Cost-minimisation analysis of a treat-and-extend regimen with anti-VEGFs in patients with neovascular age-related macular degeneration.

PURPOSE: Although intraocular anti-vascular endothelial growth factors (anti-VEGFs) are effective as treatment of neovascular age-related macular degeneration (nAMD), the (economic) burden on the healthcare system is considerable. A treat-and-extend (T&E) regimen is associated with a lower number of injections without compromising the effectiveness and can therefore help optimise nAMD treatment. This study investigates the per-patient costs associated with nAMD treatment, when using aflibercept, bevacizumab, or ranibizumab with a T&E regimen. METHODS: In this cost-minimisation model, the per-patient costs in the Netherlands were modelled using a healthcare payers' perspective over a 3-year time horizon with the assumption that efficacy of treatments is similar. Additionally, the break-even price of the different anti-VEGFs was calculated relative to the cheapest option and injection frequency. RESULTS: The injection frequency varied from 14.2 for aflibercept to 27.4 for bevacizumab in 3 years. Nonetheless, bevacizumab remains the cheapest treatment option (€14,215), followed by aflibercept (€18,202) and ranibizumab (€31,048). The medication covers the majority of the per-patient costs for aflibercept and ranibizumab, while administration covers the majority of the per-patient costs for bevacizumab. The break-even prices of aflibercept and ranibizumab are respectively €507 and €60.58 per injection. Brolucizumab was included in the scenario analysis and was more expensive than aflibercept (€20,446). Brolucizumab should reduce to 13.8 injections over 3 years to be as costly as aflibercept. CONCLUSION: Bevacizumab is the cheapest anti-VEGF treatment. The list prices of all anti-VEGFs should reduce to be as costly as bevacizumab. Aflibercept is the second-choice treatment and so far brolucizumab is not.

Tumor immune microenvironment of primary colorectal adenocarcinomas metastasizing to the liver or lungs.

BACKGROUND: Because of the heterogeneity of metastatic colorectal cancer (mCRC), a genome-wide analysis was performed to characterize the tumor immune microenvironment (TIME). METHODS: RNA-seq analysis of 62 primary CRCs without and 63 with systemic metastasis (SM- and SM+ groups) was conducted, and the data were used in a training set after adjustment by propensity score matching. Samples were further subdivided into those with hepatic metastasis (CHM subgroup), pulmonary metastasis (CPM subgroup), or concurrent CHM and CPM (concurrent group). Validation was done by quantitative reverse-transcription polymerase chain reaction using another 40 primary CRC samples. RESULTS: Compared with the CHM or CPM subgroups, the concurrent group showed upregulated in inflammatory or immune processes, cytokine secretion, and myeloid leukocyte migration. Nine candidate genes were selected: SM-specific IDO1, JAM3, and PDE2A; CHM- or CPM-specific BIRC7; CPM-specific HISI1H2BK, and both SM-specific and CHM- or CPM-specific EPHB6, LPL, THBD, and PPBP. In a validation set of primary CRCs, JAM3 and IDO1 (p = 0.044 and p = 0.036, respectively) were confirmed to show significant upregulation and downregulation, respectively, in the SM+ group, whereas HIST1H2BK (p = 0.017) was significantly upregulated in the CPM subgroup. CONCLUSIONS: Our findings indicate that a host-suppressive TIME is established in the primary tumor of mCRC and identify immune-related site-specific markers of mCRC.

Comparison between postmortem computed tomography and autopsy in the detection of traumatic head injuries.

INTRODUCTION: The aim of this study was to assess the agreement between postmortem computed tomography (PMCT) and autopsy in detecting traumatic head injuries. MATERIALS AND METHODS: Consecutive cases of death that underwent both unenhanced PMCT and conventional autopsy were collected from our institution database during a period of 3 years and reviewed retrospectively. PMCT images were reviewed for the presence of fractures (cranial vault, skull base, facial bones and atlas/axis) and intracranial hemorrhage. Kappa values were calculated to determine the agreement between PMCT and autopsy reports. RESULTS: 73 cases were included, of which 44 (60%) had head trauma. Agreement between PMCT and autopsy was almost perfect (κ = 0.95) for fractures and substantial (κ = 0.75) for intracranial hemorrhage. PMCT was superior to autopsy in detecting facial bone and upper cervical spine fractures, and intraventricular hemorrhage. However, in some cases thin extra-axial blood collections were missed on PMCT. CONCLUSIONS: The agreement between PMCT and autopsy in detecting traumatic head injuries was good. Using a combination of both techniques increases the quality of postmortem evaluation because more lesions are detected.

Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level.

Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+ ) and a reduced form (NADH). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+ /NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two-photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT-mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.

Mechanotechnical faults and particular issues of anastomotic complications following robot-assisted anterior resection in 968 rectal cancer patients.

BACKGROUND: As most risk factors for anastomotic complications (AC) in rectal cancer patients appear to be noncorrectable, it is needed to find the correctable causes. Additionally, the outcomes of indocyanine-green fluorescence imaging (IFI) and robot-stapled anastomosis have yet been undetermined. METHODS: This study retrospectively analyzed 968 consecutive patients with rectal cancer, who underwent curative robot-assisted anterior resections between 2010 and 2018. IFI parameters and stapling features in the surgical records were reviewed, and reconfirmed. RESULTS: AC occurred in 54 patients (5.6%), 34 (3.5%) with anastomotic leakage (AL) and 24 (2.5%) with anastomotic stenosis (AS). Mechanotechnical faults including defective stapling configurations, including angles lesser than or equal to 150° and outer deviation (more than half from the center of the circle) of linear staples, between the two linear staples were independently associated with AL (P < .001 each). IFI significantly reduced AL rate (2.5% vs 5.3%, P = .029) and AS rate (2% vs 18.8%, P = .006), respectively. Robot linear stapling enabled to maintain the obtuse angle during consecutive staplings and reduced console time. AL and AS were independent risk factors for disease-free survival (P = .02) and local recurrence (P = .03), respectively. CONCLUSIONS: AC were associated with some correctable causes, namely, mechanotechnical errors and lack of use of IFI.

Needs and preferences of informal caregivers regarding outpatient care for the elderly: a systematic literature review.

BACKGROUND: Informal caregivers are an essential pillar for ensuring and maintaining the outpatient care of the frail elderly. Due to demographic changes, including an increase in the number of people in need of care as well as changing social structures (full-time employment of women, increasing number of single households, etc.) these informal care structures are fraught by considerable challenges. To support and facilitate informal caregivers in their role of nursing, it is important to identify their preferences, needs, and thus create a preference-oriented system. METHODS: A systematic review was conducted to identify preferences and needs regarding the organization of informal care. The database searches were performed by using EMBASE, Scopus and Dimdi. RESULTS: A total of 44 studies were included in the present review. Studies from 17 different countries provide broad international perspectives. Besides the preferences for long-term care structure, the following four principal topics were identified: (1) informational needs; (2) support needs; (3) organizational needs, and (4) needs for societal recognition. CONCLUSION: To meet the current challenges in the outpatient or home-based care of elders, it is essential to strengthen the role of informal caregivers. Therefore, it is necessary to adopt and further develop informal care structures according to the needs of informal caregivers. However, demographic, financial and cultural aspects of each country need to be considered as these may influence the preferences and needs of informal caregivers.

High temperature aggravates the effects of pesticides in goldfish.

In human-altered rivers, fish are often conjointly exposed to an increase in water temperature due to global warming and to a contamination by organic pollutants such as pesticides, but their combined effects are still elusive. Thermal and chemical stressors could potentially interact because high temperature increases metabolism and toxicant uptake, and can alter the ability of organisms to set up adequate stress responses and to maintain homeostasis. These combined stressors could thus potentially result in higher level of molecular and cellular damage, and stronger effects on behavior and physiology, but experimental evidence across biological levels is still scarce. In this study, goldfish Carassius auratus were experimentally exposed to an environmentally realistic cocktail of pesticides (S-metolachlor, isoproturon, linuron, atrazine-desethyl, aclonifen, pendimethalin and tebuconazol) commonly found in rivers of South-West of France at low or high dose in two different thermal conditions: a common summer temperature (22 °C) or a high temperature recorded during heat waves (32 °C). Results showed that high temperature alone caused behavioral and physiological changes (increased swimming activity, increased hepatosomatic index, decreased reproductive index) but limited cellular damage. However, high temperature aggravated the effects of pesticides at the molecular and cellular level. Indeed, pesticide exposure resulted in higher genotoxic effects (micronuclei rate) and irreversible cellular damage of the gills and liver (apoptosis, inflammation, necrosis) at 32 °C compared to 22 °C. This suggests potential synergistic effects of climate change and pollution, and highlights the need for multiple stress approaches to better predict the impacts of human activities on aquatic wildlife.

Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage whole-genome sequencing of maternal plasma DNA: review of 1982 consecutive cases in a single center.

OBJECTIVE: To review the performance of non-invasive prenatal testing (NIPT) by low-coverage whole-genome sequencing of maternal plasma DNA at a single center. METHODS: The NIPT result and pregnancy outcome of 1982 consecutive cases were reviewed. NIPT was based on low coverage (0.1×) whole-genome sequencing of maternal plasma DNA. All subjects were contacted for pregnancy and fetal outcome. RESULTS: Of the 1982 NIPT tests, a repeat blood sample was required in 23 (1.16%). In one case, a conclusive report could not be issued, probably because of an abnormal vanished twin fetus. NIPT was positive for common trisomies in 29 cases (23 were trisomy 21, four were trisomy 18 and two were trisomy 13); all were confirmed by prenatal karyotyping (specificity=100%). In addition, 11 cases were positive for sex-chromosomal abnormalities (SCA), and nine cases were positive for other aneuploidies or deletion/duplication. Fourteen of these 20 subjects agreed to undergo further investigations, and the abnormality was found to be of fetal origin in seven, confined placental mosaicism (CPM) in four, of maternal origin in two and not confirmed in one. Overall, 85.7% of the NIPT-suspected SCA were of fetal origin, and 66.7% of the other abnormalities were caused by CPM. Two of the six cases suspected or confirmed to have CPM were complicated by early-onset growth restriction requiring delivery before 34 weeks. Fetal outcome of the NIPT-negative cases was ascertained in 1645 (85.15%). Three chromosomal abnormalities were not detected by NIPT, including one case each of a balanced translocation, unbalanced translocation and triploidy. There were no known false negatives involving the common trisomies (sensitivity=100%). CONCLUSIONS: Low-coverage whole-genome sequencing of maternal plasma DNA was highly accurate in detecting common trisomies. It also enabled the detection of other aneuploidies and structural chromosomal abnormalities with high positive predictive value.

Cost-effectiveness of ravulizumab compared with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria in the Netherlands.

OBJECTIVES: The aim of this study was to evaluate the cost-effectiveness of ravulizumab compared with eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) in the Netherlands. METHODS: A cost-effectiveness analysis was conducted based on a Markov cohort model simulating the course of patients with PNH with clinical symptom(s) indicative of high disease activity, or who are clinically stable after having been treated with eculizumab for at least the past six months. Costs, quality of life, and the incremental cost-effectiveness ratio (ICER) were estimated over a lifetime horizon from a Dutch societal perspective. Several additional analyses were performed, including a one-way sensitivity analysis, a probabilistic sensitivity analysis, and scenario analysis. RESULTS: When compared with eculizumab, ravulizumab saves €266,833 and 1.57 quality adjusted life years (QALYs) are gained, resulting in a dominant ICER. Drug costs account for the majority of the total costs in both intervention groups. Cost savings were driven by the difference in total treatment costs of ravulizumab compared with eculizumab caused by the reduced administration frequency, accounting for 98% of the total cost savings. The QALY gain with ravulizumab is largely attributable to the improved quality of life associated with less frequent infusions and BTH events. At a willingness-to-pay threshold of €20,000/QALY, there is a 76.6% probability that ravulizumab would be cost-effective. CONCLUSIONS: The cost reduction and QALY gain associated with the lower rates of BTH and less frequent administration make ravulizumab a cost-saving and clinically beneficial substitute for eculizumab for adults with PNH in the Netherlands.

Model and Empirical Data-Based Cost-Utility Studies of Continuous Glucose Monitoring in Individuals with Type 1 Diabetes: A Protocol of a Systematic Review on Methodology and Quality.

INTRODUCTION: This review aims to critically appraise differences in methodology and quality of model-based and empirical-data-based cost-utility studies to address key limitations, opportunities, and challenges to inform future cost-utility analyses of continuous glucose monitoring (CGM) in type 1 diabetes. This protocol is registered at PROSPERO (CRD42023391284). METHODS: The review will be conducted in accordance with the PRISMA guideline for systematic reviews. Searches will be conducted in MEDLINE, Embase, Web of Science, Cochrane Library, and Econlit from 2000 to January 2023. Model and empirical data-based studies evaluating the cost-utility of any CGM system in type 1 diabetes will be considered for inclusion. Studies that only report on cost per life year or any other clinical outcome, or reporting only costs or only clinical outcomes studies in type 2 diabetes populations, and studies on bi-hormonal closed loops and do-it-yourself hybrid closed loop devices will be excluded. Two reviewers will independently screen each study for inclusion. Data on the intervention, population, model settings (such as perspective, time horizon), model type and structure, clinical outcomes used to populate the model, validation, and uncertainty will be extracted and qualitatively synthesised. Quality will be assessed using the Philips et al. 2006 (model-based studies) or Consensus Health Economic Criteria (empirical data-based studies) checklists. Model validation will be assessed using the AdViSHE checklist. DISCUSSION: Now that CGM is being used more broadly in practice, critical appraisal of existing cost-utility methodology and quality is important to inform future cost-utility analyses of CGM in type 1 diabetes in various settings.

Complications and survival of conversion to total hip arthroplasty after failed primary osteosynthesis compared to primary total hip arthroplasty in femoral neck fractures.

INTRODUCTION: Surgical treatment options for patients with an intracapsular fracture of the femoral neck (FFN) are primary osteosynthesis as a femoral head-spearing technique or primary (hemi)arthroplasty. The most common complications after primary osteosynthesis, such as avascular necrosis (AVN) or non-union, can result in conversion to Total Hip Arthroplasty (cTHA). Data concerning complications and survival rates of cTHA in comparison to primary Total Hip Arthroplasty (pTHA) after FFN are limited due to the absence of well-designed studies. METHODS: A multicentre retrospective cohort study was conducted in three Dutch hospitals comparing the rate of postoperative dislocations, periprosthetic fractures, prosthetic joint infections, blood loss during surgery (>1000 mL), postoperative cardiac- and pulmonary complications after pTHA and cTHA in the first year after surgery. As a secondary outcome implant survival of pTHA and cTHA in terms of revision rates was evaluated. RESULTS: In total 548 patients were included (pTHA n = 264 and cTHA n = 284) with a mean follow-up of 5 years (±3.5 SD). No significant differences were found in postoperative complications rates. The revision rate in the pTHA group was 7.2% in comparison to 7.7% in the cTHA group (p = 0.81). No difference in the short-term implant survival was found between both groups (p = 0.81). CONCLUSION: This study showed no significant differences in terms of postoperative complication rates in the first year after pTHA and cTHA in patients with FFN. Also, no significant difference in short-term implant survival of primary and conversion total hip arthroplasty was found.

A single Inertial Measurement Unit on the shank to assess the Shank-to-Vertical Angle.

The Shank-to-Vertical Angle (SVA) is a commonly used parameter to describe orthotic alignment. 3D gait analysis (3DGA) or 2D video analysis are usually used to assess the SVA, but are not always feasible in clinical practice. As an alternative, an Inertial Measurement Unit (IMU) attached and aligned to the shank might be used. This study aimed to investigate the validity, inter-rater reliability and optimal location of a single IMU on the shank to assess the SVA. Thirteen healthy participants (7 m/6f, mean age: 45 ± 18 years) were recorded during quiet standing and barefoot walking using a 3D motion capture system and, simultaneously, with IMUs on the shank. The IMUs were anatomically placed and aligned at two different locations, i.e. anterior, in line with the tibial tuberosity and midline of the ankle (anterior IMU), and lateral, in line with the lateral epicondyle and lateral malleolus (lateral IMU). For each participant, the IMUs were placed by two different researchers. A paired t-test, Bland Altmann analysis (mean difference, repeatability coefficient) and intraclass correlation coefficient (ICC) between the 3DGA and both IMUs, and between raters, was performed. Although validity and reliability of the lateral IMU was low, good validity and inter-rater reliability was found for the anterior IMU (Rater1: mean difference: -0.7 ± 2.1, p = 0.27; ICC = 0.83 and Rater2: mean difference: -0.4 ± 1.9, p = 0.46; ICC = 0.86). Hence, a single IMU placed at the anterior side of the shank is a valid and reliable method to assess the SVA during standing and walking in healthy adults.

Test-retest reliability of stability outcome measures during treadmill walking in patients with balance problems and healthy controls.

BACKGROUND: Improvement of balance control is an important rehabilitation goal for patients with motor and sensory impairments. To quantify balance control during walking, various stability outcome measures have described differences between healthy controls and patient groups with balance problems. To be useful for the evaluation of interventions or monitoring of individual patients, stability outcome measures need to be reliable. RESEARCH QUESTION: What is the test-retest reliability of six stability outcome measures during gait? METHODS: Patients with balance problems (n = 45) and healthy controls (n = 20) performed two times a two-minute walk test (2MWT). The intraclass correlation coefficient (ICC) and Bland-Altman analysis (coefficient of repeatability; CR) were used to evaluate the test-retest reliability of six stability outcome measures: dynamic stability margin (DSM), margin of stability (MoS), distance between the extrapolated centre of mass (XCoM) and centre of pressure (CoP) in anterior-posterior (XCoM-CoPAP) and medial-lateral (XCoM-CoPML) direction, and inclination angle between centre of mass (CoM) and CoP in anterior-posterior (CoM-CoPAP-angle) and medial-lateral (CoM-CoPML-angle) direction. A two way mixed ANOVA was performed to reveal measurement- and group-effects. RESULTS: The ICCs of all stability outcome measures ranged between 0.51 and 0.97. Significant differences between the measurements were found for the DSM (p = 0.017), XCoM-CoPAP (p = 0.008) and CoM-CoPAP-angle (p = 0.001). Significant differences between controls and patients were found for all stability outcome measures (p < 0.01) except for the MoS (p = 0.32). For the XCoM-CoP distances and CoM-CoP angles, the CRs were smaller than the difference between patients and controls. SIGNIFICANCE: Based on the ICCs, the reliability of all stability outcome measures was moderate to excellent. Since the XCoM-CoPML and CoM-CoPML-angle showed no differences between the measurements and smaller CRs than the differences between patients and controls, the XCoM-CoPML and CoM-CoPML-angle seem the most promising stability outcome measures to evaluate interventions and monitor individual patients.

Biomechanical loading of the porcine femorotibial joint during maximal movements: An exploratory, ex vivo study.

Thus far, there is a lack of scientific investigation regarding the hypothesis that biomechanical factors contribute to the cross-species pathogenesis of osteochondrosis (OC). Therefore, the aim of this pilot study was to investigate whether high (peak) pressures occur in the porcine femorotibial (FT) joint. In this experimental, ex vivo study, the right hind limbs of seven weaned piglets were subjected to maximal joint excursions, as a priori radiologically estimated. Subsequently, the intra-articular pressures were measured using sensors placed in both the medial and the lateral compartments of the FT joint. The overall highest individual peak pressure was found in the lateral FT joint during maximal extension (2611 kPa; group mean ± standard deviation (SD) 982.3 ± 988.2 kPa). In the medial FT joint, the highest individual peak pressure was found during maximal adduction (1481 kPa; group mean ± SD 664.9 ± 393.2 kPa). Moreover, nearly 30% of the ex vivo peak pressures were above published thresholds for cartilage catabolism (>500 kPa/0.5 MPa), but not for interfering with cell viability (>5 MPa). In conclusion, this ex vivo study on FT joint pressures in weaned piglets showed that FT joint movements at maximal excursions are related to concomitant internal peak joint pressures. More studies should be performed to evaluate the possible biomechanical relation of these observations with osteochondrosis, which would allow the design of preventive measures in the pig industry, to avoid extreme limb movements and concomitant joint peak pressures in vivo.

Effect of intraperitoneal chemotherapy concentration on morbidity and survival.

BACKGROUND: Selected patients with colorectal peritoneal metastases are treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The concentration of intraperitoneal chemotherapy reflects the administered dose and perfusate volume. The aim of this study was to calculate intraperitoneal chemotherapy concentration during HIPEC and see whether this was related to clinical outcomes. METHODS: An observational multicentre study included consecutive patients with colorectal peritoneal metastases who were treated with CRS-HIPEC between 2010 and 2018 at three Dutch centres. Data were retrieved from prospectively developed databases. Chemotherapy dose and total circulating volumes of carrier solution were used to calculate chemotherapy concentrations. Postoperative complications, disease-free and overall survival were correlated with intraoperative chemotherapy concentrations. Univariable and multivariable logistic regression, Cox regression and survival analyses were performed. RESULTS: Of 320 patients, 220 received intraperitoneal mitomycin C (MMC) and 100 received oxaliplatin. Median perfusate volume for HIPEC was 5·0 (range 0·7-10·0) litres. Median intraperitoneal chemotherapy concentration was 13·3 (range 7·0-76·0) mg/l for MMC and 156·0 (91·9-377·6) mg/l in patients treated with oxaliplatin. Grade III or higher complications occurred in 75 patients (23·4 per cent). Median overall survival was 36·9 (i.q.r. 19·5-62·9) months. Intraperitoneal chemotherapy concentrations were not associated with postoperative complications or survival. CONCLUSION: CRS-HIPEC was performed with a wide variation in intraperitoneal chemotherapy concentrations that were not associated with complications or survival.

ANTECEDENTES: Ciertos pacientes seleccionados con metástasis peritoneales de cáncer colorrectal (peritoneal metastases, PM) se tratan con cirugía citorreductora (cytoreductive surgery, CRS) y quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC). La concentración de quimioterapia intraperitoneal refleja la dosis administrada y el volumen perfundido. El objetivo de este estudio fue calcular la concentración de quimioterapia intraperitoneal durante HIPEC y evaluar si ello se relacionaba con los resultados clínicos. MÉTODOS: Estudio observacional multicéntrico en el que se incluyeron pacientes consecutivos con PM de cáncer colorrectal que fueron tratados con CRS-HIPEC entre 2010 y 2018 en tres centros holandeses. Se obtuvieron los datos a partir de bases de datos mantenidas de forma prospectiva. La dosis de quimioterapia y los volúmenes circulantes totales de solución de perfusión se usaron para calcular las concentraciones de quimioterapia. Las complicaciones postoperatorias y las supervivencias libre de enfermedad y global se correlacionaron con las concentraciones de quimioterapia intraoperatoria. Se realizaron regresiones logísticas univariable y multivariable, regresión de Cox y análisis de supervivencia. RESULTADOS: De 320 pacientes, 220 recibieron mitomicina C intraperitoneal (MMC) y 100 oxaliplatino (OXA). El volumen medio de perfusión para HIPEC fue 5,0 L (rango 0,7-10,0). La mediana de concentración intraperitoneal del agente quimioterápico fue de 13,3 mg/L (rango 7,0-76,0) para MMC y 156,0 mg/L (rango 91,9 - 377,6) en pacientes tratados con OXA. Las complicaciones de grado 3 o mayores ocurrieron en 23,4% (n = 75). La mediana de supervivencia global fue de 36,9 meses (rango intercuartílico 19,5-62,9). Las concentraciones de quimioterapia intraperitoneal no se asociaron con las complicaciones postoperatorias ni con la supervivencia. CONCLUSIÓN: La CRS-HIPEC se realizó con una amplia variación en las concentraciones de quimioterapia intraperitoneal que no se asociaron con las complicaciones ni con la supervivencia.

Hypersensitivity pneumonitis caused by occupational exposure to phytase.

A 43-yr-old male presented with a 6-month history of episodes of coughing, shortness of breath and fever. He suffered from dyspnoea on minor exertion. The patient worked in a cattle feed factory and noticed that he had more complaints after his working hours. His symptoms could be ascribed to hypersensitivity pneumonitis due to contact with phytase, an enzyme added to cattle feed to strengthen bone and diminish phosphorus excretion. The diagnosis was supported by bibasal lung crackles on physical examination, restrictive ventilatory defect (with decreased diffusion capacity for carbon monoxide), typical radiographical findings, lymphocytosis in bronchoalveolar lavage fluid and a positive exposure test performed at the workplace. Blood examination showed high immunoglobulin G levels to phytase. After treatment and cessation of phytase contact the patient became symptom free and lung function normalised. Phytase should be considered as a cause of occupational hypersensitivity pneumonitis in the animal feed industry.

Fluorescent labeling of nascent RNA reveals transcription by RNA polymerase II in domains scattered throughout the nucleus.

Several nuclear activities and components are concentrated in discrete nuclear compartments. To understand the functional significance of nuclear compartmentalization, knowledge on the spatial distribution of transcriptionally active chromatin is essential. We have examined the distribution of sites of transcription by RNA polymerase II (RPII) by labeling nascent RNA with 5-bromouridine 5'-triphosphate, in vitro and in vivo. Nascent RPII transcripts were found in over 100 defined areas, scattered throughout the nucleoplasm. No preferential localization was observed in either the nuclear interior or the periphery. Each transcription site may represent the activity of a single gene or, considering the number of active pre-mRNA genes in a cell, of a cluster of active genes. The relation between the distribution of nascent RPII transcripts and that of the essential splicing factor SC-35 was investigated in double labeling experiments. Antibodies against SC-35 recognize a number of well-defined, intensely labeled nuclear domains, in addition to labeling of more diffuse areas between these domains (Spector, D. L., X. -D. Fu, and T. Maniatis. 1991. EMBO (Eur. Mol. Biol. Organ.) J. 10:3467-3481). We observe no correlation between intensely labeled SC-35 domains and sites of pre-mRNA synthesis. However, many sites of RPII synthesis colocalize with weakly stained areas. This implies that contranscriptional splicing takes place in these weakly stained areas. These areas may also be sites where splicing is completed posttranscriptionally. Intensely labeled SC-35 domains may function as sites for assembly, storage, or regeneration of splicing components, or as compartments for degradation of introns.

Retinoids selective for retinoid X receptor response pathways.

Retinoids have a broad spectrum of biological activities and are useful therapeutic agents. Their physiological activities are mediated by two types of receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). RARs, as well as several related receptors, require heterodimerization with RXRs for effective DNA binding and function. However, in the presence of 9-cis-retinoic acid, a ligand for both RARs and RXRs, RXRs can also form homodimers. A series of retinoids is reported that selectively activates RXR homodimers but does not affect RAR-RXR heterodimers and thus demonstrates that both retinoid response pathways can be independently activated.