Interleukin-6 is an efficacious marker of axonal transport disruption during experimental glaucoma and stimulates neuritogenesis in cultured retinal ganglion cells

It is increasingly recognised that chronically activated glia contribute to the pathology of various neurodegenerative diseases, including glaucoma. One means by which this can occur is through the release of neurotoxic, proinflammatory factors. In the current study, we therefore investigated the spatio-temporal patterns of expression of three such cytokines, IL-1β, TNFα and IL-6, in a validated rat model of experimental glaucoma. First, only weak evidence was found for increased expression of IL-1β and TNFα following induction of ocular hypertension. Second, and much more striking, was that robust evidence was uncovered showing IL-6 to be synthesised by injured retinal ganglion cells following elevation of intraocular pressure and transported in an orthograde fashion along the nerve, accumulating at sites of axonal disruption in the optic nerve head. Verification that IL-6 represents a novel marker of disrupted axonal transport in this model was obtained by performing double labelling immunofluorescence with recognised markers of fast axonal transport. The stimulus for IL-6 synthesis and axonal transport during experimental glaucoma arose from axonal injury rather than ocular hypertension, as the response was identical after optic nerve crush and bilateral occlusion of the carotid arteries, each of which is independent of elevated intraocular pressure. Moreover, the response of IL-6 was not a generalised feature of the gp130 family of cytokines, as it was not mimicked by another family member, ciliary neurotrophic factor. Finally, further study suggested that IL-6 may be an early part of the endogenous regenerative response as the cytokine colocalised with growth-associated membrane phosphoprotein-43 in some putative regenerating axons, and potently stimulated neuritogenesis in retinal ganglion cells in culture, an effect that was additive to that of ciliary neurotrophic factor. These data comprise clear evidence that IL-6 is actively involved in the attempt of injured retinal ganglion cells to regenerate their axons.

Tuberculosis in HIV-Negative and HIV-Infected Patients in a Low-Incidence Country: Clinical Characteristics and Treatment Outcomes

Background In Switzerland and other developed countries, the number of tuberculosis (TB) cases has been decreasing for decades, but HIV-infected patients and migrants remain risk groups. The aim of this study was to compare characteristics of TB in HIV-negative and HIV-infected patients diagnosed in Switzerland, and between coinfected patients enrolled and not enrolled in the national Swiss HIV Cohort Study (SHCS). Methods and Findings All patients diagnosed with culture-confirmed TB in the SHCS and a random sample of culture-confirmed cases reported to the national TB registry 2000–2008 were included. Outcomes were assessed in HIV-infected patients and considered successful in case of cure or treatment completion. Ninety-three SHCS patients and 288 patients selected randomly from 4221 registered patients were analyzed. The registry sample included 10 (3.5%) coinfected patients not enrolled in the SHCS: the estimated number of HIV-infected patients not enrolled in the SHCS but reported to the registry 2000–2008 was 146 (95% CI 122–173). Coinfected patients were more likely to be from sub-Saharan Africa (51.5% versus 15.8%, P<0.0001) and to present disseminated disease (23.9% vs. 3.4%, P<0.0001) than HIV-negative patients. Coinfected patients not enrolled in the SHCS were asylum seekers or migrant workers, with lower CD4 cell counts at TB diagnosis (median CD4 count 79 cells/µL compared to 149 cells/µL among SHCS patients, P = 0.07). There were 6 patients (60.0%) with successful outcomes compared to 82 (88.2%) patients in the SHCS (P = 0.023). Conclusions The clinical presentation of coinfected patients differed from HIV-negative TB patients. The number of HIV-infected patients diagnosed with TB outside the SHCS is similar to the number diagnosed within the cohort but outcomes are poorer in patients not followed up in the national cohort. Special efforts are required to address the needs of this vulnerable population.

First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07)

Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma.

Azacytidine for acute myeloid leukemia in elderly or frail patients: A phase II trial (SAKK 30/07)

Abstract This phase II trial treated elderly or frail AML patients with single agent subcutaneous azacytidine at 100 mg/m(2), on 5 of 28 days for up to 6 cycles. Treatment was stopped for lack of response, or continued to progression in responders. Primary endpoint was response within 6 months. A response rate >34% was considered a positive trial outcome. From 9/2008-4/2010, 45 patients from 10 centres (median age 74 (55-86) years) were accrued. Patients received 4 (1-21) cycles. Best response was CR/CRi in 8 (18%; 95% CI: 8%-32%.), 0 (0%) PR, 7 (16%) hematologic improvement, 17 (38%) stable disease. Three nonresponding patients stopped treatment after 6 cycles, 31 patients had stopped early and 11 patients continued treatment for 8-21 cycles. Adverse events (grade >III) were infections (13), febrile neutropenia (14), thrombocytopenia (7), dyspnea (6), bleeding (5) and anemia (4 patients). Median overall survival was 6 months. Peripheral blood blast counts, grouped at 30% had a borderline significant association with response (p = 0.07). This modified azacytidine schedule is feasible for elderly or frail AML patients in an outpatient setting with moderate, mainly hematologic, toxicity and response in a proportion of patients, although the primary objective was not reached.

Sleep-wake habits and disorders in a series of 100 adult epilepsy patients--a prospective study

The aim of the study was to assess sleep-wake habits and disorders and excessive daytime sleepiness (EDS) in an unselected outpatient epilepsy population. Sleep-wake habits and presence of sleep disorders were assessed by means of a clinical interview and a standard questionnaire in 100 consecutive patients with epilepsy and 90 controls. The questionnaire includes three validated instruments: the Epworth Sleepiness Scale (ESS) for EDS, SA-SDQ for sleep apnea (SA), and the Ullanlinna Narcolepsy Scale (UNS) for narcolepsy. Sleep complaints were reported by 30% of epilepsy patients compared to 10% of controls (p=0.001). The average total sleep time was similar in both groups. Insufficient sleep times were suspected in 24% of patients and 33% of controls. Sleep maintenance insomnia was more frequent in epilepsy patients (52% vs. 38%, p=0.06), whereas nightmares (6% vs. 16%, p=0.04) and bruxism (10% vs. 19%, p=0.07) were more frequent in controls. Sleep onset insomnia (34% vs. 28%), EDS (ESS >or=10, 19% vs. 14%), SA (9% vs. 3%), restless legs symptoms (RL-symptoms, 18% vs. 12%) and most parasomnias were similarly frequent in both groups. In a stepwise logistic regression model loud snoring and RL-symptoms were found to be the only independent predictors of EDS in epilepsy patients. In conclusion, sleep-wake habits and the frequency of most sleep disorders are similar in non-selected epilepsy patients as compared to controls. In epilepsy patients, EDS was predicted by a history of loud snoring and RL-symptoms but not by SA or epilepsy-related variables (including type of epilepsy, frequency of seizures, and number of antiepileptic drugs).

Comparative efficacy of two mouthrinses in a 6-month study

Objective: The objective of this study was to compare the effects of a commercial CPC (cetylpyridinium chloride) mouthrinse containing 0.07% CPC (Crest® ProHealth Rinse) versus those provided by a commercial essential flavor oil mouthrinse (Listerine® Antiseptic) on dental plaque accumulation and prevention of gingivitis in an unsupervised 6 month clinical study. Methods: This was a double blind, 6-month, parallel group, positive controlled study involving 128 subjects who were balanced and randomly assigned to either positive control (essential oil) or experimental (CPC) mouthrinse treatment groups. The CPC mouthrinse passed proposed performance assays by the FDA for an OTC CPC mouthrinse. At baseline, subjects received a dental prophylaxis and began unsupervised rinsing twice daily with 20 ml. of their assigned mouthrinse for 30 seconds after brushing their teeth for 1 min. Subjects were assessed for gingivitis and gingival bleeding by the Gingival Index (GI) of Loe and Silness and plaque by the Silness and Loe Plaque Index (PI) at baseline and after 3 and 6 months of product use. Oral soft tissue health was also assessed. Microbiological samples were also taken for community profiling by the DNA-DNA checkerboard method. Results: Results show that after 3 and 6 months use there was no significant difference (p = 0.05) between the CPC and essential oil mouthrinse treatment groups for overall gingivitis status, gingival bleeding, and plaque. At 6 months the covariant (baseline) –adjusted mean GI and bleeding sites numbers for the CPC and essential oil mouthrinses were 0.52 and 0.53 and 5.5 and 6.3, respectively. Both mouth rinses were well tolerated by the subjects. Microbiological community profiles were similar for the 2 treatment group. Conclusion: This study shows that the 0.07% CPC mouthrinse can provide similar plaque and gingivitis benefits to those provided by an essential oil mouthrinse over a 6 month period.

The self-administered 24-item geriatric pain measure (GPM-24-SA): psychometric properties in three European populations of community-dwelling older adults

OBJECTIVE: To explore the feasibility and psychometric properties of a self-administered version of the 24-item Geriatric Pain Measure (GPM-24-SA). DESIGN: Secondary analysis of baseline data from the Prevention in Older People-Assessment in Generalists' practices trial, an international multi-center study of a health-risk appraisal system. PARTICIPANTS: One thousand seventy-two community dwelling nondisabled older adults self-reporting pain from London, UK; Hamburg, Germany; and Solothurn, Switzerland. OUTCOME MEASURES: GPM-24-SA as part of a multidimensional Health Risk Appraisal Questionnaire including self-reported demographic and health-related information. RESULTS: Among the 1,072 subjects, 655 had complete GPM-24-SA data, 404 had 30% missing GPM-24-SA data. In psychometric analyses across the three European populations with complete GPM-24-SA data, the measure exhibited stable internal consistency, good convergent, divergent and discriminant validity, and produced stable pain measurements. However, factor analysis indicated differences in the GPM-24-SA across sites with discrepancies mainly related to items of a single subscale that failed to load appropriately. Analyses including imputation for subjects with

Aspirin, but not propranolol, attenuates the acute stress-induced increase in circulating levels of interleukin-6: a randomized, double-blind, placebo-controlled study

Psychosocial stress might increase the risk of atherothrombotic events by setting off an elevation in circulating levels of the proinflammatory cytokine interleukin (IL)-6. We investigated the effect of aspirin and propranolol on the responsiveness of plasma IL-6 levels to acute psychosocial stress. For 5 days, 64 healthy subjects were randomized, double-blind, to daily oral aspirin 100mg plus long-acting propranolol 80 mg, aspirin 100mg plus placebo, long-acting propranolol 80 mg plus placebo, or placebo plus placebo. Thereafter, all subjects underwent the 13-min Trier Social Stress Test, which combines a preparation phase, a job interview, and a mental arithmetic task. Plasma IL-6 levels were measured in blood samples collected immediately pre- and post-stress, and 45 min and 105 min thereafter. The change in IL-6 from pre-stress to 105 min post-stress differed between subjects with aspirin medication and those without (p =0.033; eta p2=0.059). IL-6 levels increased less from pre-stress to 105 min post-stress (p <0.027) and were lower (p =0.010) at 105 min post-stress in subjects with aspirin than in subjects without aspirin. The significance of these results was maintained when controlling for gender, age, waist-to-hip ratio, mean arterial blood pressure, and smoking status. Medication with propranolol was not significantly associated with the stress-induced change in IL-6 levels. Also, aspirin and propranolol did not significantly interact in determining the IL-6 stress response. Aspirin but not propranolol attenuated the stress-induced increase in plasma IL-6 levels. This suggests one mechanism by which aspirin treatment might reduce the risk of atherothrombotic events triggered by acute mental stress.

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07

BACKGROUND We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Vapnikite Ca3UO6 – a new double-perovskite mineral from pyrometamorphic larnite rocks of the Jabel Harmun, Palestinian Autonomy, Israel

The new mineral species vapnikite, Ca3UO6, was found in larnite pyrometamorphic rocks of the Hatrurim Formation at Jabel Harmun in the Judean desert, Palestinian Autonomy, Israel. Vapnikite is an analogue of the synthetic ordered double-perovskite β-Ca3UO6 and is isostructural with the natural fluorperovskite – cryolite Na3AlF6. Vapnikite Ca3UO6 (P21/n,Z = 2, a = 5.739(1), b = 5.951(1), c = 8.312(1) Å, β = 90.4(1)°, V = 283.9(1) Å3) forms yellow-brown xenomorphic grains with a strong vitreous lustre. Small grains up to 20 – 30 m m in size are wedged between larnite, brownmillerite and ye'elimite. Vapnikite has irregular fracture, cleavage and parting were not observed. The calculated density is 5.322 g cm–3, the microhardness is VHN25 = 534 kg mm–2 (mean of seven measurements) corresponding to the hardness of ~5 on the Mohs scale. The crystal structure of vapnikite Ca3UO6 differs from that of its synthetic analogue β-Ca3UO6 by having a larger degree of Ca, U disorder. Vapnikite formed at the high-temperature retrograde stage of pyrometamorphism when larnite rocks were altered by fluids/melts of high alkalinity.