Blood oxygen transport and organ weights of two shrew species (S. etruscus and C. russula).

Blood parameters concerning oxygen transport and relative organ weights of 11 Suncus etruscus and 13 Crocidura russula under light halothane anesthesia were investigated. Mean body weight of S. etruscus was 2.5 g and for C. russula was 9 g, hemoglobin concentration was 17.4 and 15.6 g/100 ml blood, hematocrit was 50 and 44%, red blood cells were 18 and 11 X 10(6)/microliter, respectively. Mean corpuscular volume was calculated to be 26 and 41 micron3, mean diameter 5.5 and 7 micron, and mean thickness 1.2 and 1.1 micron, respectively. Mean corpuscular hemoglobin concentration was in the normal range of mammalian red blood cells. A blood oxygen half-saturation pressure of 35 and 34 Torr at pH 7.4, 37 degrees C and a Bohr factor deltalog P50/deltapH of -0.61 and -0.66 was measured. Experiments with stripped hemoglobin showed that 2,3-diphosphoglycerate is the main oxygen affinity reducing allosteric factor. Relative weights of heart, kidney, and liver are remarkably high in S. etruscus. The maximal oxygen transport of 400 ml . kg-1 . min-1 of S. etruscus is feasible by an enormous heart rate, a large relative stroke volume, a high hemoglobin concentration combined with a low oxygen affinity, and a large Bohr effect.     

Exceptions to the rule: healthy deprived areas and unhealthy wealthy areas

In general, inhabitants of low socio-economic areas are unhealthier than inhabitants of high socio-economic areas, but some areas are an exception to this rule. These exceptions imply that other factors besides the socio-economic level of an area contribute to the health of the inhabitants of an area, e.g. environmental factors. In our study we concentrate on areas within the Netherlands that are healthier or unhealthier than could be expected based on their socio-economic level. This study first identifies these areas and secondly determines which area characteristics distinguish these areas from those areas where the level of health is in agreement with their socio-economic level. We used nation-wide data on neighbourhood differences in population composition (gender, age, marital status and ethnicity), urbanisation and two health indicators: mortality and hospitalisation rates. In the Netherlands, many areas are healthier or unhealthier than could be expected based on their income level alone. Areas with higher mortality rates than expected are mainly urban areas with high percentages of elderly people and persons living alone. Similar but opposite associations are observed for areas with lower mortality rates than expected, which are further characterised by a low percentage of non-western immigrants. Areas with lower hospitalisation rates than expected are mainly rural areas with few non-western immigrants. From these results, we conclude that urbanisation and residential segregation based on age, ethnicity and marital status might be important contributors to geographical health inequalities.     

Recurrence of Melanoma Following T Cell Treatment: Continued Antigen Expression in a Tumor That Evades T Cell Recruitment

Clinical therapy with T cells shows promise for cancer patients, but is currently challenged by incomplete responses and tumor relapse. The exact mechanisms that contribute to tumor relapse remain largely unclear. Here, we treated mouse melanomas with T cell receptor-engineered T cells directed against a human peptide-major histocompatibility complex antigen in immune-competent mice. T cells resulted in significant tumor regression, which was followed by relapse in about 80–90% of mice. Molecular analysis revealed that relapsed tumors harbored nonmutated antigen genes, not silenced by promoter methylation, and functionally expressed surface antigen at levels equal to nontreated tumors. Relapsed tumors resisted a second in vivo T cell treatment, but regained sensitivity to T cell treatment upon retransplantation in mice. Notably, relapsed tumors demonstrated decreased levels of CD8 T cells and monocytes, which were substantiated by downregulated expression of chemoattractants and adhesion molecules. These observations were confirmed when using T cells specific for a less immunogenic, endogenous mouse melanoma antigen. We conclude that tumors, when exposed to T cell treatment, can relapse without loss of antigen and develop a milieu that evades recruitment of effector CD8 T cells. Our findings support the concept to target the tumor milieu to aid T cell therapy in limiting tumor relapse     

Internal diameters of the ventriculo-arterial junctions and great arteries of normal infants and children: a data base for evaluation of congenital cardiac malformations

In order to obtain reference data for a better evaluation of the operability of infants and children with congenital heart malformations, investigations were made on the growth of the aortic ventriculo-arterial junction along with the aortic arch as well as of the pulmonary root and the pulmonary tree. The internal diameters of the junctions and of various sites of both great arteries were measured in fresh post mortem specimens of 126 children having an age from 21 weeks of gestation up to 10 years after birth and who died from noncardiac diseases. Linear correlations were found between the internal diameters and body length. The post mortem data were in agreement with echocardiographic observations.     

Comparing Approaches to Normalize,Quantify, and Characterize Urinary Extracellular Vesicles

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Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated in three cohorts with a maximum of 10 infusions of a total of 0.2 to 2.1 × 10⁹ CAR T cells. CTC grade 2–4 liver enzyme disturbances occurred at the lowest CAR T cell doses, necessitating cessation of treatment in four out of eight patients in cohorts 1 and 2. Examination of liver biopsies revealed CAIX expression on bile duct epithelium with infiltration of T cells, including CAR T cells. Subsequently four patients were pre-treated with CAIX monoclonal antibody (mAb) G250 to prevent CAR-specific toxicity and showed no liver toxicities and indications for enhanced peripheral T cell persistence. No clinical responses were recorded. This report shows that CAIX-targeting CAR T cells exerted antigen-specific effects in vivo and induced liver toxicity at the lowest dose of 0.2 × 10⁹ T cells applied, illustrating the potency of receptor-modified T cells. We provide in-patient proof that the observed “on-target” toxicity is antigen-directed and can be prevented by blocking antigenic sites in off-tumor organs and allowing higher T cell doses.     

The Aicardi-Goutières syndrome: Variable clinical expression in two siblings

We report 2 siblings with the Aicardi-Goutières syndrome (encephalopathy, basal ganglia calcifications, and persistent cerebrospinal fluid pleiocytosis). The eldest sibling is severely retarded; his younger brother has only mild, slowly progressive neurological deficits. To our knowledge, such a striking difference in clinical expression has not been reported previously.