Integrated functional and spatial profiling of tumour immune responses induced by immunotherapy: the iPROFILER platform.

BACKGROUND: Cancer immunotherapy elicits functional activation and changes in immune cell distribution in cancer. Tumour heterogeneity is a reason for treatment failure but is difficult to capture in experimental settings. This proof-of-principle study describes the integrated functional and digital spatial profiling platform iPROFILER to capture in-situ immune activation patterns with high precision. MATERIALS AND METHODS: iPROFILER combines an algorithm-based image analysis approach for spatial profiling with functional analyses of patient-derived tumour fragments (PDTFs). This study utilized a folate receptor 1 (FOLR1)xCD3 bispecific antibody in dual-affinity re-targeting (DART) format as a tool for inducing T-cell responses in patient tumour samples, and an in-depth investigation of the immune perturbations induced in the tumour microenvironment was performed. RESULTS: Ex-vivo DART stimulation induces upregulation of multiple activation markers in CD4+ and CD8+ T-cell populations and secretion of pro-inflammatory cytokines in FOLR1-positive tumour specimens. This response was reduced or absent in tissue samples that did not express FOLR1. Immunological responses were driven by a strong induction of interferon gamma (IFNγ) and IFNγ-induced chemokines suggestive of activation of cytotoxic or Th1-like T cells. Ex-vivo DART treatment led to a numerical increase in effector T cells and an upregulation of immune activation markers in the tumour microenvironment as captured by digital image analysis. Analysis of immune activation in tumour and stromal regions further supported the potential of the platform to measure local differences in cell-type-specific activation patterns. CONCLUSIONS: iPROFILER effectively combines functional and spatial readouts to investigate immune responses ex vivo in human tumour samples.

Early infant feeding and risk of type 1 diabetes mellitus-a nationwide population-based case-control study in pre-school children.

BACKGROUND: The evidence on the role of environmental factors in the development of type 1 diabetes is conflicting. Reducing potential bias and the variety of exposures, we investigated the association between type 1 diabetes risk and nutritional and environmental exposures in pre-school children. METHODS: This nationwide population-based case-control study included 760 cases under 5 years of age newly diagnosed with type 1 diabetes during 1992-1995. From the general population, 1,871 controls were randomly selected and individually matched on age ( +/- 1 year), sex, and residence. Information on infant diet, foetal, perinatal and socio-economic factors, and familial diabetes was obtained by a parent-administered questionnaire. Data were analysed by multiple conditional logistic regression. RESULTS: Duration of breastfeeding and age at introduction of bottle-feeding were inversely associated with type 1 diabetes risk according to a dose-response relationship (trend test p < 0.05). Adjusted odd ratios (95% CI) for a long breastfeeding period and a late introduction of bottle-feeding (>or=5 month versus < 2 weeks) were 0.71 (0.54-0.93) and 0.80 (0.62-1.04), respectively. Familial type 1 diabetes, maternal age > 40 years, and low birth weight were found more frequently among diabetic than among control children. Current cow's milk consumption, higher social status, and a larger family were associated with a reduced diabetes risk. Up to one half of the diabetic cases in the population could be attributed to modifiable exposures. CONCLUSIONS: Our findings indicate that infant feeding is associated with type 1 diabetes risk and that a considerable part of new type 1 diabetic cases is potentially preventable.

Early nutrition and risk of Type 1 diabetes mellitus--a nationwide case-control study in preschool children.

The evidence on the role of environmental factors in the development of type 1 diabetes is conflicting. Reducing potential bias and the variety of exposures we investigated the association between type 1 diabetes risk and nutritional and other environmental exposures in preschool children. This nationwide case-control study included 760 cases newly diagnosed with type 1 diabetes under five years of age during 1992-1995. 630 controls of the same age were selected from the case families' acquaintance. Information on infant diet, foetal, perinatal and socio-economic factors, and family history of diabetes was obtained by a parent-administered questionnaire. Data were analysed by multiple unconditional logistic regression. Duration of breastfeeding and age at introduction of bottle-feeding were inversely associated with type 1 diabetes risk according to a dose-response relationship (trend test p<0.05). Adjusted odd ratios (95%-CI) for a short breastfeeding period and an early introduction of formula feeding (<5 vs. > or =5 months) were 1.31 (1.01-1.69) and 1.34 (1.03-1.74), respectively. Familial type 1 diabetes was found more frequently among diabetic than among control children. Higher social status, late introduction of solid food (> or =5 month), and higher current cow's milk consumption (> or =200 ml/d) were associated with a reduced diabetes risk. A considerable proportion of the diabetic risk among preschool children was explained by modifiable exposures. Our findings indicate that infant feeding is causally associated with type 1 diabetes risk and that a considerable part of new type 1 diabetic cases is potentially preventable.

Simplest tasks have greatest dual task interference with balance in brain injured adults.

Attention difficulties and poor balance are both common sequel following a brain injury. This study aimed to determine whether brain injured adults had greater difficulty than controls in performing a basic balance task while concurrently completing several different cognitive tasks varying in visuo-spatial attentional load and complexity. Twenty brain injured adults and 20 age-, sex- and education level-matched controls performed a balance-only task (step stance held for 30 s), five cognitive-only tasks (simple and complex non-spatial, visuo-spatial, and a control articulation task), and both together (dual tasks). Brain injured adults showed a greater centre of pressure (COP) excursion and velocity in all conditions than controls. Brain injured adults also demonstrated greater interference with balance when concurrently performing two cognitive tasks than control subjects. These were the control articulation and the simple non-spatial task. It is likely that distractibility during these simple tasks contributed to an increase in COP motion and interference with postural stability in stance. Performing visuo-spatial tasks concurrently with the balance task did not result in any change in COP motion. Dual task interference in this group is thus unlikely to be due to structural interference. Similarly, as the more complex tasks did not uniformly result in increased interference, a reduction in attentional capacity in the brain injured population is unlikely to be the primary cause of dual task interference in this group.

Physiological responses to repeated bouts of high-intensity ultraendurance cycling--a field study case report.

The present study aimed to 1) examine the relationship between laboratory-based measures and high-intensity ultraendurance (HIU) performance during an intermittent 24-h relay ultraendurance mountain bike race (approximately 20 min cycling, approximately 60 min recovery), and 2) examine physiological and performance based changes throughout the HIU event. Prior to the HIU event, four highly-trained male cyclists (age = 24.0 +/- 2.1 yr; mass = 75.0 +/- 2.7 kg; VO2peak = 70 +/- 3 ml x kg(-1) x min(-1)) performed 1) a progressive exercise test to determine peak volume of oxygen uptake (VO2peak), peak power output (PPO), and ventilatory threshold (T(vent)), 2) time-to-fatigue tests at 100% (TF100) and 150% of PPO (TF150), and 3) a laboratory simulated 40-km time trial (TT40). Blood lactate (Lac(-)), haematocrit and haemoglobin were measured at 6-h intervals throughout the HIU event, while heart rate (HR) was recorded continuously. Intermittent HIU performance, performance HR, recovery HR, and Lac(-) declined (P < 0.05), while plasma volume expanded (P < 0.05) during the HIU event. TF100 was related to the decline in lap time (r = -0.96; P < 0.05), and a trend (P = 0.081) was found between TF150 and average intermittent HIU speed (r = 0.92). However, other measures (VO2peak, PPO, T(vent), and TT40) were not related to HIU performance. Measures of high-intensity endurance performance (TF100, TF150) were better predictors of intermittent HIU performance than traditional laboratory-based measures of aerobic capacity.

Atopic eczema in early childhood could be protective against Type 1 diabetes.

AIMS/HYPOTHESIS: According to the Th1/Th2 paradigm Type 1 diabetes and atopic diseases are assumed to be mutually exclusive on the individual level. We analysed the association between Type 1 diabetes and atopic diseases in a case-control design in order to test the hypothesis that atopic diseases in early childhood could protect against Type 1 diabetes. METHODS: We carried out a nationwide population-based case-control study enrolling 760 cases newly-diagnosed with Type 1 diabetes under five years of age between July 1992 and December 1995 and 1871 controls randomly selected from the general population and individually matched on sex, age and place of residence. Information on atopic diseases was obtained by a mailed parent-administered questionnaire. Data were analysed by multivariate logistic regression adjusting for potential confounders (family history of diabetes, social status, duration of overall breast feeding, number of children in family, maternal age at delivery). RESULTS: Atopic eczema was less frequent in diabetic (13.3%) than in non-diabetic children (18.0%) and was significantly associated with a reduced risk of Type 1 diabetes. The adjusted odds ratio was 0.71 (95% CI 0.53-0.96). Hay fever and asthma were not significantly associated with diabetes risk (OR 0.98 (95% CI 0.47-2.01) and 1.46 (95% CI 0.70-3.06), respectively). CONCLUSION/INTERPRETATION: In this large population-based case-control study in pre-school children an inverse association was observed between atopic eczema and Type 1 diabetes. Thus, in accordance with the Th1/Th2 paradigm development of atopic eczema in early childhood could be protective against childhood Type 1 diabetes.

On the generation of point groups in spaces of various dimensions.

In this paper the use of Clifford algebra in the parametrization of point groups in spaces of various dimensions is shown. Higher-dimensional spaces are of great interest especially when modulated crystals or quasicrystals are studied. While the quaternion units, which are useful to parametrize rotations in 3 dimensions, can be identified with rotations, the basic Clifford units may be regarded as mirrors from which all proper and improper symmetry operations can be generated. The practical implementation of this method of parametrization is demonstrated for the group of the hypercube in the 4-dimensional space, and generalisations to spaces of dimensions higher than 4 are suggested.

Temporal, seasonal, and geographical incidence patterns of type I diabetes mellitus in children under 5 years of age in Germany.

AIMS/HYPOTHESIS: To estimate the national incidence of Type I (insulin-dependent) diabetes mellitus in children under 5 years of age in Germany and to analyse temporal, seasonal, and geographical patterns of the diabetes incidence. METHODS: During 1993-1995 newly diagnosed subjects were prospectively registered by the hospital-based 'German Paediatric Surveillance Unit' with monthly inquiries in all paediatric departments in Germany. Level of ascertainment was estimated by capture-recapture-analysis using two independent regional data sources. RESULTS: During 1993-1995 the national incidence was 8.10 (95 %-CI: 7.61, 8.61) per 100 000 person-years, ranging in-between lower rates in west European countries and higher rates in northern Europe. Degree of ascertainment was about 85 %. Male to female ratio was 1.11 (95 %-CI: 0.98, 1.25). Compared with results of previous regional studies in the east and the south-west of Germany a 3- and 1.3-fold incidence increase was observed, respectively. Multivariate Poisson regression analysis showed season, geographical region, and interactions of age at onset with sex and calendar year to be independent significant predictors of the incidence. Incidence variation by age was different between boys and girls. A significant incidence increase by calendar year was found in 3- and 4-year-old children only. In summer and fall the incidence was higher than in winter and springtime, in the northern parts of the country higher than in the southern parts. CONCLUSION/INTERPRETATION: This study reports first national incidence data of Type I diabetes in children under the age of 5 years in Germany. Observed marked temporal, seasonal, and geographical incidence variations strongly support the causal role of environmental factors in disease aetiology.

Pertussis complications in Germany--3 years of hospital-based surveillance during the introduction of acellular vaccines.

Between 1 November 1993 and 31 October 1996, admissions to paediatric departments for Bordetella pertussis complications were reported to a nationwide, hospital-based active surveillance system. The case definition included pertussis complicated by pneumonia, apnoea requiring assisted ventilation, seizures, encephalopathy or a combination of these. Two hundred sixteen cases of pertussis complications were registered. 57.4% of them were in infants, 50.9% of them less than 6 months old. There were five deaths, three previously healthy children died. At the time of hospital admission, 106 cases would have been eligible for at least three doses of pertussis vaccine, only four (3.8%) had received the recommended number of immunisations. From the second quarter of 1995, the reported number of cases declined. The decrease coincides with an improvement of pertussis vaccination coverage between 1992 and 1995 due to an increased use of acellular vaccines. The reduction of complicated pertussis was observed even in age-groups too young for the recommended vaccinations. The observed decrease could be due to the increase in vaccination coverage with interruption of the chain of transmission to the younger age-groups, to a cyclic decrease in pertussis cases, or to a combination of both. Continued surveillance will provide information on the epidemiological trend of hospitalisations for pertussis complications in the first European country to have introduced vaccination with acellular vaccines on a large scale.

[Ranking of color-coded duplex ultrasonography (CCDU) in the staging of breast tumors]. / Stellenwert der farbkodierten Duplexsonographie (FKDS) bei der Dignitätsbestimmung von Mammatumoren.

PURPOSE: of the study was to detect vessels indirectly in conspicuous focal findings of the breast by means of measurement of blood flow by using colour-coded duplex sonography (CCDS) and to examine whether additional criteria can be defined to determine the pathological relevance of breast tumours. MATERIALS AND METHODS: In a prospective study 149 patients were investigated, in whom either palpable breast lesions had been noticed or focal findings in imaging diagnostics. The perfusion in the focus and its surroundings (if present) was demonstrated and documented by means of CCDS. The investigation results were compared and contrasted with the histological findings after the operation. RESULTS: Indirect detection of the vessels depended on the size of the malignant tumours and was successful in 41.7% of cases with a tumour diameter of < or = 1 cm, in 90% of cases with a diameter of 1-2 cm and in 100% of cases with a diameter of > 2 cm. Carcinoma and metastases could be detected with a sensitivity of 87.5% and overall specificity of 56.9%. No typical perfusion pattern allowing appraisal of the pathologic relevance was seen. Postoperative scars did not show perfusion in any case. CONCLUSIONS: CCDS is of limited suitability only for determining the relevance of breast tumours, but provides additional diagnostic information especially on T1 tumours having a diameter between 1 and 2 cm. According to our results obtained so far, CCDS appears to be reliable and informative in differential diagnosis of tumour recurrence and an older scar.

S-fimbriae mediated adhesion of Escherichia coli to human buccal epithelial cells is age independent.

S-fimbriated Escherichia coli, which cause sepsis and meningitis in the newborn, bind to sialic acid-containing glycoprotein structures on the surface of human buccal epithelial cells. The dependence of this binding on host age was examined. S-fimbriated E. coli adhered in comparable numbers to cells in newborns, infants, children and adults (23.0 +/- 8.6; 23.1 +/- 11.5; 24.7 +/- 7.9; 28.9 +/- 8.8). Thus, the increased susceptibility of neonates to infections caused by S-fimbriated E. coli cannot be explained by enhanced adhesion to epithelial cells.