Patterns of pain freedom response in 497 cases with classical trigeminal neuralgia and at least one year of follow-up treated by gamma knife radiosurgery

Purpose: To identify patterns of initially pain freedom response in patients with classical trigeminal neuralgia (CTN) with Gamma Knife surgery (GKS) and to compare their associated hypoesthesia and recurrence rates. Methods: In this study we analysed only 497 patients treated between July 1992 and November 2010, with a follow-up longer than 1 year, after excluding megadolichobasilar artery and multiple sclerosis related trigeminal neuralgia, as well as the second GKS treatments so as to have only cases with CTN and single radiosurgical treatment. GKS using a Gamma Knife (model B or C or Perfexion) was performed, based on both MRI and computer tomography (CT) targeting. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.8 mm (range 4.5-14) anteriorly to the emergence of the nerve. A median maximum dose of 85 Gy (range 70-90) was delivered. After empiric methods but also by using a chart with clear cut-off periods of pain free distribution, we were able to divide the initially pain free patients into 3 separate groups: within the first 48 hours, after 48 hours till 30 days and after 30 days, respectively. Results: The median follow- up period was 43.75 months (range 12-174.41). Four hundred and fifty-four patients (91.75%) were initially pain free in a median time of 10 days (range 1-459): 169 (37.2%) became pain free within the first 48 hours (pf<=48 h), compared to 194 (42.8%) between the 3-rd day and the day 30 (pf (>48 h, <=30 d)), inclusively and 91 (20%) patients after 30 days (pf>30d). Differences in terms of postoperative hypoesthesia were found with a p value of 0.014 as follows: the group pf<=48 h had 18 (13.7%) compared to pf (>48 h, <=30 d) with 30 (19%) and pf>30d with 22 (30.5%) patients developing a postoperative GKS hypoesthesia. One hundred and fifty seven (34.4%) patients initially pain free experienced a recurrence with a median delay of 24 months (range 0.62-150.06). There were no statistically significant differences between the three groups concerning recurrence (p value of 0.515). Conclusions: An important number of patients (169 cases, 37.2%) became pain free in the first 48 hours. Hypoesthesia rate was higher within the group becoming pain free after 30 days with a statistically significant difference between the three populations (p= 0.014). Further analysis will eventually help to elucidate the differences observed among groups.

Unusual astrocyte reactivity caused by the food mycotoxin ochratoxin A in aggregating rat brain cell cultures.

Ochratoxin A (OTA), a mycotoxin and widespread food contaminant, is known for its patent nephrotoxicity and potential neurotoxicity. Previous observations in vitro showed that in the CNS, glial cells were particularly sensitive to OTA. In the search for the molecular mechanisms underlying OTA neurotoxicity, we investigated the relationship between OTA toxicity and glial reactivity, in serum-free aggregating brain cell cultures. Using quantitative reverse transcriptase-polymerase chain reaction to analyze changes in gene expression, we found that in astrocytes, non cytotoxic concentrations of OTA down-regulated glial fibrillary acidic protein, while it up-regulated vimentin and the peroxisome proliferator-activated receptor-gamma expression. OTA also up-regulated the inducible nitric oxide synthase and the heme oxygenase-1. These OTA-induced alterations in gene expression were more pronounced in cultures at an advanced stage of maturation. The natural peroxisome proliferator-activated receptor-gamma ligand, 15-deoxy-delta(12,14) prostaglandin J2, and the cyclic AMP analog, bromo cyclic AMP, significantly attenuated the strong induction of peroxisome proliferator-activated receptor-gamma and inducible nitric oxide synthase, while they partially reversed the inhibitory effect of OTA on glial fibrillary acidic protein. The present results show that OTA affects the cytoskeletal integrity of astrocytes as well as the expression of genes pertaining to the brain inflammatory response system, and suggest that a relationship exists between the inflammatory events and the cytoskeletal changes induced by OTA. Furthermore, these results suggest that, by inducing an atypical glial reactivity, OTA may severely affect the neuroprotective capacity of glial cells.

Expression pattern of sirtuins in innate immune cells and influence of Sirtuin 1/2 inhibition on innate immune responses to Toll-like receptor ligands and to infection

Purpose/Objective: The family of histone deacetylases comprises 18 members in mammals, among which seven sirtuins (SIRT1-7). Sirtuins are NADP-dependent enzymes that have been involved in the control of cell metabolism, proliferation and survival. The expression pattern of sirtuins and their influence on host response to microbial infection remain largely unknown. The aim of the study was to analyze the expression of SIRT1-7 and to address the effects of SIRT1/2 inhibition on innate immune responses in vitro and in vivo.. Materials and methods: in vitro: Bone marrow (BM), BM-derived macrophages (BMDMs) and dendritic cells (BMDCs) and RAW 264.7 and J774.1 macrophage cell lines were stimulated for 0, 2, 6 and 18 h with LPS, Pam3CSK4 and CpG ODN. SIRT1-7 mRNA was quantified by real time-PCR. TNF was measured by ELISA. In vivo: BALB/c mice were challenged with LPS (350 lg i.p.) with or without a SIRT1/2 inhibitor. Blood and organs were collected after 0, 1, 4, 8 and 24 h to quantify SIRT1-7 and TNF. Mortality was assessed daily. Results: Bone marrow, macrophages and DCs express, in order of abundance, SIRT2 > > SIRT1, SIRT3 and SIRT6 > SIRT4, SIRT5 and SIRT7. Microbial products decrease the expression of all sirtuins except SIRT6 in a time dependent manner in BMDMs (0_24 h). SIRT2 is the most expressed sirtuin also in the liver, kidney (together with SIRT3) and spleen. Upon LPS challenge, SIRT1, SIRT3, SIRT4 and SIRT7 mRNA levels decrease in the liver (from 4 h to 24 h), whereas SIRT1-7 mRNA levels decrease within 1 h in both kidney and spleen. Pharmacological inhibition of SIRT1/2 decreases TNF production by macrophages stimulated with LPS, Pam3CSK4 and CpG ODN (n = 6; P < 0.001). In agreement, prophylactic treatment with a SIRT1/2 inhibitor decreases TNF production (n = 8; P = 0.04) and increases survival (n = 13, P = 0.03) of mice challenged with LPS. Conclusions: Sirtuins are expressed in innate immune cells. Inhibition of SIRT1/2 activity decreases cytokine production by macrophages and protects from endotoxemia, suggesting that sirtuin inhibitors may represent novel adjunctive therapy for treating inflammatory disorders such as sepsis.

Risk determinants of acute mountain sickness in trekkers in the Nepali Himalaya: a 24-year follow-up.

OBJECTIVE: Exposure to altitude may lead to acute mountain sickness (AMS) in nonacclimatized individuals. We surveyed AMS prevalence and potential risk factors in trekkers crossing a 5400-m pass in Nepal and compared the results with those of 2 similar studies conducted 12 and 24 years earlier. METHODS: In April 2010, 500 surveys were distributed to English-speaking trekkers at 3500 m on their way to 5400 m, of which 332 (66%) surveys were returned complete. Acute mountain sickness was quantified with the Lake Louise Scoring System (LLSS, cutoff ≥3 and ≥5) and the Environmental Statistical Questionnaire III AMS-C score (ESQ-III, cutoff ≥0.7). We surveyed demographics, body mass index (BMI), smoking habit, rate of ascent, awareness of AMS, and acetazolamide use. RESULTS: Prevalence of AMS was 22%, 23%, and 48% (ESQ-III ≥0.7, LLSS ≥5, and LLSS ≥3, respectively) lower when compared with earlier studies. Risk factors for AMS were younger age, female sex, higher BMI, and smoking habit. Forty-two percent had elementary knowledge about the risk and prevention of AMS. Forty-four percent used acetazolamide. Trekkers took longer to climb from 3500 to 5400 m than in earlier studies. CONCLUSIONS: Prevalence of AMS continued to decline over a period of 24 years, likely as a result of slower ascent and increased use of acetazolamide. The AMS risk factors of younger age, female sex, and high BMI are consistent with prior studies. Awareness of risk and prevention of AMS remains low, indicating an opportunity to better educate trekkers and potentially further reduce AMS prevalence.

Health problems among detainees in Switzerland: a study using the ICPC-2 classification.

BACKGROUND: Little is known about the health status of prisoners in Switzerland. The aim of this study was to provide a detailed description of the health problems presented by detainees in Switzerland's largest remand prison. METHODS: In this retrospective cross-sectional study we reviewed the health records of all detainees leaving Switzerland's largest remand prison in 2007. The health problems were coded using the International Classification for Primary Care (ICPC-2). Analyses were descriptive, stratified by gender. RESULTS: A total of 2195 health records were reviewed. Mean age was 29.5 years (SD 9.5); 95% were male; 87.8% were migrants. Mean length of stay was 80 days (SD 160). Illicit drug use (40.2%) and mental health problems (32.6%) were frequent, but most of these detainees (57.6%) had more generic primary care problems, such as skin (27.0%), infectious diseases (23.5%), musculoskeletal (19.2%), injury related (18.3%), digestive (15.0%) or respiratory problems (14.0%). Furthermore, 7.9% reported exposure to violence during arrest by the police. CONCLUSION: Morbidity is high in this young, predominantly male population of detainees, in particular in relation to substance abuse. Other health problems more commonly seen in general practice are also frequent. These findings support the further development of coordinated primary care and mental health services within detention centers.

Thirteen years of surgical site infection surveillance in Swiss hospitals.

BACKGROUND: Surveillance is an essential element of surgical site infection (SSI) prevention. Few studies have evaluated the long-term effect of these programmes. AIM: To present data from a 13-year multicentre SSI surveillance programme from western and southern Switzerland. METHODS: Surveillance with post-discharge follow-up was performed according to the US National Nosocomial Infections Surveillance (NNIS) system methods. SSI rates were calculated for each surveyed type of surgery, overall and by year of participation in the programme. Risk factors for SSI and the effect of surveillance time on SSI rates were analysed by multiple logistic regression. FINDINGS: Overall SSI rates were 18.2% after 7411 colectomies, 6.4% after 6383 appendicectomies, 2.3% after 7411 cholecystectomies, 1.7% after 9933 herniorrhaphies, 1.6% after 6341 hip arthroplasties, and 1.3% after 3667 knee arthroplasties. The frequency of SSI detected after discharge varied between 21% for colectomy and 94% for knee arthroplasty. Independent risk factors for SSI differed between operations. The NNIS risk index was predictive of SSI in gastrointestinal surgery only. Laparoscopic technique was protective overall, but associated with higher rates of organ-space infections after appendicectomy. The duration of participation in the surveillance programme was not associated with a decreased SSI rate for any of the included procedure. CONCLUSION: These data confirm the effect of post-discharge surveillance on SSI rates and the protective effect of laparoscopy. There is a need to establish alternative case-mix adjustment methods. In contrast to other European programmes, no positive impact of surveillance duration on SSI rates was observed.

Gefitinib in Combination With Irradiation With or Without Cisplatin in Patients With Inoperable Stage III Non-Small Cell Lung Cancer: A Phase I Trial.

Purpose : To establish the feasibility and tolerability of gefitinib (ZD1839, Iressa) with radiation (RT) or concurrent chemoradiation (CRT) with cisplatin (CDDP) in patients with advanced non small cell lung cancer (NSCLC).Patients and Methods : In this multicenter Phase I study, 5 patients with unresectable NSCLC received 250 mg gefitinib daily starting 1 week before RT at a dose of 63 Gy (Step 1). After a first safety analysis, 9 patients were treated daily with 250 mg gefitinib plus CRT in the form of RT and weekly CDDP 35 mg/m(2) (Step 2). Gefitinib was maintained for up to 2 years until disease progression or toxicity.Results : Fourteen patients were assessed in the two steps. In Step 1 (five patients were administered only gefitinib and RT), no lung toxicities were seen, and there was no dose-limiting toxicity (DLT). Adverse events were skin and subcutaneous tissue reactions, limited to Grade 1-2. In Step 2, two of nine patients (22.2%) had DLT. One patient suffered from dyspnea and dehydration associated with neutropenic pneumonia, and another showed elevated liver enzymes. In both steps combined, 5 of 14 patients (35.7%) experienced one or more treatment interruptions.Conclusions : Gefitinib (250 mg daily) in combination with RT and CDDP in patients with Stage HI NSCLC is feasible, but CDDP likely enhances toxicity. The impact of gefitinib on survival and disease control as a first-line treatment in combination with RT remains to be determined. (C) 2011 Elsevier Inc.

Methods for the ex vivo characterization of human CD8+ T subsets based on gene expression and replicative history analysis.

The generation of an antigen-specific T-lymphocyte response is a complex multi-step process. Upon T-cell receptor-mediated recognition of antigen presented by activated dendritic cells, naive T-lymphocytes enter a program of proliferation and differentiation, during the course of which they acquire effector functions and may ultimately become memory T-cells. A major goal of modern immunology is to precisely identify and characterize effector and memory T-cell subpopulations that may be most efficient in disease protection. Sensitive methods are required to address these questions in exceedingly low numbers of antigen-specific lymphocytes recovered from clinical samples, and not manipulated in vitro. We have developed new techniques to dissect immune responses against viral or tumor antigens. These allow the isolation of various subsets of antigen-specific T-cells (with major histocompatibility complex [MHC]-peptide multimers and five-color FACS sorting) and the monitoring of gene expression in individual cells (by five-cell reverse transcription-polymerase chain reaction [RT-PCR]). We can also follow their proliferative life history by flow-fluorescence in situ hybridization (FISH) analysis of average telomere length. Recently, using these tools, we have identified subpopulations of CD8+ T-lymphocytes with distinct proliferative history and partial effector-like properties. Our data suggest that these subsets descend from recently activated T-cells and are committed to become differentiated effector T-lymphocytes.

Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer.

BACKGROUND: The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and letrozole is superior to letrozole therapy alone. METHODS: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment with the other. We compared the sequential treatments with letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of letrozole versus tamoxifen monotherapy in 4922 women. RESULTS: At a median follow-up of 71 months after randomization, disease-free survival was not significantly improved with either sequential treatment as compared with letrozole alone (hazard ratio for tamoxifen followed by letrozole, 1.05; 99% confidence interval [CI], 0.84 to 1.32; hazard ratio for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76 to 1.21). There were more early relapses among women who were assigned to tamoxifen followed by letrozole than among those who were assigned to letrozole alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with letrozole and those assigned to treatment with tamoxifen (hazard ratio for letrozole, 0.87; 95% CI, 0.75 to 1.02; P=0.08). The rate of adverse events was as expected on the basis of previous reports of letrozole and tamoxifen therapy. CONCLUSIONS: Among postmenopausal women with endocrine-responsive breast cancer, sequential treatment with letrozole and tamoxifen, as compared with letrozole monotherapy, did not improve disease-free survival. The difference in overall survival with letrozole monotherapy and tamoxifen monotherapy was not statistically significant. (ClinicalTrials.gov number, NCT00004205.)

Probing the interactions of NK cell receptors with ligand expressed in trans and cis.

Certain receptors on natural killer (NK) cells, which are specific for MHC class I (MHC-I) molecules, do not only interact with ligand expressed on opposing cell membranes (in trans) but also interact with those on the same cell membrane (in cis). Cis interactions have been demonstrated for only a small number of cell surface receptors. However, this has not been tested systematically, raising the possibility that additional receptors may be able to bind ligand expressed in cis. Here we describe a number of approaches to evaluate trans and cis binding of the Ly49A NK cell receptor to its H-2D(d) ligand. These procedures should facilitate the investigation of cis/trans interactions of other receptor-ligand pairs and simplify the analysis of NK cell receptor variants.

Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism.

BACKGROUND: The Outpatient Bleeding Risk Index (OBRI) and the Kuijer, RIETE and Kearon scores are clinical prognostic scores for bleeding in patients receiving oral anticoagulants for venous thromboembolism (VTE). We prospectively compared the performance of these scores in elderly patients with VTE. METHODS: In a prospective multicenter Swiss cohort study, we studied 663 patients aged ≥ 65 years with acute VTE. The outcome was a first major bleeding at 90 days. We classified patients into three categories of bleeding risk (low, intermediate and high) according to each score and dichotomized patients as high vs. low or intermediate risk. We calculated the area under the receiver-operating characteristic (ROC) curve, positive predictive values and likelihood ratios for each score. RESULTS: Overall, 28 out of 663 patients (4.2%, 95% confidence interval [CI] 2.8-6.0%) had a first major bleeding within 90 days. According to different scores, the rate of major bleeding varied from 1.9% to 2.1% in low-risk, from 4.2% to 5.0% in intermediate-risk and from 3.1% to 6.6% in high-risk patients. The discriminative power of the scores was poor to moderate, with areas under the ROC curve ranging from 0.49 to 0.60 (P = 0.21). The positive predictive values and positive likelihood ratios were low and varied from 3.1% to 6.6% and from 0.72 to 1.59, respectively. CONCLUSION: In elderly patients with VTE, existing bleeding risk scores do not have sufficient accuracy and power to discriminate between patients with VTE who are at a high risk of short-term major bleeding and those who are not.

Modern cataract surgery for radiation-induced cataracts in retinoblastoma.

Background Surgery of radiation-induced cataracts in children with retinoblastoma (RB) is a challenge as early intervention is weighted against the need to delay surgery until complete tumour control is obtained. This study analyses the safety and functional results of such surgery. Methods In a retrospective, non-comparative, consecutive case series, we reviewed medical records of RB patients </=14 y of age who underwent either external beam radiotherapy or plaque treatment and were operated for radiation-induced cataract between 1985 and 2008. Results In total, 21 eyes of 20 RB patients were included and 18 out of the 21 eyes had Reese-Ellsworth stage V or ABC classification group D/E RB. Median interval between last treatment for RB and cataract surgery was 21.5 months, range 3-164 months. Phacoaspiration was performed in 13 eyes (61%), extra-capsular cataract extraction in 8 (39%) and intraocular lens implantation in 19 eyes (90%). The majority of cases, 11/21 (52%), underwent posterior capsulorhexis or capsulotomy and 6/21 (28%) an anterior vitrectomy. Postoperative visual acuity was >/=20/200 in 13 eyes and <20/200 in 5 eyes. Intraocular tumour recurrence was noted in three eyes. Mean postoperative follow up was 90 months+/-69 months. Conclusions Modern cataract surgery, including clear cornea approach, lens aspiration with posterior capsulotomy, anterior vitrectomy and IOL implantation is a safe procedure for radiation-induced cataract as long as RB is controlled. The visual prognosis is limited by initial tumour involvement of the macula and by corneal complications of radiotherapy. We recommend a minimal interval of 9 months between completion of treatment of retinoblastoma and cataract surgery.

Physical activity and energy expenditure in haemodialysis patients: an international survey.

BACKGROUND: The assessment of physical activity and energy expenditure is relevant to the care of maintenance haemodialysis (MHD) patients. In the current study, we aimed to evaluate measurements of physical activity and energy expenditure in MHD patients from different centres and countries and explored the predictors of physical activity in these patients.¦METHODS: In this cross-sectional multicentre study, 134 MHD patients from four countries (France, Switzerland, Sweden and Brazil) were included. The physical activity was evaluated for 5.0 ± 1.4 days (mean ± SD) by a multisensory device (SenseWear Armband) and comprised the assessment of number of steps per day, activity-related energy expenditure (activity-related EE) and physical activity level (PAL).¦RESULTS: The number of steps per day, activity-related EE and PAL from the MHD patients were compatible with a sedentary lifestyle. In addition, all parameters were significantly lower in dialysis days when compared to non-dialysis days (P < 0.001). The multivariate regression analysis revealed that diabetes and higher body mass index (BMI) predicted a lower PAL and older age and diabetes predicted a reduced number of steps.¦CONCLUSIONS: The physical activity parameters of MHD patients were compatible with a sedentary lifestyle. This inactivity was worsened by aging, diabetes and higher BMI. Our results indicate that MHD patients should be encouraged by the health care team to increase their physical activity.

AIDS defining opportunistic infections in patients with high CD4 counts in the combination antiretroviral therapy (cART) era: things ain't what they used to be.

INTRODUCTION: According to reports from observational databases, classic AIDS-defining opportunistic infections (ADOIs) occur in patients with CD4 counts above 500/µL on and off cART. Adjudication of these events is usually not performed. However, ADOIs are often used as endpoints, for example, in analyses on when to start cART. MATERIALS AND METHODS: In the database, Swiss HIV Cohort Study (SHCS) database, we identified 91 cases of ADOIs that occurred from 1996 onwards in patients with the nearest CD4 count >500/µL. Cases of tuberculosis and recurrent bacterial pneumonia were excluded as they also occur in non-immunocompromised patients. Chart review was performed in 82 cases, and in 50 cases we identified CD4 counts within six months before until one month after ADOI and had chart review material to allow an in-depth review. In these 50 cases, we assessed whether (1) the ADOI fulfilled the SHCS diagnostic criteria (www.shcs.ch), and (2) HIV infection with CD4 >500/µL was the main immune-compromising condition to cause the ADOI. Adjudication of cases was done by two experienced clinicians who had to agree on the interpretation. RESULTS: More than 13,000 participants were followed in SHCS in the period of interest. Twenty-four (48%) of the chart-reviewed 50 patients with ADOI and CD4 >500/µL had an HIV RNA <400 copies/mL at the time of ADOI. In the 50 cases, candida oesophagitis was the most frequent ADOI in 30 patients (60%) followed by pneumocystis pneumonia and chronic ulcerative HSV disease (Table 1). Overall chronic HIV infection with a CD4 count >500/µL was the likely explanation for the ADOI in only seven cases (14%). Other reasons (Table 1) were ADOIs occurring during primary HIV infection in 5 (10%) cases, unmasking IRIS in 1 (2%) case, chronic HIV infection with CD4 counts <500/µL near the ADOI in 13 (26%) cases, diagnosis not according to SHCS diagnostic criteria in 7 (14%) cases and most importantly other additional immune-compromising conditions such as immunosuppressive drugs in 14 (34%). CONCLUSIONS: In patients with CD4 counts >500/ µL, chronic HIV infection is the cause of ADOIs in only a minority of cases. Other immuno-compromising conditions are more likely explanations in one-third of the patients, especially in cases of candida oesophagitis. ADOIs in HIV patients with high CD4 counts should be used as endpoints only with much caution in studies based on observational databases.