Mammalian target of rapamycin and its downstream signalling components are activated in psoriatic skin.

BACKGROUND: Mammalian target of rapamycin (mTOR) signalling integrates signals leading to cellular growth, proliferation and differentiation. Disturbance of this tightly regulated interplay leads to malignancies, as reflected by altered mTOR signalling in epidermal tumours. As psoriatic keratinocytes also show features of perturbed cell growth and differentiation, the question arises as to whether mTOR signalling also plays a role in the pathogenesis of psoriasis. OBJECTIVES: To investigate the activation status of mTOR signalling components in psoriasis. METHODS: Biopsies from lesional and nonlesional skin of patients with psoriasis (n = 10), as well as samples from healthy donors (n = 3), were analysed by immunohistochemistry and Western blot, utilizing antibodies detecting phosphorylated mTOR, phospho-S6 kinase and phospho-S6 ribosomal protein. RESULTS: We found mTOR and its downstream signalling molecule, the ribosomal protein S6, to be activated in lesional psoriatic skin. While mTOR is activated throughout the whole epidermis, with particularly strong activation in the basal layer, S6 is active in suprabasal layers of differentiating keratinocytes. CONCLUSIONS: Altogether these results suggest a role for mTOR signalling in the epidermal changes leading to the psoriatic phenotype. mTOR inhibition might be a mode of action to explore in developing innovative antipsoriatic drugs.

External validation of prognostic model of one-year mortality in patients requiring prolonged mechanical ventilation.

BACKGROUND: External validation of prognostic model for one-year mortality in patients ventilated for 21 days or more. A measure that identifies patients who are at high risk of mortality after prolonged ventilation will help physicians communicate prognoses to patients or surrogate decision makers. Our objective was to validate a prognostic model developed by Carson et al in a different setting. METHODS: An observational study was conducted from September 2002 to September 2007 in 30 beds Medical/Surgical Intensive Care Unit (ICU) at Mercy Fitzgerald Hospital (MFH) and 20 beds Medical/Surgical ICU at Mercy Philadelphia Hospital (MPH). One hundred and fifty medical and surgical patients requiring mechanical ventilation after acute illness for at least 21 days after initial intubation were enrolled. RESULTS: One year mortality was 45.4%. Area under the receiver operating characteristic curve for three month mortality was 0.90 and for one year mortality was 0.92. For identifying patients who had ≥90% risk of death at 3 month had sensitivity of 40% and specificity of 95% and risk of death at 1 year had sensitivity of 70% and specificity of 99%. Four predictive variables, requirement of vasopressors, hemodalysis, platelet count ≤ 150 x 10 9/L and age ≥50 yrs can be used as a simple prognostic score that clearly identifies low-risk patients and high-risk patients. CONCLUSIONS: Simple clinical variables measured on day 21 of mechanical ventilation can identify patients at highest and lowest risk of death from prolonged mechanical ventilation.

The patient physician relationship in the Internet age: future prospects and the research agenda.

In the "Internet Age," physicians and patients have unique technological resources available to improve the patient physician relationship. How they both utilize online medical information will influence the course of their relationship and possibly influence health outcomes. The decision-making process may improve if efforts are made to share the burden of responsibility for knowledge. Further benefits may arise from physicians who assist patients in the information-gathering process. However, further research is necessary to understand these differences in the patient physician relationship along with their corresponding effects on patient and physician satisfaction as well as clinical outcomes.

Electronic communication in ethics committees: experience and challenges.

Experience with electronic communication in ethics committees at two hospitals is reviewed and discussed. A listserver of ethics committee members transmitted a synopsis of the ethics consultation shortly after the consultation was initiated. Committee comments were sometimes incorporated into the recommendations. This input proved to be most useful in unusual cases where additional, diverse inputs were informative. Efforts to ensure confidentiality are vital to this approach. They include not naming the patient in the e-mail, requiring a password for access to the listserver, and possibly encryption. How this electronic communication process alters group interactions in ethics committees is a fruitful area for future investigation.

The underachieving advance directive: recommendations for increasing advance directive completion.

Advance directives have failed to achieve a substantial completion rate nationwide despite prior efforts. We hypothesize that the continued low completion rate itself inhibits their utility and application. In this commentary we recommend linking the completion of advance directives to the time when health insurance is initiated or renewed by amending the Patient Self Determination Act. This would relocate the time and locus of their completion from the emotional turmoil of hospital admission and acute illness to a more equanimous time when family and others can be consulted and involved. Moreover actuating increased utilization may require non-coercive incentives as well as education. Amending the Patient Self Determination Act to require providing advance directive forms at the initiation of healthcare insurance in conjunction with educational and/or incentives could be more effective than the current arrangements.

Phasic and enduring negative symptoms in schizophrenia: biological markers and relationship to outcome.

Negative symptoms have been associated with poor response to neuroleptics, enlarged ventricles, cognitive impairment, and poor outcome in schizophrenia. These associations appear, however, to be dependent on the phase of study, suggesting that acute-phase (phasic) negative symptoms may be pathophysiologically distinct from enduring negative symptoms that persist through the residual phase. To compare correlates of enduring and phasic negative symptoms, we studied 60 drug-free schizophrenic patients (DSM-III-R and SADS/RDC) at baseline, 4 weeks after neuroleptic treatment, and assessed the 1 year outcome. We rated positive and negative symptoms at baseline and 4 weeks after treatment. At baseline, premorbid function, neuropsychological function, ventricle-brain ratio (VBR) and symptom response to an anticholinergic agent were assessed, and a two-night sleep EEG and 1mg dexamethasone suppression test (DST) were conducted. Phasic negative symptoms were defined as the change in negative symptoms (baseline to 4 weeks) and enduring negative symptoms as severity of negative symptoms at 4 weeks. Patients had varying proportions of phasic and enduring symptoms; the two did not define distinct subgroups. Phasic negative symptoms were significantly correlated with global treatment response, positive symptom treatment response, response to anticholinergic agent, baseline post-dexamethasone cortisol, and shortened REM latency. Enduring negative symptoms were significantly correlated with residual positive symptoms and global psychopathology, VBR, poor performance on neuropsychological testing, decreased slow-wave sleep, poor premorbid function, and poor 1 year outcome. These data suggest that phasic negative symptoms and enduring negative symptoms may be caused by different pathophysiological mechanisms.

Effects of antipsychotic treatment on polysomnographic measures in schizophrenia: a replication and extension.

OBJECTIVE: The authors sought to replicate and extend previous observations of improvement in some EEG sleep measures during the course of antipsychotic treatment in schizophrenia patients. METHOD: Fourteen medication-free patients with schizophrenia underwent 2 nights of sleep EEG monitoring before and after 3-4 weeks of treatment with clinically determined doses of haloperidol or thiothixene. RESULTS: Measures of sleep continuity improved consistently. REM latency increased, although five of 14 patients continued to exhibit short REM latencies (less than 60 minutes). Stage 3 sleep increased during neuroleptic treatment, while stage 4 sleep did not change. CONCLUSIONS: These data demonstrate partial improvement of some but not all EEG sleep measures in schizophrenic patients through the course of neuroleptic treatment. They suggest that shortened REM latency and disturbed sleep continuity might represent reversible state abnormalities, while reduced slow-wave sleep may represent a more persistent trait abnormality in schizophrenia.

Sustained dapsone-induced remission of hypocomplementemic urticarial vasculitis--a case report.

Hypocomplementemic urticarial vasculitis (HUV) is often misdiagnosed. The response to drug therapy may be unsatisfactory, and immunosuppressive therapy may be associated with significant side effects. A 35-year-old patient whose condition was resistant to cyclophosphamide, corticosteroids, pentoxyphylline, cyproheptadine, sulindac, and colchicine was maintained in remission with dapsone, which may be the drug of choice for HUV. Emphysema has been reported to complicate HUV, but this is the first account of vasculitis-related emphysema with no confounding history of tobacco smoke exposure. The relationship of proteolytic injury to the pulmonary and other manifestations is considered, as is the possible role for dapsone in reducing it.

Sleep-onset rapid eye movement after electroconvulsive therapy is more frequent in patients who respond less well to electroconvulsive therapy.

The response to electroconvulsive therapy (ECT) was monitored with sleep polysomnography studies (SPS) performed pre- and post-ECT, in 25 patients with major depressive disorder (MDD). Patients included in this study met research diagnostic criteria for MDD and had been free of psychotropic medication for at least 10 days before SPS were performed. We compared ECT responders and nonresponders on SPS, demographic, and clinical parameters. Many SPS parameters, regardless of the clinical response, changed significantly with ECT. The presence of delusions was significantly associated with SOREM post-ECT. The presence of sleep-onset REM periods post-ECT was associated with poor response to ECT. SPS performed during a course of ECT may help identify patients at risk of responding less well to this modality of treatment.

Discontinuing dialysis in persistent vegetative state: the roles of autonomy, community, and professional moral agency.

This report proposes a policy for discontinuing dialysis in persistent vegetative state (PVS) patients and attempts to address autonomy and community-based values while maintaining professional moral agency. It is recommended that the policy be adopted at a regional level (eg, the ESRD Network). The involved physicians and ethicists would communicate with the next-of-kin and surrogate decision-makers, and the local ethics committee would perform a double review of the case to assure the appropriateness of the policy to the case. Given the unique nature of PVS with its permanent loss of consciousness and autonomy, we hold that a community-based consensus can form a guideline that limits futile dialysis while respecting patient and professional moral agency. Prior consent of dialysis patients to the regional policy at a time shortly after initiating dialysis will add to its ethical impetus.

Phlebotomy for pulmonary edema in dialysis patients.

STUDY OBJECTIVE: To assess the efficacy of phlebotomy in the treatment of pulmonary edema in hemodialysis patients. PROCEDURE: Maintenance hemodialysis patients presenting to the emergency room in respiratory distress from apparent pulmonary edema were assessed with regard to clinical response, change in blood pressure, change in hematocrit, and interval until the next hemodialysis treatment, RESULTS: Twenty-one patients underwent phlebotomy and seventeen improved markedly and did not require intubation or emergent dialysis. Hemodialysis was initiated 15.6 +/- 13.6 SD hours later. Four were able to have their treatment 24 or more hours later. Thirteen of 21 (62%) were hypertensive at the time of treatment and blood pressure tended to normalize in this subset. Four of 21 (19%) developed transient hypotension without permanent sequelae. Pre-mean hematocrit = 25.0 + 6.0 and post phlebotomy = 22.6 + 4.6 SD. All patients receiving phlebotomy survived to hospital discharge. CONCLUSION: Phlebotomy can often obviate the need for intubation or emergent dialysis in ESRD patients presenting with pulmonary edema.

Polysomnographic studies in patients referred for ECT: pre-ECT studies.

Forty-one patients referred for electroconvulsive therapy (ECT) were evaluated with a standardized clinical protocol and had polysomnographic studies performed pre-ECT after 10 or more days drug free. Clinical evaluations were performed by blind investigators and included the Research Diagnostic Criteria and the Hamilton Rating Scale for Depression (HRSD). Patients were categorized according to the clinical response. Thirty patients (73%) reached a post-ECT HRSD < or = 10, whereas 21 of them (51.2%) reached a post-ECT HRSD score < or = 6. Sleep-onset rapid eye movement (SOREM) periods were present in 27 (66%) of the patients. Few polysomnographic variables differentiated between excellent responders and patients with residual symptoms. Older patients had significantly more disrupted polysomnographic study parameters. Although present in a significant proportion of patients, baseline SOREM was not a factor in outcome.

Organizational effectiveness. Primary care and the congruence model.

The congruence model is a framework used to analyze organizational strengths and weaknesses and pinpoint specific areas for improving effectiveness. This article provides an overview of organizations as open systems, with examples in the primary care arena. It explains and applies the congruence model in the context of primary care issues and functions, including methods by which the model can be used to diagnose organizational problems and generate solutions. Changes needed in primary care due to the managed care environment, and areas of potential problems and sensitivities requiring organizational changes to meet market and regulatory demands now placed on PCOs are examined.

Withdrawal from dialysis: the role of autonomy and community-based values.

By examining the ethical features of dialysis withdrawal as well as tr transcultural differences in attitudes toward withdrawal, one can have a better understanding of the role of autonomy and community-based values on medical decision-making. Three distinctive patterns of withdrawal are described herein. The first concerns patients suffering from an advanced state of physical or mental decline. When a patient or health care surrogate decision maker requests cessation of therapy because it fails to be beneficial for the patient in his or her totality, the physician should be prepared to cooperate, in accord with beneficence and nonmaleficence as well as autonomy. The second pattern occurs when the patient loses decisional capacity, and the surrogate decision maker makes unreasonable requests for nonbeneficial care. At issue is what constitutes nonmaleficence and beneficence in this setting, the provider and surrogate differing on whether continuing dialysis constitutes beneficence. Such a dilemma can alleviated by community-based consensus guidelines with consent of the patient before losing capacity. The dialysis network is potentially a unit of patient and professional community. In third pattern, the patient's decision to withdraw appears to be inappropriate to their potential for benefit from continued therapy. The nephrologist and patient are conflicted on what constitutes beneficence, with the former holding that continuation is morally superior. In such cases, the physician must mediate the situation in a beneficent fashion not solely dictated by a constraining view of patient autonomy.

Shortened REM latency PostECT is associated with rapid recurrence of depressive symptomatology.

Electroconvulsive therapy (ECT) is highly effective in the treatment of major depressive disorder (MDD). The 1-year relapse rates are reported to be high and in the 30%-60% range, however. To test whether polysomnography (PS) can identify patients with a propensity for relapse we studied 20 patients, responders to a course of ECT, with PS studies. All patients met baseline diagnostic criteria for MDD, were treated with ECT following standardized protocols, had PS studies performed after the course of ECT in a medication-free state, received maintenance antidepressants postECT, and were followed periodically with phone interviews. The recurrence of depressive symptoms was determined at 3 months and 6 months after discharge. Fifty-five percent of the patients were symptomatic when evaluated 6 months after the ECT. Sleep Onset rapid eye movement (REM) periods were identified in 55% of the patients. As a group, patients who had experienced a recurrence of depressive symptoms by 6 months after discharge, had significantly shorter REM latencies after the course of ECT. A shorter REM latency after ECT identified patients who at six months demonstrated significant depressive symptomatology. Shortened REM latency after ECT in patients with MDD appears to be a correlate of vulnerability for relapse.

Treatment of lupus interstitial lung disease with intravenous cyclophosphamide.

Intravenous pulse cyclophosphamide (IPC) was used to treat lupus interstitial lung disease in 2 patients. Vital capacity increased by 67-110% of baseline values with IPC treatment. Total lung capacity and diffusing capacity also improved. Dyspnea and other manifestations of lupus improved dramatically. This is the first report documenting the efficacy of the early use of IPC for acute and chronic interstitial lung disease associated with lupus.

Sleep Electroencephalographic Studies After ECT.

Forty-one patients with major depressive disorder were treated with electroconvulsive therapy (ECT). Sleep polysomnography studies (SPSs) were performed after the course of ECT. The hypotheses tested were that age is a significant factor in post-ECT SPS results and that some SPS parameters are correlates of outcome of ECT. An interaction between age and response to ECT could not be identified; however, older patients demon strated significantly disrupted sleep post-ECT. Response to ECT was associated with lower REM activity and lower REM density. Sleep-onset REM periods post-ECT were observed in almost 50% of the patients regardless of age. The SPS monitoring of recovery after a course of ECT may identify sleep correlates of response to ECT and variables associated with poorer longitudinal outcome.