How antipsychotics work: the patients' perspective

BACKGROUND: While much is known about the neuropharmacology and objective efficacy of antipsychotics, little is known about how these drugs act on psychosis from the patients' perspective. Most previous studies of the patient's perspective have focused on drug tolerability and acceptability-rather than their effects on psychosis per se. METHODS: The authors examined how antipsychotics work from a patient's perspective by analyzing their responses to a subjective questionnaire. Ninety-one patients with schizophrenia (cross-sectional component) and eight neuroleptic na?ve patients (before and after treatment, longitudinal component) participated. The patients' responses to the questionnaire were analyzed using Principal Component Analysis (PCA) and general linear models. RESULTS: Analysis of the patients' responses showed that from their perspective the drugs were substantially more effective in: "help deal, help stop thinking, and make the symptoms not bother" rather than "take away" or "change my mind". This differentiation was clear in the raw data and was supported by a formal PCA. Two underlying factors-the first termed detachment and second eradication-explained 71% of the variance in the patients' perspective on how antipsychotics work for them. Neuroleptic na?ve patients, who had no prior exposure, expected drugs to help with both detachment and eradication, but, changed their mind with just 6 weeks of experience with the medications. CONCLUSIONS: From the patients' perspective the action of antipsychotics is best characterized by a detachment from symptoms-rather than an eradication or elimination of symptoms. They have more wide-ranging expectations prior to antipsychotic exposure, but, even 6 weeks of exposure is sufficient to change their mind in favor of detachment. This finding is consistent with some of the very earliest ideas that antipsychotics produced a state of "indifference" and is also consistent with the more recent, neurobiologically informed notions that antipsychotics work by dampening the salience of psychotic symptoms.     

The impact of personality on symptom expression in obsessive-compulsive disorder

Previous research conducted on the five-factor model of personality (FFM) in obsessive-compulsive disorder (OCD) has demonstrated that community and clinical participants score significantly higher than controls on the domains and facets of neuroticism and extraversion and selective facets of agreeableness and conscientiousness. However, studies have yet to examine the extent to which personality traits, as assessed by the FFM, are associated with the specific symptoms of OCD. The purpose of this study was to examine further the personality predictors of obsessive-compulsive symptoms in clinical participants using the facets of the FFM. Patients with a DSM-IV diagnosis of OCD (N = 56) completed the Revised NEO Personality Inventory, the Yale Brown Obsession Compulsion Scale, and the Beck Depression Inventory. Lower scores on openness to ideas were uniquely associated with greater obsession severity, whereas lower openness to actions was uniquely associated with greater compulsive severity. In contrast with past research that has emphasized the association between neuroticism and extraversion and dimensionally rated obsessive-compulsive symptoms, this study demonstrates the specific associations between selective facet traits of openness and clinical obsessions and compulsions. Whereas tendencies toward negative affectivity may confer a nonspecific vulnerability to the development of OCD, facets of openness may impact on the particular expression and severity of obsessive-compulsive symptoms.     

Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of (125)I-AngI to (125)I-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 +/- 2.9 fmol AngII/min/ micro g protein with a mean maximal conversion of 55% +/- 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell-associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell-initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression.     

Familial Cervical Cancer: Case Reports,Review and Clinical Implications

We report three Dutch families with familial clustering of (pre)neoplastic cervical disease, review the literature on familial risks of cervical intraepithelial neoplasia (CIN) and cervical cancer, and discuss possible practical guidelines for women with a family history of cervical cancer. Daughters and sisters of women with cervical cancer have been reported to have a relative risk of 1.5-2.3 to develop this type of cancer. From a practical clinical point of view, we suggest that as in women with an increased non-genetic risk to develop cervical cancer (e.g. because of immunosuppressive therapy) increased surveillance to detect this tumour should be considered in women with an increased risk based on family history. Cessation of smoking should be advised. As the use of condoms at least prevents HPV re-infection its use can be recommended as a way to lower the cervical cancer risk. Future studies to determine the genetic contribution to the development of cervical cancer should include the paternal family history of cancer and, because genetic predisposition might express itself as a higher risk to develop precursors of cervical cancer, carcinoma in situ and CIN grade II-III.     

Multifocal osteolysis with nephropathy

A patient with progressive osteolysis of the carpal and tarsal bones with glomerulonephritis of unusual severity is described. There was a notable absence of osteodystrophy in this and other reported cases who had chronic renal failure.     

Human fibroblast tissue factor is inhibited by lipoprotein-associated coagulation inhibitor and placental anticoagulant protein but not by apolipoprotein A-II

Studies of proteins that inhibit tissue factor activity have generally been conducted using either an extracted tissue homogenate ("thromboplastin") or tissue factor protein reconstituted into phospholipid vesicles rather than with tissue factor expressed in cell membranes (its physiological environment). In the present study, a human fibroblast cell strain was used to evaluate the effects of lipoprotein associated coagulation inhibitor (LACI), placental anticoagulant protein (PAP), and apolipoprotein A-II (apo A-II) on human tissue factor in cell membranes. LACI was tested from 7.8 to 500 pmol/L on fibroblasts cultured at cell densities ranging from 3,500 to 9,925 cells/well, and caused a progressive inhibition of tissue factor activity. PAP was tested from 3.9 nmol/L to 1 mumol/L at cell densities ranging from 4,500 to 15,400 cells/well and caused up to 83% inhibition of tissue factor activity. Inhibition by these proteins appeared to be influenced by cell density as well as whether the cells were intact or disrupted. Apo A-II, up to 1 mumol/L, did not inhibit the tissue factor activity of intact or disrupted fibroblasts at any cell density examined even though it did inhibit the activity of tissue factor in phospholipid vesicles. Of these inhibitors of tissue factor-dependent activation of factor X, LACI was the most effective in suppressing the generation of factor Xa activity. The effects obtained with apo A-II are clearly dependent on the nature of the tissue factor preparation with which it is tested. The disparity between the inhibitory effect of apo A-II on the activity of tissue factor reconstituted into lipid vesicles and the absence of effect on the activity of tissue factor remaining in cell membranes serves to reemphasize the necessity of reexamining results obtained with model systems using as nearly physiological reagents as possible.