Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error.

BACKGROUND: Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. METHODS: Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. RESULTS: Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. CONCLUSIONS: Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.

Depression in adults with intellectual disability: symptoms and challenging behaviour.

BACKGROUND: Psychiatric evaluation of adults with intellectual disability (ID) remains complex because of limitations in verbal abilities, atypical clinical presentation and challenging behaviour. This study examines the clinical presentation of adults with depression compared with bipolar disorder, anxiety disorders and non-psychiatric control patients. METHOD: This study is a retrospective record review of the initial psychiatric diagnostic evaluation for 300 adult patients with ID drawn from a clinic population. Patients with major depression (n = 85) were compared with those with bipolar disorder (n = 70), anxiety disorders (n = 30) and control patients without psychiatric disorder (n = 27). Key symptoms of depression assessed during the interview were examined as well as challenging behaviour. RESULTS: Three symptoms were useful in differentiating depressed patients from all other groups: sad mood, crying, and anhedonia. Withdrawal, suicidality, and awakening during the night were significant compared with anxiety patients and controls; however, few patients reported suicidality. Bipolar patients were significantly different from depressed patients for elevated mood, acute anger episodes, increase in verbalization, pressure of speech, talk of sexual themes, increase in appetite and poor concentration. Anxiety patients had more fearfulness without withdrawal, sad mood, crying, anhedonia and suicidality. Challenging behaviour was most pronounced in bipolar patients; for depressed patients, aggression and impulsivity were significant compared with anxiety patients and controls. Overall, the control patients presented with few symptoms in any category. CONCLUSIONS: Sad mood, crying and anhedonia are key significant features of depression. Most patients with ID cannot meet the required number of DSM criteria or suggested DM-ID adapted criteria for major depression. Many depressive symptoms were reported in modest numbers and this was probably related to deficiencies in self-report or observational skills of caregivers. Challenging behaviour is not diagnostically specific. It is, however, a key atypical feature of depression.

Do the mentally retarded suffer from affective illness?

Twenty-five published reports were reviewed regarding the occurrence of affective illness, ie, depression and mania, in mentally retarded individuals, using the DSM-III criteria to assess the validity of both diagnoses. Individuals with mental retardation (MR) were found to manifest the full range of affective disorders. Developmentally impaired social functioning and intelligence influence the clinical presentation, but not the development, of affective symptomatology. Affective disorder diagnoses can be made for patients with all levels of MR severity. In individuals with MR of mild and moderate severity, the diagnosis can be made using standard DSM-III criteria. For those with severe and profound MR, a clinically useful diagnosis can be based on changes in behavior and vegetative functioning, as well as family history of affective illness. The psychiatrically symptomatic person with MR should always be evaluated for affective symptomatology and be considered as a candidate for the full range of treatments, including psychotherapy and pharmacotherapy with antidepressants as well as lithium carbonate.

Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS)

We describe the clinical effects of cholesterol supplementation in 6 children with the RSH-"Smith-Lemli-Opitz" syndrome (SLOS). The children ranged in age from birth to 11 years at the onset of therapy, with pretreatment cholesterol levels ranging from 8 to 62 mg/dl. Clinical benefits of therapy were seen in all patients, irrespective of age at onset of treatment, or severity of cholesterol defect. Effects of treatment included improved growth, more rapid developmental progress, and a lessening of problem behaviors. Pubertal progression in older patients, a better tolerance of infection, improvement of gastrointestinal symptoms, and a diminution in photosensitivity and skin rashes were also noted. There were no adverse reactions to treatment with cholesterol. This preliminary study suggests that cholesterol supplementation may be of benefit to patients with the SLOS.

Anorexia nervosa and mental retardation: a case report.

This is the first published report of a retarded individual developing anorexia nervosa. The authors discuss the interaction between subnormal intelligence and the presentation of anorexic symptomatology. They also discuss the relationship between this disorder and depression. Anorexia nervosa may not be uncommon in retarded adolescents but may go undiagnosed because of the belief that mentally retarded individuals do not develop this disorder.

Two cases of suicide attempt by patients with Down's syndrome.

This report documents cases of suicide attempts by two persons with Down's syndrome. The patients experienced dysphoric affect and feelings of hopelessness about unmet needs associated with their disability. During the course of a major depressive episode, each individual made a suicide attempt that could have been fatal. Although suicidal ideation and attempts are infrequent among patients with mental retardation, completed suicides and potentially fatal attempts have been reported. It is vitally important that mental health practitioners appreciate the seriousness of suicidal ideation among persons who have mental retardation and treat the underlying psychiatric disorder.

Six cases of patients with mental retardation who have antisocial personality disorder.

Evidence that antisocial personality disorder occurs in association with mental retardation is presented through case reports of six mildly to moderately retarded men who received a diagnosis of antisocial personality disorder. The men were identified when referred by care providers for more thorough psychological and psychiatric assessments. Their histories were marked by thefts, rapes, multiple assaults, arson, and other predatory acts; a lack of remorse for such actions; criminal charges; and predisposing factors such as an impoverished family. Only one man had received the diagnosis of antisocial personality disorder before the assessments, suggesting that clinicians are reluctant to find sociopathic behavior clinically significant in the presence of mental retardation.

Individual psychotherapy with mentally retarded individuals: a review and call for research.

Although most mental health professionals doubt the capacity of mentally retarded patients to benefit from psychotherapy, a review of case studies, writings, and research revealed that mentally retarded patients responded positively to treatment. Practitioners familiar with this population developed six major recommendations for adapting psychotherapeutic approaches to mentally retarded patients. In order for therapy to be successful, it is recommended that clinicians adapt standard technique to the patient's cognitive level, be directive in approach, be flexible during therapy, engage significant others in the therapeutic process, carefully manage transference and countertransference issues, and directly address the issue of mental retardation as a disability. The results of three research studies suggested that mentally retarded patients benefit from psychotherapy, although a fourth study showed negative results. There is a great need for systematic research to develop a knowledge base to support the growing applications of psychotherapeutic methods to this population.

Language and learning disorders of older boys with Duchenne muscular dystrophy.

The IQs of 25 males with Duchenne muscular dystrophy were determined and the results were pooled with those for 76 others reported in the literature to examine the relationship between IQ and age. Verbal IQ was significantly lower than Performance IQ among the younger boys, but not the older. The distribution of Verbal IQ of the older boys was bimodal, suggesting that a verbal deficit persists in some cases. Detailed examination of the cognitive and reading skills of 15 older patients revealed a similar pattern of deficient phonological processing and reading skills in about half of this group.

Neuropsychological testing and survey forms to indicate possible loss of neurological functioning.

Thirty spina bifida-hydrocephalic patients susceptible to changes in intracranial pressure and/or in spinal cord involvement underwent systematic surveillance of neurological, neuropsychological and behavioural status for up to two years. Behavioural status was monitored monthly through survey forms completed by direct caretakers while a neuropsychological battery was administered every three months. Patients were also followed in a Spina Bifida Clinic and definitive diagnosis of neurological change was determined through standard medical techniques. Analysis of results indicate that behavioural changes are often observed by direct caretakers and neurologists without occurrence of definitive neurological change. In contrast, the neuropsychological assessment revealed a group of reproducible measures that remain stable during periods of non-definitive neurological change. The neuropsychological measures provide quantitative information on the subjects' neurological function. This information can be used for comparison purposes after a period of stable neurological functioning has occurred.

Patients with and without intellectual disability seeking outpatient psychiatric services: diagnoses and prescribing pattern.

BACKGROUND: The present study examined the presenting problem of psychiatric outpatients, and resulting diagnostic and prescribing patterns, comparing patients with intellectual disability (ID) with non-ID (N-ID) patients seen in the same clinic. METHODS: This study was a retrospective medical chart review of information in the first psychiatric diagnostic evaluation for the most recent 100 adult patients with mild ID, 100 patients with moderate, severe or profound ID, and 100 matching N-ID patients. RESULTS: There were significant differences in rates of medical illness, disabilities, history of marriage, children, independent living, and family history of psychiatric and neurological disorders. Individuals with ID were more likely to present with aggression, self-injurious behaviour or physical complaints, whereas N-ID subjects presented more frequently with depression and anxiety complaints. For all groups, depressive disorders were the most frequent class of diagnoses. For those with ID, antipsychotics were used in 32% of subjects, with mood stabilizers in 28% and antidepressants in 27%. The N-ID subjects were most frequently prescribed antidepressants (40%) and anxiolytics (22%). Polypharmacy did not differ significantly among groups. CONCLUSIONS: Psychiatric practitioners relied on the diagnostic examination to formulate their diagnosis, whereas the chief complaint reflected the view of caregivers of the subjects with ID. In contrast to previous studies, outpatient providers frequently diagnosed depression, and the prescribing pattern showed increased usage of antidepressants and mood stabilizers.

Comparison of spina bifida, hydrocephalic patients and matched controls on neuropsychological tests.

Thirty adolescents with spina bifida and hydrocephalus were matched for age and I.Q. with thirty controls of different aetiology. A battery of eleven neuropsychological measures including the Wechsler Intelligence Scale, conceptual and planning skills, simple motor speed, simple tactile sensitivity, complex motor skill and complex tactile perception were administered to both groups. The index subjects differed from the controls in having a greater difference between verbal and performance I.Q., better complex motor skills, and slower left hand finger tapping speed. A step-wise multiple linear regression analysis correctly identified 80% of the subjects using the above three measures as the discriminating variables.