Family psychiatric morbidity of acute and transient psychotic disorders and their relationship to schizophrenia and bipolar disorder.

BACKGROUND: Although transient psychotic disorders are currently classified as a category separate from schizophrenia (SZ) and affective disorders, their distinctive features remain uncertain. This study examines the family psychiatric morbidity of the ICD-10 category of 'acute and transient psychotic disorders' (ATPDs), pointing out differences from SZ and bipolar disorder (BD). METHOD: From a cohort of 2.5 million persons, we identified all patients enrolled in the Danish Psychiatric Register who were ever admitted with ATPDs (n=2537), SZ (n = 10639) and BD disorder (n=5292) between 1996 and 2008. The relative risk (RR) of ATPDs, SZ and BD associated with psychiatric morbidity in first-degree relatives (FDRs) was calculated as the incidence rate ratio using Poisson regression. RESULTS: The RR of ATPDs [1.93, 95% confidence interval (CI) 1.76-2.11] was higher if patients with ATPDs had at least one FDR admitted with any mental disorder than patients without family psychiatric antecedents. An additional risk arose if they had FDRs admitted not only with ATPDs (RR 1.60, 95% CI 1.33-1.92) but also with SZ (RR 2.06, 95% CI 1.70-2.50) and/or BD (RR 1.55, 95% CI 1.23-1.96). Despite some overlap, the risk of SZ (RR 2.80, 95% CI 2.58-3.04) and BD (RR 3.68, 95% CI 3.29-4.12) was markedly higher if patients with SZ and BD had FDRs admitted with the same condition. CONCLUSIONS: These findings suggest that family psychiatric predisposition has a relatively modest impact on ATPDs and argue against a sharp differentiation of ATPDs from SZ and BD.

Excess mortality of acute and transient psychotic disorders: comparison with bipolar affective disorder and schizophrenia.

OBJECTIVE: To investigate mortality and causes of death of short-lived psychotic disorders, by carrying out a comparison with bipolar disorder and schizophrenia. METHOD: Record linkage study to the official register of causes of death of all cases aged 15-64 years who were listed for the first time in the Danish Psychiatric Register between 1995 and 2008 with an ICD-10 diagnosis of 'acute and transient psychotic disorders' (ATPDs; n = 4157), bipolar disorder (n = 3200) and schizophrenia (n = 4576). RESULTS: A total of 232 patients (5.6%) with ATPDs, 172 (5.4%) with bipolar disorder and 233 (5.1%) with schizophrenia had died over a mean follow-up period of 6.6 years. The standardized mortality ratio for all causes, natural causes and unnatural causes was significantly high for the three conditions. Mortality of ATPDs was greater in men, with about two-thirds of all deaths resulting from natural causes mainly cardiovascular, digestive, neoplastic and respiratory diseases. Suicide was the major cause of premature death in patients with ATPDs. CONCLUSION: These findings suggest that ATPDs are associated with an increased mortality from both natural causes and suicide.

Combined use of positron emission tomography and volume doubling time in lung cancer screening with low-dose CT scanning.

BACKGROUND: In lung cancer screening the ability to distinguish malignant from benign nodules is a key issue. This study evaluates the ability of positron emission tomography (PET) and volume doubling time (VDT) to discriminate between benign and malignant nodules. METHODS: From the Danish Lung Cancer Screening Trial, participants with indeterminate nodules who were referred for a 3-month rescan were investigated. Resected nodules and indolent nodules (ie, stable for at least 2 years) were included. Between the initial scan and the 3-month rescan, participants were referred for PET. Uptake on PET was categorised as most likely benign to malignant (grades I-IV). VDT was calculated from volume measurements on repeated CT scans using semiautomated pulmonary nodule evaluation software. Receiver operating characteristic (ROC) analyses were used to determine the sensitivity and specificity of PET and VDT. RESULTS: A total of 54 nodules were included. The prevalence of lung cancer was 37%. In the multivariate model both PET (OR 2.63, p<0.01) and VDT (OR 2.69, p<0.01) were associated with lung cancer. The sensitivities and specificities of both PET and VDT were 71% and 91%, respectively. Cut-off points for malignancy were PET>II and VDT<1 year, respectively. Combining PET and VDT resulted in a sensitivity of 90% and a specificity of 82%; ROC cut-off point was either PET or VDT indicating malignancy. CONCLUSION: PET and VDT predict lung cancer independently of each other. The use of both PET and VDT in combination is recommended when screening for lung cancer with low-dose CT.

Infection with Prevotella nigrescens induces TLR2 signalling and low levels of p65 mediated inflammation in Cystic Fibrosis bronchial epithelial cells.

Prevotella spp. are frequently identified in Cystic Fibrosis sputum. This study examined whether infection with Prevotella nigrescens, a frequently identified member of this species, contributes to inflammation in CF bronchial epithelial cells through activation of TLR- and NF-κB signalling pathways. CFBE41o- cells were infected with either P.nigrescens or Pseudomonas aeruginosa and incubated under anaerobic conditions for 4h. P.nigrescens activated TLR2 signalling but not TLR4 signalling while P.aeruginosa activated TLR4 signalling with a lesser effect on TLR2. P.aeruginosa induced significant IκBα phosphorylation 10min post infection with a return to control levels by 30min post infection. A significant induction in nuclear p65 DNA binding was observed at 2h post infection. In contrast, infection with P.nigrescens induced phosphorylation of IκBα 120min post infection, with significant induction in nuclear p65 DNA binding at 4h post infection only. Cytokine gene and protein responses were lower for P.nigrescens compared to P.aeruginosa. This study demonstrates the ability of a clinical P.nigrescens isolate to provoke a delayed NF-κB(p65) driven response through induction in TLR2 signalling and activation of sustained levels of IKKα.

Use of robot technology in passive mobilization of acute hospitalized geriatric medicine patients: a pilot test and feasibility study.

BACKGROUND: Along with an aging population, the field of robot technology in rehabilitation is expanding. As new technologies develop, it is important to test these clinically before implementation. To assess the possibilities of undertaking a future randomized controlled trial (RCT), the aim of this study was to pilot test and investigate the feasibility of a newly developed passive mobilization robot device in geriatric medicine patients. METHODS: We used a robot to perform passive mobilization for all recruited patients while they were lying in bed. Inclusion criteria include the following: ≥ 65 years of age, able to walk before hospitalization, and not capable of walking > 2 m at the first day of hospitalization. Exclusion criteria include the following: known moderate/severe dementia, unstable fractures (back, pelvis, or legs), high intracranial pressure, pressure ulcers/risk of developing pressure ulcers due to fragile skin, positive Confusion and Assessment Method (CAM) score, not able to understand Danish, and medical instability. A mixed-methods approach, including structured interviews for patients and relatives, questionnaires and semi-structured interviews for the staff, and observations in the clinic were used as data collection methods. A 6-week pilot test preceded the feasibility study to test study design, safety, interview guide, and setting, and to become familiar with the robot. RESULTS: The pilot test included 13 patients, made the staff confident in the use of the robot, and led to the correction of the interview guide. In the feasibility study, 177 patients were screened, 14 patients (four men, nine women) included, and 13 completed the intervention (median [IQR] age 86 [82-92] years). Overall, the robot was easy to use during passive mobilization and fully accepted by patients and relatives. Staff, however, found the robot difficult to maneuver. No adverse events were reported. CONCLUSIONS: Use of robot technology in passive mobilization of older patients was feasible and well accepted by patients, relatives, and staff. Technical and workflow-related issues, as well as the robot not performing active mobilization, affects the launch of a RCT and thereby its implementation in geriatric medicine patients.

Prediction of radiation-induced mucositis of H&N cancer patients based on a large patient cohort.

PURPOSE/OBJECTIVE: Radiation-induced mucositis is a severe acute side effect, which can jeopardize treatment compliance and cause weight loss during treatment. The study aimed to develop robust models to predict the risk of severe mucositis. MATERIALS/METHODS: Mucosal toxicity scores were prospectively recorded for 802 consecutive Head and Neck (H&N) cancer patients and dichotomised into non-severe event (grade 0-2) and severe event (grade 3+) groups. Two different model approaches were utilised to evaluate the robustness of the models. These used LASSO and Best Subset selection combined with 10-fold cross-validation performed on two-thirds of the patient cohort using principal component analysis of DVHs. The remaining one-third of the patients were used for validation. Model performance was tested through calibration plot and model performance metrics. RESULTS: The main predicted risk factors were treatment acceleration and the first two principal dose components, which reflect the mean dose and the balance between high and low doses to the oral cavity. For the LASSO model, gender and current smoker status were also included in the model. The AUC values of the two models on the validation cohort were 0.797 (95%CI: 0.741-0.857) and 0.808 (95%CI: 0.749-0.859), respectively. The two models predicted very similar risk values with an internal Pearson coefficient of 0.954, indicating their robustness. CONCLUSIONS: Robust prediction models of the risk of severe mucositis have been developed based on information from the entire dose distribution for a large cohort of patients consisting of all patients treated H&N for within our institution over a five year period.

Generic Dry-Contact Ear-EEG.

Generic dry-contact ear-EEG allows for discreet, user-friendly, unobtrusive, cost-effective and convenient recordings of EEG in real-life settings. In this study we introduce a new generic earpiece design with larger internal ear electrode distances, resulting in an increased spatial coverage compared to previous generic earpiece designs. The signal quality of ear-Fpz, within-ear (the measuring and reference electrode located in the same ear) and cross-ear (the measuring electrodes located in one ear and the reference electrode in the opposite ear) electrode configurations of the developed generic earpiece was evaluated with auditory steady-state responses (ASSR) and compared to dry-contact cEEGrid. Ten subjects with different ear sizes were included. The recordings were performed in a sleep setup, where the subjects were lying on a bed and the effect of sleeping position (back vs. sides) was investigated. We found that the generic earpiece attained statistically significant ASSRs with ear-Fpz, within-ear and cross-ear electrode configurations. However, the dry-contact cEEGrid achieved significantly higher average ASSR signal-to-noise ratio (SNR) compared to the generic earpiece. Additionally, this study showed no significant difference between back and side positions for the ear-EEG.

Do we agree about when patients are psychotic?

OBJECTIVE: To investigate into the use of the term 'psychotic' as defined by ICD-10 or by the concept of impaired reality testing, among psychiatric staff members. METHOD: Questionnaire investigation using 11 short case vignettes. RESULTS: Responses were received from 266 psychiatric staff members: psychiatrists, nursing staff and psychologists. When using ICD-10, patients were identified as psychotic with a sensitivity ranging from 90% to 55%. Specificity ranged from 60% to 75%. According to the concept of impaired reality testing, all three groups showed a sensitivity of about 60%, whereas specificity ranged from 65% to 50%. The combined use of the terms correlated significantly with responses regarding indication for legal detention for psychiatrists and nursing staff. CONCLUSION: In identifying a patient as 'psychotic' a broad concept of impaired reality testing was widely used particularly in cases with legal issues. Psychotic symptoms, however, were identified with high sensitivity and specificity.

Induction of cell growth regulatory genes by p53.

Transcriptionally regulated growth-response genes play a pivotal role in the determination of the fate of a cell. p53 is known to transcriptionally regulate genes important in regulating cell growth potential. Using differential reverse transcription-PCR analysis of rat embryo fibroblast cells containing a temperature-sensitive p53 allele, we were able to isolate several transcripts up-regulated specifically in cells harboring functional p53 protein. Two of these genes, SM20 and microsomal epoxide hydrolase (mEH), are previously described genes. Two previously uncharacterized cDNAs, cell growth regulatory (CGR) genes CGR11 and CGR19, were isolated. The predicted amino acid sequence of these novel proteins contain known motifs; EF-hand domains (CGR11) and a ring-finger domain (CGR19), suggestive of function. CGR11 and CGR19 appear to be primary response genes expressed to moderate levels in functional p53 cells. Both CGR11 and CGR19 are able to inhibit the growth of several cell lines.

Serial analysis of gene expression in non-small cell lung cancer.

We used the serial analysis of gene expression (SAGE) method to systematically analyze transcripts present in non-small cell lung cancer. Over 226,000 SAGE tags were sequence analyzed from two independent primary lung cancers and two normal human bronchial/tracheal epithelial cell cultures. A total of 226,000 SAGE tags were sequence identified, representing 43,254 unique transcripts. Comparison of the tags present in the tumor with those identified in the normal tissue revealed 175 transcript tags that were overrepresented in the normal tissue and 142 tags that were overexpressed in the tumor by 10-fold or more. Northern hybridization was performed on 15 of the most abundantly expressed tags identified in the tumors. These tags were derived from either a known gene or a matched expressed sequence tag clone. The transcripts for 3 of the 15 genes, PGP 9.5, B-myb, and human mutT, were abundantly expressed in primary lung cancers (10 of 18, 15 of 18, and 6 of 12 tumors, respectively). In contrast, the presence of PGP9.5 and B-myb was much less frequent in primary tumors derived from other tissue origins. These results suggest that at least a portion of the transcripts identified by SAGE are frequently associated with lung cancer, and that their overexpression may contribute to lung tumorigenesis. The identification and further characterization of genes generated by SAGE should provide potential new targets for the diagnosis, prognosis, and therapy of lung cancer.

Induction of the inflammatory regulator A20 by gibberellic acid in airway epithelial cells.

BACKGROUND AND PURPOSE: NF-κB-driven inflammation is negatively regulated by the zinc finger protein A20. Gibberellic acid (GA3 ) is a plant-derived diterpenoid with documented anti-inflammatory activity, which is reported to induce A20-like zinc finger proteins in plants. Here, we sought to investigate the anti-inflammatory effect of GA3 in airway epithelial cells and determine if the anti-inflammatory action relates to A20 induction. EXPERIMENTAL APPROACH: Primary nasal epithelial cells and a human bronchial epithelial cell line (16HBE14o-) were used. Cells were pre-incubated with GA3 , stimulated with Pseudomonas aeruginosa LPS; IL-6 and IL-8 release, A20, NF-κB and IκBα expression were then evaluated. To determine if any observed anti-inflammatory effect occurred via an A20-dependent mechanism, A20 was silenced using siRNA. KEY RESULTS: Cells pre-incubated with GA3 had significantly increased levels of A20 mRNA (4 h) and protein (24 h), resulting in a significant reduction in IL-6 and IL-8 release. This effect was mediated via reduced IκBα degradation and reduced NF-κB (p65) expression. Furthermore, the anti-inflammatory action of GA3 was abolished in A20-silenced cells. CONCLUSIONS AND IMPLICATIONS: We showed that A20 induction by GA3 attenuates inflammation in airway epithelial cells, at least in part through its effect on NF-κB and IκBα. GA3 or gibberellin-derived derivatives could potentially be developed into anti-inflammatory drugs for the treatment of chronic inflammatory diseases associated with A20 dysfunction.

SAGE transcript profiles for p53-dependent growth regulation.

Serial analysis of gene expression (SAGE) allows for a quantitative, representative, and comprehensive profile of gene expression. We have utilized SAGE technology to contrast the differential gene expression profile in rat embryo fibroblast cells producing temperature-sensitive p53 tumor suppressor protein at permissive or non-permissive temperatures. Analysis of approximately 15,000 genes revealed that the expression of 14 genes (P < 0.001, > or = 0.03% abundance) was dependent on functional p53 protein, whereas the expression of three genes was significantly higher in cells producing non-functional p53 protein. Those genes whose expression was increased by functional p53 include RAS, U6 snRNA, cyclin G, EGR-1, and several novel genes. The expression of actin, tubulin, and HSP70 genes was elevated at the non-permissive temperature for p53 function. Interestingly, the expression of several genes was dependent on a non-temperature-sensitive mutant p53 suggesting altered transcription profiles dependent on specific p53 mutant proteins. These results demonstrate the utility of SAGE for rapidly and reproducibly evaluating global transcriptional responses within different cell populations.

Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer's Danish identical and fraternal discordant twins.

Margit Fischer reported in 1971 that the risk of schizophrenia in the offspring of her Danish schizophrenic monozygotic twins and their normal cotwins was equal and not different from the risks in the children of schizophrenics in the literature. All of her identical and fraternal twins who had children and all of their offspring have been followed up through the Danish National Psychiatric Register as of 1985, some 18 years after study by Fischer. The morbid risk (age-corrected) for schizophrenia and schizophrenia-related disorders in the offspring of schizophrenic identical twins is 16.8%; it is 17.4% in their normal cotwins' offspring. The risks in the offspring of schizophrenic fraternal twins and their normal cotwins are 17.4% and 2.1%, respectively. The results suggest that discordance in identical twins may primarily be explained by the capacity of a schizophrenic genotype or diathesis to be unexpressed unless it is released by some kinds of environmental, including nonfamilial, stressors. Sporadic cases and phenocopies caused by cerebral abnormalities, diseases, or viruses would thus be deemphasized as necessary or sufficient explanatory causes for schizophrenia in our study but could account for some of the remaining discordance, infrequent phenocopies should encourage linkage researchers, but unexpression of genotypes will frustrate them.

Therapeutic targeting of the p53 tumor suppressor gene.

The p53 tumor suppressor gene is a logical target for cancer therapy. Several therapeutic strategies can be envisioned based upon recent advances concerning structure and function of the p53 protein, its interaction with cellular and viral proteins and its roles in repairing DNA, regulating cell division and promoting apoptosis.

Multiple forms of peptidyl alpha-amidating enzyme: purification from rat medullary thyroid carcinoma CA-77 cell-conditioned medium.

Conditioned medium from cultures of rat medullary thyroid carcinoma CA-77 cells was used as a source for purification of the secreted forms of peptidyl alpha-amidating enzyme. The alpha-amidating enzyme activity was partially purified using a combination of weak anion exchange and gel filtration chromatography. Subsequent strong anion exchange chromatography at pH 6.0 resolved this partially pure enzyme into four distinct peaks of activity, termed Ia, Ib, II, and III. Peaks Ia and Ib exhibited broad pH optima between pH 6.0-8.5, whereas peaks II and III both exhibited pH optima at approximately pH 5.0. The peak III activity was further purified to electrophoretic homogeneity using hydrophobic interactive chromatography followed by strong anion exchange chromatography at pH 8.0. The enzyme exhibited an apparent molecular mass of 75K, a pH optimum of approximately pH 5.0, and a maximal turnover number of 580 min-1 in the presence of L-ascorbate. Kinetic studies demonstrated that the enzyme probably functions through a ping-pong mechanism with respect to the binding of the glycine-extended peptide substrate and the L-ascorbate cofactor. The peak III enzyme exhibits several distinctive characteristics compared to amidating enzymes isolated and characterized by other laboratories.

Localized irradiation of testes with carcinoma in situ: effects on Leydig cell function and eradication of malignant germ cells in 20 patients.

Twenty men (median age, 31 yr) previously treated for unilateral testicular cancer received localized irradiation in a dose of 20 Gray in 10 fractions for carcinoma in situ of the remaining testis. Follow-up testicular biopsies performed 3 (n = 19) and 24 (n = 14) months after the treatment showed in all cases a Sertoli cell-only pattern. Hormonal evaluation was performed before as well as 3, 12, 24, and 36 months after radiation treatment. Endocrine parameters were followed for a median of 30 months (3-36 months). Baseline serum testosterone values decreased during the follow-up period from 13.3 +/- 6.0 to 10.8 +/- 6.4 nmol/L (mean +/- SD), although the decrease was not statistically significant (P = 0.06). Serum LH values increased during the first 3 months of follow-up from 10.4 +/- 5.4 to 15.6 +/- 7.3 IU/L (P less than 0.0001) and then remained unchanged. Significant decreases in GnRH- and hCG-stimulated testosterone levels also indicated an impairment of Leydig cell function. FSH levels increased (P less than 0.0001) during the first 3 months of follow-up from 21.8 +/- 11.1 to 33.2 +/- 13.2 IU/L. We conclude that localized irradiation of 20 Gray eradicated carcinoma in situ germ cells. Development of a second testicular cancer has until now been prevented. Leydig cell function was partially impaired by the radiation dose given.

Glucocorticoid regulation of amidating enzyme in a neoplastic C-cell line.

Posttranslational carboxyl-terminal amidation of many peptides is accomplished by peptidylglycine alpha-amidating monooxygenase. We have previously demonstrated that glucocorticoids stimulate production of amidated products by the CA-77 rat medullary thyroid carcinoma cell line. The present investigation was undertaken to determine whether amidation enzyme activity changes in parallel. Enzyme activity, similar to that found in other tissues, was readily detected in cell extracts and conditioned cultured medium. Stimulation with the calcitonin secretagogue calcium increased secretion of enzyme activity and lowered cell extract activity. Treatment of cultures with dexamethasone, but no other steroid, decreased by 50-70% the basal amidation enzyme activity secreted. There was no associated change in cellular activity. The decrease in medium activity was partially reversible and steroid-dose dependent. The glucocorticoid-induced change in medium activity was due to a decreased Vm. These experiments demonstrate that the alpha-amidating activity of the CA-77 cells can be hormonally regulated.

Schizoaffective psychoses: genetical clues to classification.

The diagnostic classification of schizoaffective psychoses has varied much since Kasanin introduced the concept in 1933. The various classifications have agreed that schizoaffective psychoses present a combination of schizophreniform and affective symptoms, but the diagnostic criteria differ as to the number, quality, and time sequence of the symptoms even in recent classifications like RDC, DSM-III-R, and ICD-10. The classifications are syndromatical, and the etiology of the schizoaffective psychoses is still undetermined apart from evidence for a strong genetic factor. Results from family, twin, and adoption studies are divergent, but all the same, support a separate classification of broadly defined schizoaffective psychoses as possibly being phenotypical variations or expressions of genetic interforms between schizophrenia and affective psychoses.