The personal impact of living with a myeloproliferative neoplasm.

OBJECTIVE: The aim of this study is to gain insight into the physical, psychological and social impact of having a myeloproliferative neoplasm (MPN), a rare type of cancer with an often chronic course. METHODS: An online survey was conducted among 455 Dutch MPN patients (62.7% female, age M 63) to explore the impact of the disease by measuring the MPN symptom burden (MPN-SAF TSS) and quality of life (QoL) (EORTC QLQ-C30) and its subscales within a hierarchical QoL model. We examined differences in MPN symptom burden and QoL in relation to sociodemographic and disease-related factors. Hierarchical regression analysis was used to explain variances in QoL. RESULTS: Most patients (97%) experienced MPN-related health complaints, with a significantly higher MPN symptom burden in women (M 31.50) compared to men (M 24.10). Regarding to fatigue and cognitive functioning MPN patients suffered more compared to a reference group of other cancers. MPN subtype or type of treatment did not show significant differences in MPN symptom burden or QoL. However, experiencing side effects, complications or comorbidities significantly negatively affected MPN symptom burden and QoL. 48.8% of patients reported that MPN affected their ability to work. The explained variance in overall QoL was 58%, most importantly by disease progression, comorbidities, MPN symptom burden and role, emotional and social functioning. CONCLUSION: This study revealed that having an MPN has a negative impact on several domains of QoL. Symptom assessment and support should be included in the healthcare management of MPN patients.

Age-associated systemic factors change central and peripheral immunity in adult male mice.

Aging coincides with major changes in brain immunity that aid in a decline in neuronal function. Here, we postulate that systemic, pro-aging factors contribute to immunological changes that occur within the brain during aging. To investigate this hypothesis, we comprehensively characterized the central and peripheral immune landscape of 20-month-old male mice using cytometry by time-of-flight (CyTOF) and investigated the role of age-associated circulating factors. We found that CD8+ T cells expressing programmed cell death protein 1 (PD1) and tissue-resident memory CD8+ T cells accumulated in the aged brain while levels of memory T cells rose in the periphery. Injections of plasma derived from 20-month-old mice into 5-month-old receiving mice decreased the frequency of splenic and circulating naïve T cells, increased memory CD8+ T cells, and non-classical, patrolling monocytes in the spleen, and elevated levels of regulatory T cells and non-classical monocytes in the blood. Notably, CD8+ T cells accumulated within white matter areas of plasma-treated mice, which coincided with the expression of vascular cell adhesion molecule 1 (VCAM-1), a mediator of immune cell trafficking, on the brain vasculature. Taken together, we here describe age-related immune cell changes in the mouse brain and circulation and show that age-associated systemic factors induce the expansion of CD8+ T cells in the aged brain.

Facing privacy in neuroimaging: removing facial features degrades performance of image analysis methods.

BACKGROUND: Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants' privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups. METHODS: FFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer's Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests. RESULTS: Automated analysis methods failed in 0-19% of cases in FFR-processed images versus 0-2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p < 0.001). CONCLUSIONS: All three outcome measures were affected differently by FFR, including failure of analysis methods and both "random" variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants' privacy. KEY POINTS: • Protecting participants' privacy when sharing MRI data is important. • Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups. • Removing facial features degrades performance of image analysis methods.

Can mental health treatments help prevent or reduce intimate partner violence in low- and middle-income countries? A systematic review.

BACKGROUND: Epidemiological research suggests an interrelationship between mental health problems and the (re)occurrence of intimate partner violence (IPV). However, little is known about the impact of mental health treatments on IPV victimization or perpetration, especially in low- and middle-income countries (LMIC). METHODS: We conducted a systematic review to identify prospective, controlled studies of mental health treatments in LMIC. We defined 'mental health treatment' as an intervention for individuals experiencing mental ill health (including substance misuse) including a substantial psychosocial or pharmacological component. Studies had to measure a mental health and IPV outcome. We searched across multi-disciplinary databases using a structured search strategy. Screening of title/abstracts and full-text eligibility assessments were conducted by two researchers independently, data were extracted using a piloted spreadsheet, and a narrative synthesis was generated. RESULTS: We identified seven studies reported in 11 papers conducted in five middle-income countries. With the exception of blinding, studies overall showed acceptable levels of risk of bias. Four of the seven studies focused on dedicated mental health treatments in various populations, including: common mental disorders in earthquake survivors; depression in primary care; alcohol misuse in men; and alcohol misuse in female adult sex workers. The dedicated mental health treatments targeting depression or alcohol misuse consistently reduced levels of these outcomes. The two studies targeting depression also reduced short-term IPV, but no IPV benefits were identified in the two alcohol-focused studies. The other three studies evaluated integrated interventions, in which a focus on substance misuse was part of efforts to reduce HIV/AIDS and violence against particularly vulnerable women. In contrast to the dedicated mental health interventions, the integrated interventions did not consistently reduce mental ill health or alcohol misuse compared to control conditions. CONCLUSIONS: Too few studies have been conducted to judge whether mental health treatments may provide a beneficial strategy to prevent or reduce IPV in LMIC. Key future research questions include: whether promising initial evidence on the effects of depression interventions on reducing IPV hold more broadly, the required intensity of mental health components in integrated interventions, and the identification of mechanisms of IPV that are amenable to mental health intervention.

[Psoriasis and the microbiome]. / Psoriasis und Mikrobiom.

BACKGROUND: Psoriasis is a frequent chronic inflammatory systemic disease. It is associated with changes in the microbiome, which may trigger psoriasis and influence the course of the disease. OBJECTIVE: Current methods for detection and the potential role of the microbiome in the pathogenesis of psoriasis are described. MATERIAL AND METHODS: A literature search was conducted using the databases Medline and PubMed as well as a general internet and book research. RESULTS: Both skin and gut microbiota are involved in the immunopathogenesis and may substantially modulate psoriasis. Antimicrobial peptides may serve as a link between the microbiome and the immunological mechanisms in psoriasis by regulating the microbiome at interfaces and can trigger psoriasis as antigens. Recent innovative methods, such as 16S rRNA next-generation sequencing significantly facilitate microbiome analysis. CONCLUSION: The analysis of the microbiome in patients with psoriasis before, during and after treatment provides a basis for the identification of potential biomarkers for predicting individual treatment responses and facilitating the decision for a certain treatment.

Demography, maternal health and the epidemiology of malaria and other major infectious diseases in the rural department Tsamba-Magotsi, Ngounie Province, in central African Gabon.

BACKGROUND: Sub-Saharan Africa is undergoing an epidemiological transition from a predominance of infectious diseases to non-communicable and lifestyle related conditions. However, the pace of this transition and the pattern of disease epidemiology are uneven between affluent urban and rural poor populations. To address this question for a remote rural region located in the central African rainforest region of Gabon, this study was conducted to assess reasons for health care attendance and to characterize the epidemiology of malaria and other major infectious diseases for the department of Tsamba Magotsi. METHODS: Major causes for health care attendance were collected from local hospital records. Cross sectional population based surveys were performed for the assessment of local malaria epidemiology. Pregnant women attending antenatal care services were surveyed as a sentinel population for the characterization of chronic viral and parasitic infections in the community. RESULTS: Infectious diseases were responsible for 71% (7469) of a total of 10,580 consultations at the formal health care sector in 2010. Overall, malaria - defined by clinical syndrome - remained the most frequent cause for health care attendance. A cross sectional malaria survey in 840 asymptomatic individuals residing in Tsamba Magotsi resulted in a Plasmodium spp. infection prevalence of 37%. The infection rate in 2-10 year old asymptomatic children - a standard measure for malaria endemicity - was 46% (100 of 217) with P. falciparum as predominant species (79%). Infection with other plasmodial species (P. ovale and P. malariae) presented most commonly as coinfections (23.2%). Prevalence of HIV, HBV, and syphilis were 6.2, 7.3, and 2.5%, respectively, in cross-sectional assessments of antenatal care visits of pregnant women. Urogenital schistosomiasis and the filarial pathogens Loa loa and Mansonella perstans are highly prevalent chronic parasitic infections affecting the local population. CONCLUSIONS: Despite major improvements in the accessibility of Tsamba Magotsi over the past decade the epidemiological transition does not appear to have majorly changed on the spectrum of diseases in this rural Gabonese population. The high prevalence of Plasmodium infection indicates a high burden of malaria related morbidity. Infectious diseases remain one of the most important health issues and further research activities in the field of tropical medicine and infectious diseases could help improve health care for the local population.

Density functional theory of the CuA -like Cu2 S2 diamond core in Cu 2II(NGuaS)2 Cl2.

Density functional theory (DFT) calculations with localized as well as plane-wave basis functions are performed for the recently reported dicopper thiolate species Cu2 (NGuaS)2 Cl2 [NGuaS = 2-(1,1,3,3-tetramethylguanidino) benzenethiolate, C11 H16 N3 S] and its bromo derivative [Neuba et al., Angew. Chem. Int. Ed. 2012, 51, 1714.]. For both hybrid and semilocal functionals, the neutral complexes are found to have broken symmetry (BS) character, with electron paramagnetic resonance silent, antiferromagnetically coupled [Cu(2+) …Cu(2+) ] site in which the coupling is driven by super exchange interaction within the Cu2 S2 diamond core. The accurate theoretical description of the geometric structure, however, provides a major challenge for DFT: (i) the multideterminant character of the ground state wave function has to be covered by the BS approach. It requires (ii) metageneralized gradient approximations, that is hybrid functionals with an explicit dependence on the kinetic energy of the individual orbitals: In combination with a dispersion correction, the metafunctional TPSSh results in a CuCu distance close to the experimentally observed value of 2.7 Å. For the negative charge state of the complex, a mixed-valent [Cu(1.5+) …Cu(1.5+) ] electronic structure with a smaller CuCu distance of 2.6 Å is predicted, similar to the value of the CuA site of cytochrome c oxidase.

Proposal for Prevention or Alleviation of Protein/Lymph-Losing Enteropathy (PLE/LLE) After Fontan Circulation Treatment of Univentricular Hearts: Restoration of Lymph Balance With a "Lymphatic Right-to-Left Shunt."

In Fontan circulations created for univentricular hearts, systemic venous return is diverted to the lungs before returning to the heart. The Total Cavopulmonary Connection (TCPC) is often the preferred surgical procedure whereby a 4-way anastomosis is created with inflow from the superior vena cava (SVC) and inferior vena cava (IVC) and outflow to the right and left branches of the pulmonary artery. In this arrangement, the systemic venous pressure must be elevated sufficiently to perfuse the lungs passively without the normal boost of the right ventricle. Hence, unlike surgical corrections for other congenital heart conditions, the systemic venous pressures in a Fontan circuit must be elevated to make the circulation work. It is proposed here that the incidence of PLE/LLE is directly related to elevated venous and lymphatic pressures, which cause leakage of proteins/lymph into the gastrointestinal tract (GIT) and expulsion from the body. It is commonly held that elevated venous pressures are relatively better tolerated in the upper body, but much less so in the heptatosplanchnic circulation and the lower body. It is also well established that elevated venous pressure increases lymph formation, most of which is produced in the hepatosplanchnic region (liver and intestine). It is further argued here that the increase in lymph filling pressure arising from the higher lymph flow, in association with the backpressure exerted by elevated venous pressure at the main drainage point into the venous system, results in a substantial increase in pressure in the thoracic duct. This pressure is transmitted back to the intestinal lymphatics, causing dilatation with lacteal rupture and protein or bulk lymph leakage into the intestine. We propose in this paper a new approach, based on experimental evidence, to prevent and/or alleviate this condition by draining or redirecting the thoracic duct (or, alternatively, a more localized intestinal lymphatic vessel) into one of the pulmonary veins or the left atrium, which are typically at near-normal pressure in a Fontan circulation. This "lymphatic-venous right-to-left" shunt maneuver would significantly reduce the venous backpressure on the lymphatics as well as improve lymph circulation, resulting in a decrease in the intestinal lymphatic pressure and thereby prevent or alleviate protein/lymph loss, i.e. lymph balance would be restored. Moreover, the greatly facilitated lymphatic flow would encourage further capillary filtration to relieve excessive venous pressure in the hepatosplanchnic region and protect the liver and kidneys. This paper is intended as a discussion document for elicitation of comments on the soundness and viability of this proposal as well as on technical challenges and steps to explore and advance it.

Comparative evaluation of HD 2D/3D laparoscopic monitors and benchmarking to a theoretically ideal 3D pseudodisplay: even well-experienced laparoscopists perform better with 3D.

BACKGROUND: Though theoretically superior to standard 2D visualization, 3D video systems have not yet achieved a breakthrough in laparoscopy. The latest 3D monitors, including autostereoscopic displays and high-definition (HD) resolution, are designed to overcome the existing limitations. METHODS: We performed a randomized study on 48 individuals with different experience levels in laparoscopy. Three different 3D displays (glasses-based 3D monitor, autostereoscopic display, and a mirror-based theoretically ideal 3D display) were compared to a 2D HD display by assessing multiple performance and mental workload parameters and rating the subjects during a laparoscopic suturing task. Electromagnetic tracking provided information on the instruments' pathlength, movement velocity, and economy. The usability, the perception of visual discomfort, and the quality of image transmission of each monitor were subjectively rated. RESULTS: Almost all performance parameters were superior with the conventional glasses-based 3D display compared to the 2D display and the autostereoscopic display, but were often significantly exceeded by the mirror-based 3D display. Subjects performed a task faster and with greater precision when visualization was achieved with the 3D and the mirror-based display. Instrument pathlength was shortened by improved depth perception. Workload parameters (NASA TLX) did not show significant differences. Test persons complained of impaired vision while using the autostereoscopic monitor. The 3D and 2D displays were rated user-friendly and applicable in daily work. Experienced and inexperienced laparoscopists profited equally from using a 3D display, with an improvement in task performance about 20%. CONCLUSION: Novel 3D displays improve laparoscopic interventions as a result of faster performance and higher precision without causing a higher mental workload. Therefore, they have the potential to significantly impact the further development of minimally invasive surgery. However, as shown by the custom-built 3D mirror display, this effect can be improved, thus stimulating further research.

[Treatment of a subsequently detected, iatrogenic colonic perforation via minimal-invasive rendezvous procedure]. / Versorgung einer spät entdeckten, iatrogenen Kolonperforation via minimalinvasivem Rendezvous-Verfahren.

Laparoscopic surgery as primary therapeutical option for iatrogenic colonic perforation after colonoscopy can be complemented by intraoparative colonoscopy in order to detect and treat even difficult accessible lesions. Via the presented method minimal invasisve detection and therapy of perforation can be conducted safely and can lead to reduction of morbidity.

A novel FLT4 mutation identified in a patient with Milroy disease.

Milroy disease is an autosomal dominant disorder generally presenting with below the knee lymphedema at birth. It is linked to mutations in the tyrosine kinase domain of the VEGFR3 protein which is encoded in the FLT4 gene. Here we report a case of Milroy disease in a patient with a dominant pattern of inheritance, classical physical findings, and lymphatic system imaging demonstrating lack of tracer transport in the lower limbs. Genetic analysis revealed a novel missense mutation compared to a summary of reported mutations causing Milroy Disease.

Decontamination of a robot used to reprocess reusable surgical instruments.

BACKGROUND: Using robots to handle medical devices in the decontamination area of the Central Sterile Supply Department (CSSD) can reduce risks and address staff shortages. The gripper design must allow reliable cleaning using standard CSSD procedures to avoid build-up of biofilms and possible cross-contamination between different instrument trays and the gripper's functionality. This study explores the design of the robot's gripper regarding cleanability, aiming to determine whether successful cleaning can be achieved even after prolonged drying for a working shift of 8 h. METHODS: We optimized a gripper for cleanability and used it to assess the spread of different test soils depending on different forms of motion. Subsequently, we analysed the cleanability using sheep's blood as test soil, reprocessing the gripper in different assembly configurations after 4 and 8 h of drying, and measuring residual protein. FINDINGS: Based on our investigations, we documented the spread of contamination depending on the type of motion of the gripper's components. Sheep's blood exhibited the highest dispersion among the test soils, permeating through thin crevices. Importantly, all samples displayed residual protein levels below the warning threshold, irrespective of drying time and gripper disassembly or cleaning position. Cleaning in a device-specific optimized position achieved results comparable to cleaning the disassembled individual components. CONCLUSIONS: These findings indicate that cleaning even after one working shift of 8 h and without the labour-intensive disassembly of the gripper is feasible, supporting the future use of robots to handle contaminated medical devices in the CSSD decontamination area.

Torpor induces reversible tau hyperphosphorylation and accumulation in mice expressing human tau.

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer's disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies.

Busulfan exposure target attainment in adults undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiple day therapeutic drug monitoring regimen.

BACKGROUND: Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). OBJECTIVE: Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. STUDY: Design In this observational study, we included all adults who received an allogeneic HCT with intravenous once daily busulfan over 4 days as part of the conditioning regimen at the University Medical Centre Utrecht or between July 31th 2014 and November 12th 2021. The primary outcome was attainment of the therapeutic busulfan target (cumulative area under the curve [AUCcum] 80-100 mg*h/L). Dose adjustment was based on the estimated AUC of the preceding dosing day(s). Additional TDM was performed in the event of large dose adjustments (≥25%). The choice of TDM regimen was solely based on the first day the busulfan dose was administered (regimen d1+2 occurred when conditioning started on a Saturday). In all patients, blood sampling was performed on day 4 for evaluation. The AUCcum was estimated using a validated population pharmacokinetic model. Busulfan target exposure was compared between both TDM regimen groups using a propensity score adjusted logistic regression model. The variance in the AUCcum between the TDM regimens was compared using the F-test. Patients were stratified for age (categorical). RESULTS: In regimen d1, 87.6% (n = 113/129) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 97.4% was found (n = 74/76, adjusted odds ratio for non-therapeutic AUC = 0.19, 95% confidence interval 0.04-0.89). Variance of busulfan exposure in the regimen d1 group (SD = 6.8 mg*h/L) differed significantly from the variance in the regimen d1 + 2 group (SD = 3.6 mg*h/L, F-test, p < 0.001). CONCLUSION: Performing busulfan TDM on both day 1 and day 2, rather than only on day 1, improves busulfan target exposure attainment in adults undergoing HCT, provided that subsequent TDM is carried out if required.

Bis-µ-oxo and µ-η2:η2-peroxo dicopper complexes studied within (time-dependent) density-functional and many-body perturbation theory.

Based on the equilibrium geometries of [Cu2(dbdmed)2O2](2+) and [Cu2(en)2O2](2+) obtained within density-functional theory, we investigate their molecular electronic structure and optical response. Thereby results from occupation-constrained as well as time-dependent DFT (ΔSCF and TDDFT) are compared with Green's function-based approaches within many-body perturbation theory such as the GW approximation (GWA) to the quasiparticle energies and the Bethe-Salpeter equation (BSE) approach to the optical absorption. Concerning the ground-state energies and geometries, no clear trend with respect to the amount of exact exchange in the DFT calculations is found, and a strong dependence on the basis sets is to be noted. They affect the energy difference between bis-µ-oxo and µ-η(2):η(2)-peroxo complexes by as much as 0.8 eV (18 kcal/mol). Even stronger, up to 5 eV is the influence of the exchange-correlation functional on the gap values obtained from the Kohn-Sham eigenvalues. Not only the value itself but also the trends observed upon the bis-µ-oxo to µ-η(2):η(2)-peroxo transition are affected. In contrast, excitation energies obtained from ΔSCF and TDDFT are comparatively robust with respect to the details of the calculations. Noteworthy, in particular, is the near quantitative agreement between TDDFT and GWA+BSE for the optical spectra of [Cu2(en)2O2](2+).

Miss rate of colorectal cancer at CT colonography in average-risk symptomatic patients.

OBJECTIVES: Computed tomographic colonography (CTC) is a less burdensome alternative to colonoscopy in excluding colorectal cancer (CRC) in symptomatic patients. We evaluated the proportion of patients who underwent CTC in whom CRC was missed. METHODS: Patients who had undergone CTC in the period 1 January 2007 to 1 January 2011 were merged with all cases of CRC recorded in the Cancer Registry between 1 January 2007 and 1 July 2011 to identify all patients who had undergone CTC less than 2 years before CRC had been diagnosed. RESULTS: In 53 out of 1,855 patients who had undergone CTC, CRC was diagnosed. Of these, 40 patients had suspected CRC and 5 had large polyps at CTC. In five patients with an indeterminate mass, further investigation confirmed malignancy. One cancer in the caecum was missed because of poor distension. Two cancers were missed: one in the distal rectum and one in the ascending colon. Sensitivity of CTC for CRC was 94.3 % (95 % CI 88-100 %). The true miss rate, excluding the inadequate distended study, was 2 out of 53 (3.8 %). CONCLUSION: This study shows that the miss rate for CTC is low, which means that CTC is accurate in excluding CRC in symptomatic patients at a relatively low risk of CRC.

Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis.

BACKGROUND: Established prognostic factors are of limited value to predict long-term survival and benefit from metastasectomy in advanced melanoma. This study aimed to identify prognostic factors in patients with distant metastasis. METHODS: We analysed overall survival of 855 institutional melanoma patients with distant metastasis by bivariate Kaplan-Meier survival probabilities and multivariate Cox hazard regression analysis. RESULTS: Serum lactate dehydrogenases (LDH), S100B, the interval between initial diagnosis and occurrence of distant metastasis, the site of distant metastases, and the number of involved distant sites were significant independent prognostic factors in both bivariate and multivariate analyses. Visceral metastases other than lung (hazard ratio (HR) 1.8), elevated S100B (HR 1.7) and elevated LDH (HR 1.6) had the highest negative impact on survival. Complete metastasectomy was likewise an independent prognostic factor in multivariate analysis. This treatment was associated with favourable survival for patients with normal LDH and S100B values (5-year survival, 37.2%). CONCLUSION: The serum markers LDH and S100B were both found to be prognostic factors in melanoma patients with distant metastasis. Furthermore, complete metastasectomy had an independent favourable prognostic impact in particular for the patient subgroup with normal LDH and S100B values.

The role of mitochondria in axonal degeneration and tissue repair in MS.

Axonal injury is a key feature of multiple sclerosis (MS) pathology and is currently seen as the main correlate for permanent clinical disability. Although little is known about the pathogenetic mechanisms that drive axonal damage and loss, there is accumulating evidence highlighting the central role of mitochondrial dysfunction in axonal degeneration and associated neurodegeneration. The aim of this topical review is to provide a concise overview on the involvement of mitochondrial dysfunction in axonal damage and destruction in MS. Hereto, we will discuss putative pathological mechanisms leading to mitochondrial dysfunction and recent imaging studies performed in vivo in patients with MS. Moreover, we will focus on molecular mechanisms and novel imaging studies that address the role of mitochondrial metabolism in tissue repair. Finally, we will briefly review therapeutic strategies aimed at improving mitochondrial metabolism and function under neuroinflammatory conditions.

Lymphatic route of transport and pharmacokinetics of Micrurus fulvius (coral snake) venom in sheep.

The contribution of the lymphatic system to the absorption and systemic bioavailability of Micrurus fulvius venom after subcutaneous (SC) administration was assessed using a central lymph-cannulated sheep model. Micrurus fulvius venom was administered either by intravenous bolus (IV) or subcutaneous injection (SC) in 12 sheep with and without thoracic duct cannulation and drainage. Venom concentration in serum and lymph was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) in samples collected over a 6-hour period and in tissues harvested at the end of the experiment. Pharmacokinetic parameters were determined by a non-compartmental analysis. In the lymphatic cannulated group, over the 6 hours after the venom was administered, 69% of administered dose was accounted for in blood (45%) and lymph (25%). Negligible levels of venom were detected in organs and urine implying that the steady state observed after SC administration is maintained by a slow absorption process. Comparison of kinetics of the thoracic duct cannulated and non-cannulated groups showed that lymphatic absorption contributed in an important way to maintenance of this steady state. These results show that the limiting process in the pharmacokinetics of Micrurus fulvius venom following SC administration is absorption, and that the lymphatic system plays a key role in this process.