Assessment of toxicity using dehydrogenases activity and mathematical modeling

Dehydrogenase activity is frequently used to assess the general condition of microorganisms in soil and activated sludge. Many studies have investigated the inhibition of dehydrogenase activity by various compounds, including heavy metal ions. However, the time after which the measurements are carried out is often chosen arbitrarily. Thus, it can be difficult to estimate how the toxic effects of compounds vary during the reaction and when the maximum of the effect would be reached. Hence, the aim of this study was to create simple and useful mathematical model describing changes in dehydrogenase activity during exposure to substances that inactivate enzymes. Our model is based on the Lagergrens pseudo-first-order equation, the rate of chemical reactions, enzyme activity, and inactivation and was created to describe short-term changes in dehydrogenase activity. The main assumption of our model is that toxic substances cause irreversible inactivation of enzyme units. The model is able to predict the maximum direct toxic effect (MDTE) and the time to reach this maximum (T_MDTE). In order to validate our model, we present two examples: inactivation of dehydrogenase in microorganisms in soil and activated sludge. The model was applied successfully for cadmium and copper ions. Our results indicate that the predicted MDTE and T_MDTE are more appropriate than EC₅₀ and IC₅₀ for toxicity assessments, except for long exposure times.     

78. Die Verwendung automatischer Nahtger?te in der Lungenchirurgie

Zusammenfassung Anhand von 678 bis Ende 1979 operierten Patienten mit Lungenerkrankungen wird die technische Anwendung automatischer Nahtgeräte demonstriert. Sie eignen sich zum Bronehusverschluß, für Keilexcisionen sowie zum Verschluß von Lungenvenen. Technische Modalitäten sind zu beachten. Der Vorteil liegt bei sachgemäßem Vorgehen in der Sicherheit der Anwendung, der Effektivität und in der kürzeren Operationszeit. Die Insuffizienzquote beträgt einschl. der Anfangszeit 4,4% in der Spätphase 3,2%. Komplikationen bei Keilexcisionen treten ebensowenig auf wie beim Verschluß der Lungenvenen.     

Resuscitation with Recombinant Hemoglobin rHb2.0 in a Rodent Model of Hemorrhagic Shock

Background: Hemoglobin solutions combine volume effect, oxygen-carrying capacity, and vasoactive properties, the latter facilitating restoration of global hemodynamics but endangering microvascular resuscitation. Hemoglobin-evoked vasoconstriction probably is due to nitric oxide scavenging, which can be reduced by genetic modifications of the heme pocket. This study compares resuscitation with a nonhemoglobin colloid and two recombinant hemoglobin solutions with wild-type and reduced nitric oxide-scavenging capacity.

Methods: Twenty-seven awake Syrian golden hamsters fitted with dorsal skinfold chambers underwent a 30 min-hemorrhagic shock (mean arterial pressure [MAP] 30-35 mmHg) and resuscitation with shed blood volume of either 6% dextran 60 (Biophausia, Uppsala, Sweden), recombinant hemoglobin 1.1 (rHb1.1; wild-type nitric oxide-scavenging capacity; 10 g/dl), or recombinant hemoglobin 2.0 (rHb2.0; reduced nitric oxide-scavenging capacity; 10 g/dl; both Baxter Healthcare, Boulder, CO). Macrohemodynamic and laboratory parameters were assessed; microvascular parameters in the skinfold chamber were analyzed by intravital microscopy.

Results: Hemorrhagic shock reduced functional capillary density (FCD) by 70% and caused significant metabolic acidosis. Colloid resuscitation led to incomplete recovery of MAP and FCD. Infusion of rHb1.1 completely restored MAP but not FCD, with the smallest arteriolar diameters found in this group. FCD was restored best by resuscitation with rHb2.0, although MAP was lower than in rHb1.1-treated animals. Metabolic acidosis was resolved by both hemoglobin solutions, but not by dextran.     

Genetic Analyses of the Mouse Deafness Mutations Varitint-Waddler (Va) and Jerker (Espnje)

Genetic studies on spontaneous mouse mutants with hearing defects have provided important insights into the function of genes expressed in inner ear hair cells. Here we report on our genetic analyses of the deaf mutants varitint-waddler (Va) and jerker (Espnje). A high-resolution genetic map localizes VaJ to a 0.14 ± 0.08 cM region between D3Mit85 and D3Mit259 on distal chromosome 3. By comparative mapping, the human ortholog resides at 1p22.3 between markers D1S3449 and D1S2252. To study the effect of different genetic backgrounds on the hearing phenotype, Espnje and VaJ were crossed to various inbred strains. Auditory-evoked brainstem response tests on F2 progeny demonstrate that expression, inheritance, and penetrance of the hearing phenotype are solely controlled by the mutant allele. To test for a genetic interaction between Espnje and Cdh23v, auditory function was analyzed in double heterozygotes; no significant increases of thresholds of sound pressure levels were observed. The results establish the framework for cloning the Va gene and provide valuable insights into the genetics of deafness mutations in the mouse.     

Tamoxifen potentiates in vivo antitumor activity of interleukin-2

Tamoxifen, an antiestrogen with efficacy in treatment of both estrogen receptor-positive and negative breast tumors, may be immunomodulatory. We tested tamoxifen's ability to augment the antitumor activity of interleukin-2 (IL-2), a lymphokine capable of expanding and activating lymphocytes, in the treatment of established pulmonary metastases of the weakly immunogenic murine fibrosarcoma MCA-106. Age-matched C57BL/6 female mice bearing pulmonary metastases induced by a tail vein injection of MCA-106 tumor suspension (5 x 10(5) cells/mouse) were treated from days 3 through 12 with intraperitoneal saline solution or IL-2 (50,000 units twice a day). Half of the mice in each group received plain and the remainder received tamoxifen-treated (2 units/ml) drinking water ad libitum for the duration of the experiment. All mice were killed on day 18 for enumeration of pulmonary metastases. Compared with saline-treated control mice, IL-2 and tamoxifen reduced metastases by 66% (p less than 0.0002) and 30% (p less than 0.005), respectively. IL-2 and tamoxifen combined reduced metastases 95% (p less than 0.0002), significantly better than did IL-2 (p less than 0.02) or tamoxifen (p less than 0.0003) alone. In vitro, tamoxifen inhibited proliferation of the weakly estrogen receptor-positive MCA-106 tumor by approximately 30%. Tamoxifen had no effect on the generation of 3-day IL-2-activated lymphocyte cytotoxicity against both natural killer-sensitive (YAC) and natural killer-resistant (MCA-106) target cells. Both YAC and MCA-106 tumor became more resistant to lysis with increased concentration of tamoxifen. This is the first demonstration of in vivo potentiation of IL-2 antitumor activity by tamoxifen and suggests its possible use clinically.     

How Can and Do Australian Doctors Promote Physical Activity?

Background.Physical inactivity is recognized as an important public health issue. Yet little is known about doctors' knowledge, attitude, skills, and resources specifically relating to the promotion of physical activity. Our survey assessed the current practice, perceived desirable practice, confidence, and barriers related to the promotion of physical activity in family practice.Methods.A questionnaire was developed and distributed to all 1,228 family practitioners in Perth, Western Australia.Results.We received a 71% response (n= 789). Family practitioners are most likely to recommend walking to sedentary adults to improve fitness and they are aware of the major barriers to patients participating in physical activity. Doctors are less confident at providing specific advice on exercise and may require further skills, knowledge, and experience. Although they promote exercise to patients through verbal advice in the consultation, few use written materials or referral systems.Conclusions.There are significant differences between self-reports of current practice and perceived desirable practice in the promotion of physical activity by doctors. Future strategies need to address the self-efficacy of family physicians and involve resources of proven effectiveness. The potential of referral systems for supporting efforts to increase physical activity by Australians should be explored.     

Hyalinosis cutis et mucosae of the ear-nose-throat

Hyalinosis cutis et mucosae (HCM) is a rare autosomal recessive disease of unknown aetiology and pathogenesis. In the skin and mucous membranes there is characteristically a deposition of hyaline-like material in the papillary dermis, around the small blood vessels and around skin appendages. Besides the manifold skin lesions, the mucous membranes affected are found in the nasal and oral cavities, pharynx and larynx. The latter causes the most characteristic symptom, namely, hoarseness, from birth. The lesions of the vessel walls are the most significant histopathological alterations. Ultrastructurally, massive deposits of amorphous, hyaline-like material in the dermis, reduction in number and size of the collagen fibrils and, finally, thickening of the basal laminae could be observed. The findings suggest an abnormal production of noncollagenous proteins as well as the alteration of the lysosomal systems of fibroblasts, endothelial cells and pericytes in the pathogenesis of hyalinosis.     

Influence of methylphenidate on brain development – an update of recent animal experiments

Methylphenidate (MPH) is the most commonly used drug to treat attention deficit/hyperactivity disorder (ADHD) in children effectively and safely. In spite of its widespread application throughout one of the most plastic and sensitive phases of brain development, very little is known to date about its long-term effects on brain structure and function. Hence, this short review updates the influence of MPH on brain development, since recent human and animal studies suggest that MPH alters the dopaminergic system with long-term effects beyond the termination of treatment.