Factors Neutralizing the Bacteriocidal Effect of Lysolecithin

The investigations indicate that a variety of non-dialyzable proteins and peptides, including hemoglobins, blood serum proteins, casein, soy protein and hydrolyzed proteins (peptones) are able to neutralize the bacteriocidal effect of lysolecithin. A number of lysolecithin-resistant bacteria are shown to produce lysolecithin-inhibiting metabolites that also promote growth of sensitive organisms in lysolecithin-containing media. On lysolecithin-con- taining agar this can result in a characteristic satellite growth of sensitive organisms around resistant “mother colonies”. Stable resistant mutants were easily selected from a wild type of Staphylococcus aureus after heavy inoculation on lysolecithin-containing nutrient agar. The bacterial lysolecithin-neutralizing factors examined are not considered to be of enzymatic nature. The factors in culture filtrate of Escherichia coli were separated into two active fractions by gel filtration. Due to extremely small amounts of the substances responsible for the neutralizing activity, chemical analyses of these fractions proved problematic, and only a few amino acids could be demonstrated. The neutralizing activity of the bacterial factors, and some of the proteins and peptides, resisted 100° C, or more, for several min. Some aspects of the lysolecithin-inhibitor-interaction are discussed.     

A cytosolic pathway for the conversion of hydroxypyruvate to glycerate during photorespiration in Arabidopsis

Deletion of any of the core enzymes of the photorespiratory cycle, one of the major pathways of plant primary metabolism, results in severe air-sensitivity of the respective mutants. The peroxisomal enzyme hydroxypyruvate reductase (HPR1) represents the only exception to this rule. This indicates the presence of extraperoxisomal reactions of photorespiratory hydroxypyruvate metabolism. We have identified a second hydroxypyruvate reductase, HPR2, and present genetic and biochemical evidence that the enzyme provides a cytosolic bypass to the photorespiratory core cycle in Arabidopsis thaliana. Deletion of HPR2 results in elevated levels of hydroxypyruvate and other metabolites in leaves. Photosynthetic gas exchange is slightly altered, especially under long-day conditions. Otherwise, the mutant closely resembles wild-type plants. The combined deletion of both HPR1 and HPR2, however, results in distinct air-sensitivity and a dramatic reduction in photosynthetic performance. These results suggest that photorespiratory metabolism is not confined to chloroplasts, peroxisomes, and mitochondria but also extends to the cytosol. The extent to which cytosolic reactions contribute to the operation of the photorespiratory cycle in varying natural environments is not yet known, but it might be dynamically regulated by the availability of NADH in the context of peroxisomal redox homeostasis.     

Synaptic transmission regulated by a presynaptic MALS/Liprin-alpha protein complex

Neurotransmission requires proper organization of synaptic vesicle pools and rapid release of vesicle contents upon presynaptic depolarization. Genetic studies have begun to reveal a critical role for scaffolding proteins in such processes. Mutations in genes encoding components of the highly conserved MALS/CASK/Mint-1 complex cause presynaptic defects. In all three mutants, neurotransmitter release is reduced in a manner consistent with aberrant vesicle cycling to the readily releasable pool. Recently, liprin-alpha proteins, which define active zone size and morphology, were found to associate with MALS/CASK, suggesting that this complex links the presynaptic release machinery to the active zone, thereby regulating neurotransmitter release.     

Albumin Kinetics in Patients Undergoing Major Abdominal Surgery

Background

The drop in plasma albumin concentration following surgical trauma is well known, but the temporal pattern of the detailed mechanisms behind are less well described. The aim of this explorative study was to assess changes in albumin synthesis and transcapillary escape rate (TER) following major surgical trauma, at the time of peak elevations in two well-recognized markers of inflammation.

Methods

This was a clinical trial of radiolabeled human serum albumin for the study of TER and plasma volume. Ten patients were studied immediately preoperatively and on the 2nd postoperative day after major pancreatic surgery. Albumin synthesis rate was measured by the flooding dose technique employing incorporation of isotopically labelled phenylalanine.

Results

Fractional synthesis rate of albumin increased from 11.7 (95% CI: 8.9, 14.5) to 15.0 (11.7, 18.4) %/day (p = 0.027), whereas the corresponding absolute synthesis rate was unchanged, 175 (138, 212) versus 150 (107, 192) mg/kg/day (p = 0.21). TER was unchanged, 4.9 (3.1, 6.8) %/hour versus 5.5 (3.9, 7.2) (p = 0.63). Plasma volume was unchanged but plasma albumin decreased from 33.5 (30.9, 36.2) to 22.1 (19.8, 24.3) g/L. (p<0.001).

Conclusion

Two days after major abdominal surgery, at the time-point when two biomarkers of generalised inflammation were at their peak and the plasma albumin concentration had decreased by 33%, we were unable to show any difference in the absolute synthesis rate of albumin, TER and plasma volume as compared with values obtained immediately pre-operatively. This suggests that capillary leakage, if elevated postoperatively, had ceased at that time-point. The temporal relations between albumin kinetics, capillary leakage and generalised inflammation need to be further explored.

Trial Registration

clinicaltrialsregister.eu: EudraCT 2010-08529-21 ClinicalTrials.gov NCT01194492     

Effects of Hydration on Steric and Electric Charge-Induced Interstitial Volume Exclusion—a Model

The presence of collagen and charged macromolecules like glycosaminoglycans (GAGs) in the interstitial space limits the space available for plasma proteins and other macromolecules. This phenomenon, known as interstitial exclusion, is of importance for interstitial fluid volume regulation. Physical/mathematical models are presented for calculating the exclusion of electrically charged and neutral macromolecules that equilibrate in the interstitium under various degrees of hydration. Here, a central hypothesis is that the swelling of highly electrically charged GAGs with increased hydration shields parts of the neutral collagen of the interstitial matrix from interacting with electrically charged macromolecules, such that exclusion of charged macromolecules exhibits change due to steric and charge effects. GAGs are also thought to allow relatively small neutral, but also charged macromolecules neutralized by a very high ionic strength, diffuse into the interior of GAGs, whereas larger macromolecules may not. Thus, in the model, relatively small electrically charged macromolecules, such as human serum albumin, and larger neutral macromolecules such as IgG, will have quite similar total volume exclusion properties in the interstitium. Our results are in agreement with ex vivo and in vivo experiments, and suggest that the charge of GAGs or macromolecular drugs may be targeted to increase the tissue uptake of macromolecular therapeutic agents.     

Development and delivery of patient treatment in the Trondheim Hip Fracture Trial. A new geriatric in-hospital pathway for elderly patients with hip fracture

ABSTRACT: BACKGROUND: Hip fractures are common among frail elderly persons and often have serious consequences on function, mobility and mortality. Traditional treatment of these patients is performed in orthopedic departments without additional geriatric assessment. However, studies have shown that interdisciplinary geriatric treatment may be beneficial compared to traditional treatment. The aim of the present study is to investigate whether treatment of these patients in a Department of Geriatrics (DG) during the entire hospital stay gives additional benefits as compared to conventional treatment in a Department of Orthopaedic Surgery (DOS). FINDINGS: A new clinical pathway for in-hospital treatment of hip fracture patients was developed. In this pathway patients were treated pre-and postoperatively in DG. Comprehensive geriatric assessment was performed as an interdisciplinary, multidimensional, systematic assessment of all patients focusing on each patient's capabilities and limitations as recommended in guidelines and systematic reviews. Identification and treatment of co-morbidities, pain relief, hydration, oxygenation, nutrition, elimination, prevention and management of delirium, assessment of falls and osteoporosis were emphasized. Discharge planning started as early as possible. Initiation of rehabilitation with focus on early mobilisation and development of individual plans was initiated in hospital and continued after discharge from hospital. Fracture specific treatment was based upon standard treatment for the hospital, expert opinions and a review of the literature. CONCLUSION: A new treatment program for old hip fracture patients was developed, introduced and run in the DG, the potential benefits of which being compared with traditional care of hip fracture patients in the DOS in a randomised clinical trial.     

Dacarbazine and the Agonistic TRAIL Receptor-2 Antibody Lexatumumab Induce Synergistic Anticancer Effects in Melanoma

Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of cancer cells. The potency of mapatumumab and lexatumumab was assessed in mono therapy protocols, and the ability to sensitize for dacarbazine (DTIC) treatment was explored in ten different melanoma cell lines. Our data indicated that melanoma cell lines tend to be resistant to mapatumumab, most likely due to low expression of DR4, while a dose dependent response to lexatumumab was observed. Combining DTIC and lexatumumab induced an additive or synergistic effect on cell death in the various melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the anti-apoptotic proteins Bcl-XL, cIAP-1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and anti-apoptotic proteins favoring induction of apoptosis. In the more therapy resistant cell line, HHMS, no changes in the pro- and anti-apoptotic proteins were observed. FEMX-1 xenografts treated with DTIC and lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in melanoma patients.