Muscle wound healing in rainbow trout (Oncorhynchus mykiss).

We followed the progression of healing of deep excisional biopsy punch wounds over the course of 365 days in rainbow trout (Oncorhynchus mykiss) by monitoring visual wound healing and gene expression in the healing muscle at regular intervals (1, 3, 7, 14, 38 and 100 days post-wounding). In addition, we performed muscle texture analysis one year after wound infliction. The selected genes have all previously been investigated in relation to vertebrate wound healing, but only few specifically in fish. The selected genes were interleukin (IL)-1ß, IL-6, transforming growth factor (TGF)-ß1 and -ß3, matrix metalloproteinase (MMP) -9 and -13, inducible nitric oxide synthase (iNOS), fibronectin (FN), tenascin-C (TN-C), prolyl 4-hydroxylase α1-chain (P4Hα1), lysyl oxidase (LOX), collagen type I α1-chain (ColIα1), CD41 and CD163. Wound healing progressed slowly in the presented study, which is at least partially due to the low temperature of about 8.5 °C during the first 100 days. The inflammation phase lasted more than 14 days, and the genes relating to production and remodeling of new extracellular matrix (ECM) exhibited a delayed but prolonged upregulation starting 1-2 weeks post-wounding and lasting until at least 100 days post-wounding. The gene expression patterns and histology reveal limited capacity for muscle regeneration in rainbow trout, and muscle texture analyses one year after wound infliction confirm that wounds heal with fibrosis. At 100 dpw epidermis had fully regenerated, and dermis partially regenerated. Scales had not regenerated even after one year. CD163 is a marker of "wound healing"-type M2c macrophages in mammals. M2 macrophage markers are as yet poorly described in fish. The pattern of CD163 expression in the present study is consistent with the expected timing of presence of M2c macrophages in the wound. CD163 may thus potentially prove a valuable marker of M2 macrophages - or a subset hereof - in fish. We subjected a group of fish to bathing in an immunomodulatory ß-glucan product during wound healing, but found this to have very limited effect on wound healing in contrast to a previously published study on common carp.

ß-glucan enriched bath directly stimulates the wound healing process in common carp (Cyprinus carpio L.).

Wound healing is a complex and well-organized process in which physiological factors and immune mechanisms are involved. A number of different immune modulators have been found to enhance the non-specific defence system in vertebrates, among which ß-glucans are the most powerful and extensively investigated. The aim of the present study was to investigate the biological impact of two different commercially available ß glucan containing products on the wound healing process in carp. Throughout a two week experiment fish were kept either untreated (control), or in water supplemented with the two different types of ß-glucans. The wound healing process was monitored using a multispectral visualisation system. The correlation between wound closure and immune response was investigated by measuring the gene expression patterns of IL-1ß, IL-6 family member M17, IL-8 and Muc5b, and measurement of production of radical oxygen species. PAMPs/DAMPs stimulation caused by the wounding and or ß-glucans resulted in an inflammatory response by activating IL-1ß, IL-6 family member M17 and IL-8 and differences in the expression pattern were seen depending on stimuli. IL-1ß, IL-6 family member M17 and IL-8 were activated in all wounds regardless of treatment. Expression of all three interleukins was highly up regulated in control wounded muscle already at day 1 post-wounding and decreased at subsequent time-points. The reverse was the case with control wounded skin, where expression increased from day 1 through day 14. The results for the ß-glucan treated wounds were more complex. The images showed significantly faster wound contraction in both treated groups compared to the control. The obtained results clearly demonstrated that a ß glucan enriched bath promotes the closure of wounds in common carp and induce a local change in cytokine expression.

@neurIST complex information processing toolchain for the integrated management of cerebral aneurysms.

Cerebral aneurysms are a multi-factorial disease with severe consequences. A core part of the European project @neurIST was the physical characterization of aneurysms to find candidate risk factors associated with aneurysm rupture. The project investigated measures based on morphological, haemodynamic and aneurysm wall structure analyses for more than 300 cases of ruptured and unruptured aneurysms, extracting descriptors suitable for statistical studies. This paper deals with the unique challenges associated with this task, and the implemented solutions. The consistency of results required by the subsequent statistical analyses, given the heterogeneous image data sources and multiple human operators, was met by a highly automated toolchain combined with training. A testimonial of the successful automation is the positive evaluation of the toolchain by over 260 clinicians during various hands-on workshops. The specification of the analyses required thorough investigations of modelling and processing choices, discussed in a detailed analysis protocol. Finally, an abstract data model governing the management of the simulation-related data provides a framework for data provenance and supports future use of data and toolchain. This is achieved by enabling the easy modification of the modelling approaches and solution details through abstract problem descriptions, removing the need of repetition of manual processing work.

Pharmacologic treatment of cognitive deficits and hypersexuality due to "shaken-baby syndrome".

OBJECTIVE: To describe the clinical effects of amantadine and propranolol in an agitated pediatric patient with cognitive deficits, hyperactivity, and hypersexualism secondary to "shaken-baby syndrome." BACKGROUND: Patients with shaken-baby syndrome can present with cognitive and behavioral impairments. CASE: A 9-year-old girl presented with cognitive impairments secondary to shaken-baby syndrome at 3 weeks of age. She was receiving many medications, including dextroamphetamine, methylphenidate, and clonidine, that were not effective in improving her cognitive status or decreasing her hypersexuality. She was weaned from stimulants and clonidine and prescribed amantadine 100 mg bid with improvement of attention, concentration, and cognition, although hypersexuality remained. She was then started on propranolol 10 mg tid and a gradual increase to 40 mg tid with amelioration of hypersexuality and hyperactivity and no unwanted effects noted. Self-weaning of propranolol was associated with the return of hypersexuality. The combination of amantadine and propranolol led to improvement of cognition and behavior, especially intellectual functioning and appropriate socialization with peers, respectively. CONCLUSION: Cognitive deficits and hypersexuality with hyperactive features due to shaken-baby syndrome may respond to the drug regimen of amantadine and propranolol.

[Evidence-based medicine: modern scientific methods for determining usefulness]. / Evidence Based Medicine: Moderne wissenschaftliche Methoden zur Bestimmung des Nutzens.

For quite some time, clinical epidemiology has introduced the art of critical appraisal of evidence as well as the methods of how to design sound clinical studies and trials. Almost unnoticed by most medical institutions a new hierarchy of evidence has emerged which puts well thought out trials, able to document unbiased treatment benefit in terms of patient suffering, above pathophysiological theory. Many controlled trials have shown, in the meantime, that the control of laboratory or other kind of pathologies and the correction of anatomical abnormalities do not necessarily mean a benefit for the patient. Concepts relating to this dissection of evidence include: Surrogate fallacy ("cosmetics" of laboratory results or ligament or cartilage "cosmetics" in surgery), confounding (spurious causal relationships), selection bias (comparison with selected groups) as well as lead-time bias (mistaking earlier diagnosis as increase of survival), length bias (overlooking differences in the aggressiveness of diseases as determinants of disease stage distributions) and overdiagnosis bias (mistaking the increasing detection of clinically silent pathologies as improvement of prognosis). Moreover, absolute instead of relative risk reduction needs to be used to measure patient benefit. The incorporation of decision-analysis and of the concepts or clinical epidemiology will improve the efficiency and quality of medicine much more effectively than the sole focus on technical medical performance. Evidence based medicine is the systematic and critical appraisal of medical interventions, based on the understanding how to avoid the fallacies and biases mentioned.

Cost reduction with successful implementation of an antibiotic prophylaxis program in a private hospital in Ribeirão Preto, Brazil.

OBJECTIVE: To describe the implementation and results of a perioperative antibiotic prophylaxis (PAP) program. DESIGN: A protocol for correct use of PAP was implemented in December 1994. For selected months we measured the PAP protocol compliance of a random sample of clean and clean-contaminated procedures and calculated the cost of incorrect use of PAP. SELLING: A 180-bed general hospital in Ribeirão Preto, Brazil. RESULTS: The cost of unnecessary PAP in the obstetric and gynecologic, cardiothoracic, and orthopedic services dropped from $4,224.54 ($23.47/procedure) in November 1994 to $1,147.24 ($6.17/procedure, January 1995), $544.42 ($3.58/procedure, May 1995), $99.06 ($0.50/procedure, August 1995), and $30 ($0.12/procedure, March 1996). In November 1994, only 13.6% of all surgical procedures were done with correct use of PAP, compared to 59% in January 1995, 73% in August 1995, 78% in March 1996, 92% in November 1996, and 98% in May 1997. CONCLUSIONS: Incorrect PAP use wastes resources, which is a particular problem in developing countries. Our program is simple and can be implemented without the use of computers and now is being adopted in other hospitals in our region. We credit the success of our program to the commitment of all participants and to the strong support of the hospital directors.

Enantiomeric cross-inhibition in the synthesis of oligonucleotides on a nonchiral template.

NASA: Peptide nucleic acids (PNA) are used as a model for a precursor of RNA in experiments that examine enantiomeric cross-inhibition. Experiments were conducted to facilitate comparison with prior research. Results indicate that enantiomeric cross-inhibition is as problematic in the polymerization of nucleotides on PNA as in RNA and DNA templates.^ieng

Information transfer from DNA to peptide nucleic acids by template-directed syntheses.

Peptide nucleic acids (PNAs) are analogs of nucleic acids in which the ribose-phosphate backbone is replaced by a backbone held together by amide bonds. PNAs are interesting as models of alternative genetic systems because they form potentially informational base paired helical structures. Oligocytidylates have been shown to act as templates for formation of longer oligomers of G from PNA G2 dimers. In this paper we show that information can be transferred from DNA to PNA. DNA C4T2C4 is an efficient template for synthesis of PNA G4A2G4 using G2 and A2 units as substrates. The corresponding synthesis of PNA G4C2G4 on DNA C4G2C4 is less efficient. Incorporation of PNA T2 into PNA products on DNA C4A2C4 is the least efficient of the three reactions. These results, obtained using PNA dimers as substrates, parallel those obtained using monomeric activated nucleotides.

Information transfer from peptide nucleic acids to RNA by template-directed syntheses.

Peptide nucleic acids (PNAs) are uncharged analogs of DNA and RNA in which the ribose-phosphate backbone is substituted by a backbone held together by amide bonds. PNAs are interesting as models of alternative genetic systems because they form potentially informational base paired helical structures. A PNA C10 oligomer has been shown to act as template for efficient formation of oligoguanylates from activated guanosine ribonucleotides. In a previous paper we used heterosequences of DNA as templates in sequence-dependent polymerization of PNA dimers. In this paper we show that information can be transferred from PNA to RNA. We describe the reactions of activated mononucleotides on heterosequences of PNA. Adenylic, cytidylic and guanylic acids were incorporated into the products opposite their complement on PNA, although less efficiently than on DNA templates.

[The effect of lowering cholesterol on mortality]. / Der Einfluss der Cholesterin-Senkung auf die Mortalität.

There is little doubt about the validity of the lipid hypothesis as a pathogenetic theory for atherosclerosis. However, this theory does not allow the conclusion that cholesterol-lowering treatment is necessarily beneficial in practice. As a consequence of the probabilistic nature of risk factors, the classification of plasma cholesterol levels into "normal" and "pathological" can be misleading in clinical practice. The potential benefit of cholesterol-lowering treatment is a direct function of the overall coronary risk, more or less independently of plasma cholesterol. Therefore, plasma cholesterol is of clinical significance only in patients with established CHD and a high overall risk of infarction. Total mortality has been prospectively included as one end-point in addition to infarct mortality in the many intervention studies on cholesterol-lowering. Meta-analyses of these studies show a non-significant decrease in infarct mortality through cholesterol-lowering drug treatment, with a concomitant, highly significant increase in non-infarct mortality. Lowering cholesterol in asymptomatic persons and in coronary patients with a relatively low risk of infarction results in a significant increase in total mortality. Only in a very small group of coronary patients with a very high risk of myocardial infarction, due to the presence of several additional risk factors, may cholesterol-lowering treatment be beneficial.

Does routine ultrasound scanning improve outcome in pregnancy? Meta-analysis of various outcome measures.

OBJECTIVE: To evaluate the effectiveness of routine ultrasound scanning in pregnancy by a meta-analysis of various outcome measures. DESIGN: Meta-analysis of randomised controlled trials evaluating the effect of routine ultrasound scanning on perinatal mortality and morbidity. Live birth rate (that is, live births per pregnancy) is included as a measure of pregnancy outcome in addition to the conventional perinatal mortality. SUBJECTS: 15,935 pregnancies (7992 in which routine ultrasound scanning was used and 7943 controls with selective scanning) from four randomised controlled trials. MAIN OUTCOME MEASURES: Perinatal mortality, live birth rate, rate of miscarriage, Apgar score < 7 at 1 minute, and number of induced labours. RESULTS: The live birth rate was identical in both screening and control groups (odds ratio = 0.99; 95% confidence interval 0.88 to 1.12) although the perinatal mortality was significantly lower in the group who had routine ultrasonography (0.64, 0.43 to 0.97). Differences in perinatal morbidity between the two groups as measured by the proportion of newborn babies with Apgar score < 7 at 1 minute were not significant (1.05; 0.93 to 1.19). CONCLUSION: Routine ultrasound scanning does not improve the outcome of pregnancy in terms of an increased number of live births or of reduced perinatal morbidity. Routine ultrasound scanning may be effective and useful as a screening for malformation. Its use for this purpose, however, should be made explicit and take into account the risk of false positive diagnosis in addition to ethical issues.

The epidemiology of mass breast cancer screening--a plea for a valid measure of benefit.

The present paper analyses the epidemiologic effects of mass breast cancer screening. Mass mammography may possibly achieve a breast cancer mortality reduction in relative risk terms. However, this does not necessarily represent a net benefit. It is argued that the benefits and adverse effects of a screening programme must be measured in terms of absolute risks. According to this measure, the mortality reduction achieved by a mass breast screening programme is only one death per approx. 15,000 women-years. Many thousands of mammograms are needed to prevent one cancer death, and for each woman who can derive a direct benefit in terms of a prevented breast cancer death, hundreds of women have to suffer the anxiety of a positive screening mammography. Moreover, it is possible that adverse effects of breast cancer screening may contribute to mortality from other causes. Even with the assumption that screening can save lives, the net health effect of mass breast cancer screening is questionable and appears to be rather detrimental. It may be an error to recommend mass breast screening.