivity. Adjacent normal skin demonstrated CD44 immunoreactivity throughout the epidermis, including the basal layer. In addition, hair follicles and sebaceous and eccrine glands expressed CD44. The results suggest that expression of CD44 in these cutaneous epithelial tumors is not related to malignant transformation, but instead may be related to tumor progression and the ability to metastasize.

p53 expression is rare in cutaneous melanomas.

Alterations in the tumor-suppressor gene p53 are common in many types of human malignancies, but the potential role of p53 in the pathogenesis of cutaneous melanoma is controversial. The gene product, p53 protein, is normally present in very small amounts in noncancerous tissues. Missense mutations lead to accumulation of mutant p53 in the cells, which makes it detectable immunohistochemically in many cancers. Formalin-fixed, paraffin-embedded sections of 14 primary invasive melanomas, 3 cutaneous melanoma metastases, and 10 predominantly intradermal melanocytic nevi were reacted with a panel of three anti-p53 monoclonal antibodies (mAbs) (PAb240, PAb1801, and DO7) and a mAb against Ki-67 (MIB-1), a marker of cellular proliferation. p53 was not detected in morphologically normal epidermal melanocytes or nevus cells. A single primary invasive melanoma, having a very high index of proliferation (Ki-67 expression in > 50% of cells), had diffuse nuclear labeling with all three anti-p53 mAbs used. Abnormalities of p53 expression occur rarely in cutaneous melanomas, but overexpression of p53 may occur in a subset of melanomas with a high index of proliferation.

Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression.

Sporadic and familial malignant melanoma susceptibility has been linked to defects in the chromosomal region 9p21. Recently, a putative 9p21 tumor suppressor gene, the cyclin dependent kinase inhibitor 2 (CDKN2) or p16 gene, has been shown to be deleted, mutated, or rearranged in a high percentage of sporadic melanoma cell lines, as well as mutated in the germline of a proportion of familial melanoma patients. CDKN2 encodes a M(r) 16,000 protein (p16) that plays a key role in cell cycle control by binding to the cyclin-dependent kinase 4 enzyme and inhibiting its ability to phosphorylate critical substrates necessary for transition past the G1 phase of the cell cycle. Thus, mutations or deletions of the CDKN2 gene could result in abnormal proliferation via defective cell cycle control. The correlation of 9p21 cytogenetic and molecular alterations with the clinical stages of melanoma progression suggests that dysfunction of a gene within this chromosomal region is critical to the evolution of melanoma. However, it remains unclear whether this gene is the CDKN2 gene. If so, then loss of p16 is potentially an initiating or early event in melanoma progression. To address the issues of what is the potential involvement of the CDKN2 gene in sporadic melanoma and precisely when during the clinically evident stages of melanoma progression defects in CDKN2 occur, we have evaluated by immunohistochemistry the expression of p16 protein in 103 melanocytic lesions representing all stages in the progression of melanoma. Our results suggest that loss of p16 protein expression is (a) not necessary for tumor initiation in malignant melanoma because all melanomas in situ and the majority of primary invasive melanomas retain expression of this protein; and (b) potentially more related to invasiveness or the ability to metastasize, because 52% of primary invasive tumors and 72% of metastatic lesions show partial or complete loss of expression of p16.