Comprehensive serum cytokine analysis identifies IL-1RA and soluble IL-2Rα as predictors of event-free survival in T-cell lymphoma.

BACKGROUND: T-cell malignancies are heterogeneous in their clinical presentation and pathology, and have a poor prognosis. New biomarkers are needed to predict prognosis and to provide insights into signal pathways used by these cells. The goal of this study was to evaluate pretreatment serum cytokines in patients with newly diagnosed T-cell neoplasms and correlate with clinical outcome. PATIENTS AND METHODS: We evaluated 30 cytokines in pretreatment serum from 68 untreated patients and 14 normal controls. Significantly elevated cytokines were correlated with patterns of abnormalities, event-free survival (EFS) and overall survival (OS). RESULTS: Our data demonstrated significantly elevated levels (versus controls) of seven cytokines-epidermal growth factor (EGF), IL-6, IL-12, interferon gamma-induced protein (IP)-10, soluble interleukin (sIL)-2Rα, monokine induced by gamma interferon (MIG), and IL-1RA-in all T-cell neoplasms (P < 0.05). In the angioimmunoblastic subset, all seven cytokines except IP-10 and in the peripheral T-cell lymphoma (TCL)-not otherwise specified subset, only IP-10, sIL-2Rα, MIG, and IL-8 were statistically elevated compared with control. Of these, elevated cytokines all but EGF were predictive of an inferior EFS; IL-1RA, sIL-2Rα, and MIG predicted an inferior OS. In a multivariate analysis, sIL-2Rα [hazard ratio (HR) = 3.95; 95% confidence interval (CI) 1.61-8.38] and IL-1RA (HR = 3.28; 95% CI 1.47-7.29) levels remained independent predictors of inferior EFS. TCL cell lines secreted high levels of sIL-2Rα and expressed the IL-2Rα surface receptor. CONCLUSIONS: This report describes the cytokines relevant to prognosis in patients with untreated TCL and provides the rationale to include serum IL-1RA and sIL-2Rα as biomarkers in future trials. Inhibition of these cytokines may also be of therapeutic benefit.

Treatment of Truncal Incompetence and Varicose Veins with a Single Administration of a New Polidocanol Endovenous Microfoam Preparation Improves Symptoms and Appearance.

OBJECTIVE: This multicenter, parallel group study was designed to determine if a single administration of ≤15 mL of pharmaceutical-grade polidocanol endovenous microfoam (PEM, now approved in the United States as Varithena [polidocanol injectable foam], BTG International Ltd.) could alleviate symptoms and improve appearance of varicose veins in a typical population of patients with moderate to very severe symptoms of superficial venous incompetence and visible varicosities of the great saphenous vein (GSV) system. METHODS: The primary endpoint was patient-reported venous symptom improvement measured by change from baseline to Week 8 in 7-day average VVSymQ score. Co-secondary endpoints measured improvement in appearance of visible varicose veins from baseline to Week 8, as measured by the Independent Photography Review-Visible Varicose Veins (IPR-V(3)) and Patient Self-assessment of Visible Varicose Veins (PA-V(3)) scores. Patients were randomized to five groups: PEM 0.125% (control), 0.5%, 1%, 2%, or placebo. Adverse events (AEs) were recorded at each study visit. Tertiary endpoints measured duplex ultrasound response, changes in venous clinical severity score, and the modified Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms. RESULTS: At Week 8, VVSymQ scores for the pooled PEM group (0.5% + 1% + 2%; p < .0001) and individual dose concentrations (p < .001) were significantly superior to placebo. Mean changes from baseline to Week 8 in IPR-V3 and PA-V(3) scores were significantly greater for pooled PEM than for placebo (p < .0001). Most AEs were mild and resolved without sequelae. No pulmonary emboli were reported. CONCLUSIONS: This study demonstrated that a single administration of up to 15 mL of PEM is a safe, effective, and convenient treatment for the symptoms of superficial venous incompetence and the appearance of visible varicosities of the GSV system. Doses of 0.5%, 1%, and 2% PEM appear to have an acceptable risk-benefit ratio.

Pessimistic explanatory style: a psychological risk factor for poor pain and functional outcomes two years after knee replacement.

Seligman's theory of causal attribution predicts that patients with a pessimistic explanatory style will have less favourable health outcomes. We identified 702 patients who had undergone 894 primary total knee replacements between 1993 and 2005, who responded to follow-up surveys at two (n = 783 knee replacements) and/or five years (n = 443 knee replacements) and had also completed the Minnesota Multiphasic Personality Inventory long before the joint replacement (median = 16.6 and 14.5 years for two- and five-year cohorts, respectively). Scores from the Minnesota Multiphasic Personality Inventory Optimism-Pessimism scale were used to categorise patients as pessimistic (t-score > 60) or non-pessimistic (t-score < or = 60). Multivariate logistic regression models assessing the effect of pessimistic explanatory style on pain or improvement in knee function were adjusted for gender, age, distance from the place of treatment and depression score. Pessimists reported (a) significantly more moderate or severe pain at two years with odds ratio 2.21 (95% confidence interval (CI) 1.12 to 4.35; p = 0.02), but not at five years when the odds ratio was 1.21 (95% CI 0.51 to 2.83; p = 0.67); and (b) less improvement in knee function at two years when the odds ratio was 0.53 (95% CI 0.30 to 0.96; p = 0.04), but not at five years when the odds ratio was 1.26 (95% CI 0.57 to 2.77; p = 0.57). No significant associations with moderate or severe limitation of activity were seen at two or five years. We conclude that a pessimistic explanatory style is associated with worse pain and functional outcomes two years after total knee replacement.

Predictors of moderate-severe functional limitation after primary Total Knee Arthroplasty (TKA): 4701 TKAs at 2-years and 2935 TKAs at 5-years.

OBJECTIVE: Investigate whether body mass index (BMI), comorbidity, gender and age predict patient-reported functional limitation 2- and 5-years after primary Total Knee Arthroplasty (TKA). METHODS: Overall moderate-severe activity limitation was defined as > or = 2 activities (walking, stairs, rising from chair) with moderate-severe limitation. Complete dependence on walking aids or inability to walk was assessed (reference, no dependence). Multivariable logistic regression models were adjusted additionally for income, diagnosis, distance from medical center, American Society of Anesthesiologists (ASA) score and implant type. RESULTS: Overall moderate-severe activity limitation was reported by 20.7% at 2-years and 27.1% at 5-years. Significantly predictors of overall moderate-severe activity limitation 2-years post-TKA (odds (95% confidence interval)) were: BMI 30-34.9, 1.5 (1.0, 2.0), 35-39.9, 1.8 (1.3, 2.7) and > or = 40, 3.0 (2.0, 4.5) vs BMI < or = 25; higher Deyo-Charlson index, 1.7 (1.4, 2.2) per 5-point increase; female gender, 2.0 (1.7, 2.5); age 71-80, 2.1 (1.5, 2.8) and age > 80, 4.1 (2.7, 6.1) vs age < or = 60. At 5-years post-TKA, significant predictors of overall moderate-severe activity limitation were: BMI 35-39.9, 2.1 (1.4, 3.3) and > or = 40, 3.9 (2.3, 6.5); higher Deyo-Charlson index, 1.4 (1.0, 1.8); female gender, 2.2 (1.7, 2.7); age 71-80, 2.4 (1.7, 3.5) and age > 80, 4.7 (2.8, 7.9). Complete dependence on walking aids was significantly higher at 2- and 5-years, respectively, in patients with: higher comorbidity, 2.3 (1.5, 3.3) and 2.1 (1.4, 3.2); female gender 2.4 (1.5, 3.9) and 1.7 (1.1, 2.6); age 71-80, 1.4 (0.8, 2.6) and 1.5 (0.8, 2.8); and age > 80, 3.2 (1.6, 6.7) and 5.1 (2.3, 11.0). CONCLUSIONS: Modifiable (BMI, comorbidity) and non-modifiable predictors (age, gender) increased the risk of functional limitation and walking-aid dependence after primary TKA. Interventions targeting comorbidity and BMI pre-operatively may positively impact function post-TKA.

Duties and training of dental nurses: how do Irish practices conform to European standards?

AIM: The dental nurse is a key member of the dental team, having an important role in the delivery of oral healthcare. Despite this, there is considerable variation throughout Europe in relation to the level of training, permitted duties, and statutory registration of dental nurses. The purpose of this paper is to describe the opinions and attitudes of dental nurses to their roles and suitability of training in one European member state, Ireland, where statutory registration has recently been introduced. METHOD: A postal questionnaire was sent to 150 dental practitioners selected from the Irish Register of Dentists. The dentists were asked to distribute questionnaire to dental nurse(s) working in their practice. Information sought from the dental nurses included their employment setting, the nature of their employment, their level of training, additional qualifications held, their views on the key duties and responsibilities of a dental nurse, and the appropriate duration and content of a dental nurse training programme. RESULTS: Replies were received from 96 dental nurses (response rate = 64%). Fifty-five percent of respondents (n = 53) were employed in private practice, 39% (n = 37) were employed in the Health Board Dental Service, and 6% (n = 6) were employed in a dental hospital. Two thirds of respondents (n = 62) had been employed as dental nurses for more than five years. Eighty-six percent of respondents (n = 83) were in full-time employment. Seventy-three percent of respondents (n = 70) held a recognised dental nurse qualification. Sixty-five percent of respondents (n = 70) who held a dental nurse qualification felt that the appropriate duration of a dental nurse training programme was one year or less. Thirty-two percent of respondents (n = 30) had completed additional training in practice management, administration or computer skills. Ninety-five percent of respondents (n = 91) were interested in attending continuing education courses. Eighty-five percent of respondents (n = 82) felt that assistance at the administration of local anaesthetics was a key duty/responsibility for dental nurses, while only 20% of respondents (n = 19) felt that infection control procedures was a key duty. CONCLUSIONS: Within the group of dental nurses surveyed, there was a lack of clarity surrounding their perception of their key duties. This could present challenges to the effective delivery of oral healthcare regimens within Ireland. Further investigation of this situation in other European countries is indicated.

Ivor Lewis approach is superior to transhiatal approach in retrieval of lymph nodes at esophagectomy.

Lymph node involvement may impact postoperative therapeutic decision-making and prognosis in patients undergoing esophagectomy. This study evaluates which surgical approach yields the most lymph nodes. We undertook a retrospective chart review of esophagectomies performed by six surgeons from April 1994 to February 2004 using a prospective general thoracic surgery database at Mayo Clinic, Rochester, Minnesota, US. Lymph nodes were categorized into one of 17 regions per the American Joint Committee on Cancer, with the total number of lymph nodes, summed over each region, used as the primary outcome. A total of 517 esophagectomies were performed: 68 transhiatal, 392 Ivor Lewis, and 57 extended Ivor Lewis. A mean of 18.7 (SD 8.5) lymph nodes were retrieved with the Ivor Lewis approach as compared to 17.4 (SD 9.2) with the extended Ivor Lewis approach (P = 0.30). Since there was no statistical difference between the number of nodes collected in either Ivor Lewis approach, they were collapsed into one group for comparison with the transhiatal cases. Significantly more lymph nodes were collected with an Ivor Lewis approach (mean 18.5, SD 8.6) than with a transhiatal approach (mean 9.0, SD 5.0, P < 0.001). As expected, more thoracic lymph nodes were retrieved with the Ivor Lewis approach [mean 12.4 (SD 7.0) vs. 4.7 (SD 5.3), P < 0.001]. The Ivor Lewis approach was also superior for retrieval of abdominal nodes [mean 6.1 (SD 5.6) versus 4.3 (SD 4.4), P = 0.01]. More lymph nodes are obtained at esophagectomy with an Ivor Lewis than a transhiatal approach.

Inhibition of the neuronal isoform of nitric oxide synthase significantly attenuates 1-methyl-4-phenylpyridinium (MPP(+)) toxicity in vitro.

The possible protection against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) afforded by inhibitors of nitric oxide synthase (NOS) and the antagonist of N-methyl-D-aspartate receptor function, MK-801, was studied in a brain-slice superfusion system. Significant decreases in levels of dopamine and its metabolites 3,4-dihyroxyphenylacetic acid (DOPAC) and homovanillic acid were observed following incubation of slices with 25 microM MPP(+). The activity of intracellular lactate dehydrogenase (LDH), a marker of cell viability, was also significantly decreased. These effects were attenuated by preincubation with I mM 7-nitroindazole (7NI), a selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS). In contrast, the nonspecific NOS inhibitor N(omega)-nitro-L-arginine, also at 1 mM, had no effect on levels of dopamine metabolites but did show a small attenuation of the levels of dopamine. 7NI alone caused some increase in levels of dopamine and a decrease in the metabolite DOPAC, which is consistent with it also acting as an inhibitor of monoamine oxidase-B. MK-801 afforded no significant protection of aminergic cells, although changes in LDH activity suggested that there may have been some protection of non-aminergic neurons affected by this, relatively high concentration of MPP(+).

Taurine-induced attenuation of MPP+ neurotoxicity in vitro: a possible role for the GABA(A) subclass of GABA receptors.

Taurine is a sulphur-containing beta-amino acid found in high (millimolar) concentrations in excitable tissues such as brain and heart. Its suggested roles include osmoregulator, thermoregulator, neuromodulator, and potential neurotransmitter. This amino acid has also been shown to be released in large concentrations during ischaemia and excitotoxin-induced neuronal damage. Here we report a protective effect of taurine against MPP(+)-induced neurotoxicity in coronal slices from rat brain. Significant protective effects were observed at taurine concentrations of 20 and 1 mM, suggesting a potential role for taurine in cases of neuronal insult. Studies with the synthetic taurine analogues taurine phosphonate, guanidinoethane sulphonate, and trimethyltaurine suggested the observed effect to be mediated via an extracellular mechanism. The use of GABA receptor ligands muscimol and bicuculline indicated the effect to be mediated through activation of GABA(A) receptors.

Tyrosine-hydroxylase immunoreactive cells in the rat striatum following treatment with MPP+.

Tyrosine Hydroxylase is the rate-limiting enzyme in the synthesis of dopamine, and as such, it is widely used as a marker of dopaminergic cells. Within the basal ganglia, the dopaminergic cells are located in the substantia nigra pars compacta, and project to the striatum. It is this pathway which degenerates during Parkinson's disease. The data presented here illustrate examples of tyrosine-hydroxylase immunoreactive cells in striatum following intrastriatal injection with the neurotoxin MPP+. We further show by electron microscopy that these cells are, in fact, neurons and that they possess ultrastructural features of interneurons.

Directors' duty of care to monitor information systems in HMOs: some lessons from the Oxford Health Plan.

This paper examines the legal and strategic issues raised by the use of information systems in health maintenance organizations (HMOs) and other managed care organizations. Given the critical nature of information systems to an HMO's business success and regulatory compliance, the large financial investment HMOs make in their systems, and the widely publicized concerns over the year 2000 "millennium bug" problem, information systems are appropriately a matter of concern to an HMO's board of directors. The recent experience of Oxford Health Plans, Inc. offers a case study in the apparent failure of the directors to monitor adequately the in-house development of an information system. The systems disaster which this corporation suffered in 1997 led to a dramatic drop in stock price, from which the company has yet to recover, as well as intense scrutiny by state and federal regulators and countless shareholder derivative actions against the directors. Corporate directors are subject to the fiduciary duty of care. Despite statutes in some states requiring directors to act prudently, state courts almost always apply the standard of gross negligence. As a result, even when directors act without due deliberation in their decision, it is rare that a court will find them to have failed in their duty of care. The business and regulatory community may find otherwise, however, when directors fail to evaluate information systems options carefully and the business suffers as a result.

Effect of low intensity monochromatic light therapy (890 nm) on a radiation-impaired, wound-healing model in murine skin.

BACKGROUND AND OBJECTIVE: The use of low intensity laser and monochromatic light diodes as a therapeutic modality has become popular in a variety of clinical applications, including the promotion of wound repair. Despite this, the clinical evidence base for such application remains sparse; in contrast, recent studies have demonstrated a number of quantifiable photobiological effects associated with such therapy. In the present study, the effect of low intensity monochromatic light irradiation (MLI) at various radiant exposures upon a radiation-impaired wound model in murine skin was investigated. STUDY DESIGN/MATERIALS AND METHODS: Male Balb/c mice (n = 50; age matched at 10 weeks) were randomly allocated to five experimental groups (n = 10 each group). In Group 1, mice were left untreated; in Groups 2-5, a well-defined area on the dorsum was exposed to 20 Gy X-ray irradiation. At 72 hours postirradiation, all mice were anaesthetised and a 7-mm-square area wound was made on the dorsum. All wounds were videotaped alongside a marker scale until closure was complete. In Groups 3-5, mice were treated with MLI (0.18, 0.54, and 1.45 J/cm2, respectively) three times weekly using a GaAlAs 890 nm multidiode (n = 60) array unit (270 Hz; maximum rated output, 300 mW; Anodyne, Denver, CO). Subsequently, the area of each wound was measured from video using an image analysis system (Fenestra 2.1), and results were analysed using repeated measure and one-factor ANOVA statistical tests. RESULTS: X-ray irradiation caused a significant delay (P = 0.0122) in healing by day 7. MLI at 0.18 J/cm2 and 0.54 J/cm2 had no effect upon the rate of wound closure. However, a highly significant (P = 0.0001) inhibition occurred following MLI irradiation at 1.45 J/cm2 by day 16. CONCLUSION: These findings provide little evidence of the putative stimulatory effects of monochromatic light irradiation in vivo, but, rather, reveal the potential for an inhibitory effect at higher radiant exposures.

Assessment of neurotoxicity and "neuroprotection".

Coronal brain slices allow the study of neurotoxicity and "neuroprotection" under conditions where the differentiation-state and interrelationships of the neurones and glial cells are closer to those occurring in the intact tissue than is the case for co-cultured cell systems. The involvement of glial cells in the excitotoxicity of kainate and the potentiation of this toxicity by inhibition of glutamine synthase can be demonstrated. Longer-term toxicity of kainate may also be compounded by depletion of glutathione levels resulting from inhibition of gamma-glutamylcysteine synthase. The involvement of nitric oxide formation in the toxicity of N-methyl-D-aspartate can also be shown. The neurotoxicity of 1-methyl-4-phenylpyridinium can be readily demonstrated in coronal slice preparations. Taurine affords protection against this neurotoxicity. The possible mechanisms of these effects are considered in terms of the cyclic interrelationships between the different events which can lead to cell death.

Central lines inserted by clinical nurse specialists.

Historically, central venous tunnelled lines have been inserted by senior medical officers, usually in the operating theatre under general anaesthetic. This method of line placement is applied to patients requiring lines for total parenteral nutrition (TPN), chemotherapy and long-term antibiotic therapy. Since February, 1991, following extensive training, a clinical nurse specialist (CNS) has taken on this role and has expanded the service to include a central line insertion service (LIS) throughout the Oxfordshire district.

Secretion of progesterone and relaxin by the humancorpus luteum at midpregnancy and at term.

PIP: The secretion of progesterone (P) and relaxin (R):by the human corpus luteum at midpregnancy and at term was studied in 19 women, 6 of whom had their pregnancies terminated by hysterotomy at 14-18 weeks and 13 whose pregnancies went to term and were delivered by Caesarean section. Luteectomies were performed on 6 of the women at the time of Caesarean section. P and R levels were measured. R section correlated well with luteal P secretion. After Caesarean section at term the decline in serum P was parallel to that observed after hysterotomya at midtrimester. Absolute levels of P are higher at term. P decline after luteectomy was precipitous compared with Caesarean section. Results indicate that the corpus luteum in the human remains active throughout pregnancy.^ieng