Systems Biology Model of Cerebral Oxygen Delivery and Metabolism During Therapeutic Hypothermia: Application to the Piglet Model.

Hypoxic ischaemic encephalopathy (HIE) is a significant cause of death and disability. Therapeutic hypothermia (TH) is the only available standard of treatment, but 45-55% of cases still result in death or neurodevelopmental disability following TH. This work has focussed on developing a new brain tissue physiology and biochemistry systems biology model that includes temperature effects, as well as a Bayesian framework for analysis of model parameter estimation. Through this, we can simulate the effects of temperature on brain tissue oxygen delivery and metabolism, as well as analyse clinical and experimental data to identify mechanisms to explain differing behaviour and outcome. Presented here is an application of the model to data from two piglets treated with TH following hypoxic-ischaemic injury showing different responses and outcome following treatment. We identify the main mechanism for this difference as the Q10 temperature coefficient for metabolic reactions, with the severely injured piglet having a median posterior value of 0.133 as opposed to the mild injury value of 5.48. This work demonstrates the use of systems biology models to investigate underlying mechanisms behind the varying response to hypothermic treatment.

Broadband NIRS Cerebral Evaluation of the Hemodynamic and Oxidative State of Cytochrome-c-Oxidase Responses to +Gz Acceleration in Healthy Volunteers.

We used a miniature broadband NIRS system to monitor concentration changes in brain oxygenation (oxy- and deoxy- haemoglobin [HbO2], [HHb]) and oxidised cytochrome-c-oxidase ([oxCCO]) during a high +Gz acceleration, induced by a human centrifuge, on two healthy experienced volunteers (2 male, 34 and 37 years). We performed a sequence of several +Gz exposures that were terminated at the onset of visual symptoms (loss of peripheral vision). Systemic parameters were recorded (i.e. heart rate, blood pressure and arterial saturation), and brain tissue blood volume changes ([HbT] = [HbO2] + [HHb]) and oxygen delivery ([HbDiff] = [HbO2] - [HHb]) were calculated. Volunteer 1 demonstrated a decrease in [HbT] of -3.49 ± 0.02 µMol and [HbDiff] of -3.23 ± 0.44 µMol, and an increase of [oxCCO] of 0.42 ± 0.01µMol. Volunteer 2 demonstrated a decrease in [HbDiff] of -4.37 ± 0.23 µMol, and no significant change in [HbT] (0.53 ± 0.06 µMol) and [oxCCO] (0.09 ± 0.06 µMol). The variability of the brain metabolic response was related to the level of ischaemia, suggesting that suppression of metabolism was due to lack of glucose substrate delivery rather than oxygen availability.

Investigation of Confounding Factors in Measuring Tissue Saturation with NIRS Spatially Resolved Spectroscopy.

Performing absolute measurements of tissue saturation of the brain with near-infrared spectroscopy (NIRS) is a clinically desirable brain monitoring tool. Tissue oxygenation index (TOI) is an indicator of absolute tissue mixed arterial and venous oxygen saturation, and can be calculated using a NIRS technique called spatially resolved spectroscopy (SRS). SRS instruments measure the change of light attenuation with distance by using multiple light source-detector distances at two or more wavelengths. The aim of the study is to use broadband NIRS SRS data to investigate the effects on the calculation of TOI of different parameters: wavelength selection, scattering dependence, source-detector distance, and resolving for water. In total, 55 neonates with hypoxic-ischemic encephalopathy were monitored using a broadband multi-distance continuous wave NIRS system; 172 datasets were recorded. Using a "Standard" approach, TOI values between 0 and 100% ("good") were calculated in 157/172 datasets with a mean TOI of 50%. By changing the wavelength selection, the number of "good" data sets increases to 165/172 with a mean of 60%. Alteration of the dependence of scattering on wavelength acts as a constant which shifts the absolute value of TOI significantly (p < 0.05), demonstrating the importance of having a subject-appropriate estimation of scattering dependence. In general, changing the combination of source-detector distances does not significantly alter the TOI (the mean TOI ranges from 41% to 53%) which suggests that the algorithm is robust to different source-detector combinations. The study shows the broadband NIRS SRS algorithm gives the opportunity to explore the calculation of TOI and could further improve the measurement of tissue saturation in a clinical setting.

A double-blind placebo-controlled study of the effect of inhaled beclomethasone dipropionate for 2 years in patients with nonasthmatic chronic obstructive pulmonary disease.

Treatment of chronic obstructive pulmonary disease (COPD) with inhaled and oral corticosteroids is common, although their exact role is unclear. Previous studies suggest these drugs may reduce decline in lung function in this group of patients. We report a study investigating the effect of inhaled beclomethasone diproprionate (BDP) on lung function and symptoms in a group of patients with COPD. Treatment was given for 2 years, and the decline in FEV1 in individual patients calculated over this period. Ninety-eight patients were randomized for the study, 59 completing 2 years of treatment. Patients withdrawn had more severe airflow obstruction. Decline in FEV1, measured both prior to and after bronchodilator, was less in patients receiving inhaled BDP, although the differences failed to reach statistical significance except in a subgroup of patients with more severe airflow obstruction. Exacerbation rates were also reduced by inhaled BDP, but again the differences failed to reach conventional levels of statistical significance. The results of this study are consistent with previous published work, but further insight into the long-term role of corticosteroids in COPD await the publication of large studies which have recently been completed. Although the changes seen in this study and others are numerically small, the rate of decline in FEV1 returned to normal levels expected from age-related decline, and hence such treatment combined with other strategies may well have a significant role in the long-term treatment of this condition.

Efficacy of bimolane in the Malassezia ovalis model of psoriasis.

Bimolane, an analog of razoxane has been used in China with comparable efficacy but less toxicity than razoxane in the treatment of psoriasis. In an attempt to characterize further its mode of action it was administered both systemically and topically in the Malassezia ovalis animal model of psoriasis. Intravenous methotrexate and topical 0.1% betamethasone valerate were also used as positive control treatments. The animal model of psoriasis was effectively treated by bimolane, both systemically and topically, and also by parenteral methotrexate and topical betamethasone valerate. The time course of bimolane's effect with this model was different from methotrexate's suggesting the possibility of a different mode of action. Because bimolane, like razoxane, is an ethylene diamino tetraacetate acid (EDTA) derivative, it is possible that its effects on this reaction relate to its chelating properties and that inhibition of complement activation is important to its mode of action.

Transient bullous dermolysis of the newborn: two additional cases.

Two cases of transient bullous dermolysis of the newborn are reported. The first patient, a white boy, had normal skin at birth, but multiple blisters soon developed. The oral mucous membranes were not affected. All lesions healed within 4 months without scars but with many milia. At the age of 17 months the boy was reexamined and was found to have no blisters or milia. The second patient, a Japanese baby girl, had extensive denudation of her hands at birth. Generalized blisters and involvement of the oral mucous membrane developed. Blistering stopped within 1 1/4 months, and all lesions healed without scars. Histologically the blisters were subepidermal in both cases. Some lesional basal cells contained periodic acid-Schiff-positive inclusions. Electron microscopy revealed collagenolysis, diminution or loss of anchoring fibrils, and stellate inclusions in dilated rough endoplasmic reticulum in the keratinocytes of the lower epidermis. These stellate inclusions consisted of filamentous bundles with 25 to 33 nm cross-striations.

Electron microscopic detection of virus particles in the rhino mouse.

The rhino mouse, an experimental model for systemic lupus erythematosus, was found to have murine leukemia virus particles present in the skin. Immunoperoxidase studies with anti-type C virus antibody indicated viral antigen presence in the sebaceous cells and surrounding follicular cysts of the dermis. Electron microscope studies show virus particles, both type C extracellularly and type A intracellularly, around follicular cysts. Virus particle was labeled with specific ferritin-conjugated antitype C virus antibody.

Mediator release in local heat urticaria: protection with combined H1 and H2 antagonists.

Two patients with local heat urticaria were examined for evidence of histamine release and for changes in mast cell morphology after local heat challenge. Both patients demonstrated significant release of histamine into the draining venous blood in the challenged arm. Biopsy specimens revealed mucosal edema after 30 min, followed by a mononuclear, perivascular infiltrate by 6 hr, and increasing in intensity by 24 hr. Degranulated mast cells were observed by electron microscopy. Heat challenge was repeated after treatment with hydroxyzine, cimetidine, or a combination of both drugs. Neither hydroxyzine nor cimetidine alone affected the clinical response to challenge, but both drugs together completely abolished the clinical response. In addition, the combination of both drugs taken regularly completely prevented symptoms. This observation suggests that histamine is one of the major mediators of this disorder and that both H1 and H2 receptors are operative.

Self-healing juvenile cutaneous mucinosis.

A case of self-healing juvenile cutaneous mucinosis is presented. It demonstrates typical features of the disease: early age of onset, infiltrated plaque lesions of the head and torso, nodules of the face and periarticular regions, rapid onset accompanied by inflammatory phenomena, and spontaneous resolution over a few months. Skin biopsy showed the deposition of the mucin, hyaluronic acid, mainly in the upper reticular dermis, and a mild increase in fibroblasts and mast cells. Results of studies of B and T lymphocytes were normal. Although three cases have been reported in Europe, to our knowledge this is the first reported case in the English-language literature.

Comparability ratios by age: based on deaths of Metropolitan policyholders.

Comparability ratios based on 42,229 deaths of Metropolitan policyholders in 1979 were computed by age between the 8th and 9th revision ICD codes for 72 selected causes of death. Comparability ratios by age are not available elsewhere. Except for accidents and adverse effects, the comparability ratios for the major causes of death at all ages combined were in close agreement with those computed by the National Center for Health Statistics.

Widespread foreign-body granulomas and elevated serum angiotensin-converting enzyme.

A patient had extensive foreign-body granulomatous inflammation of multiple skin sites and of the inguinal lymph nodes with splenomegaly, cutaneous anergy to common skin antigens, and peripheral blood eosinophilia. The patient had an elevated serum angiotensin-converting enzyme level. Histologically, the granulomas were of the foreign-body type with lymphocytes, histiocytes, eosinophils, and giant cells, some that contained doubly refractile crystalline material. Electron-probe x-ray microanalysis identified silicon, magnesium, iron, calcium, phosphorus, zinc, titanium, and chromium in the crystalline material. These findings suggest talc, cement, and inorganic pigment as possible sources of the crystals. This case is reported for its unusual clinical, laboratory, and morphologic features.

Patch tests with killed sonicated microflora in patients with psoriasis.

Heat-killed sonicated suspensions of malassezia ovalis and Staphylococcus epidermidis were applied to the intact volar surface of the forearm of ten patients with psoriasis and ten control subjects. All ten of the patients with psoriasis reacted to M ovalis, and four patients reacted to S epidermidis. Two of the control subjects responded to M ovalis, and none responded to S epidermidis. Lesions that both clinically and histologically were consistent with those of psoriasis developed in the patients with psoriasis.

Effect of topical applications of heavy suspensions of killed Malassezia ovalis on rabbit skin.

Heavy applications of suspensions of killed Malassezia ovalis on rabbit skin produced lesions that both grossly and microscopically resembled human psoriasis. This system may afford not only a model but also an explanation for that disease.

Excessive mortality and causes of death in morbidly obese men.

A group of 200 morbidly obese men (average weight, 143.5 kg; age, 23 to 70 years) were admitted to a weight control program between 1960 and 1977 and were followed up for a mean period of 7 1/2 years. There was complete follow-up until the termination of the study or until death for 185 men. Fifteen men were followed up for fractional periods. Fifty of the 200 died during the course of the study. Life-table techniques, comparing the mortality among the obese with that among men in the general population, demonstrated a 12-fold excess mortality in the obese in the age group 25 to 34 years and a sixfold excess in the age group 35 to 44 years. This ratio diminished with advancing age. Cardiovascular disease was reported as the cause of death more frequently and malignancies less frequently than they were for men in the US general population.

Hepatitis-B surface antigen (HBsAg) and antibody (anti-HBs) prevalence among laboratory and nonlaboratory hospital personnel.

HBsAg and anti-HBs positivity was determined in hospital laboratory workers and nonlaboratory hospital workers (controls) matched for race and sex and adjusted for age. The combined prevalence of antigen-antibody positivity among white female technicians was 12% versus 0 of controls (P less than 0.005). The highest prevalence (18%) among laboratory workers was found in chemistry technicians, and significantly elevated frequencies also were noted in histocytologic, hematologic, and general laboratory technicians and blood collectors; this was not explained by a history of previous blood transfusions or hepatitis. Prevalence among pathologists (16%) was significantly greater (P less than 0.05) than among radiologists not routinely performing angiography (2%). Prevalence among black female housekeepers, both laboratory (25%) and nonlaboratory (36 %), was the highest, and was significantly greater (P less than 0.05) than among black female technicians (10%). Positivity was not correlated with current residence census tract socioeconomic indicators in black or white females. The data emphasize the need for continued identification of risks and improved protection measures in hospital workers.