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Predator-prey interactions are a main issue in ecological theory, including multispecies predator-prey relationships and intraguild predation. This knowledge is mainly based on the study of plants and animals, while its relevance for microorganisms is not well understood. The three key groups of micro-predators include protists, predatory bacteria and bacteriophages. They greatly differ in size, in prey specificity, in hunting strategies and in the resulting population dynamics. Yet, their potential to jointly control bacterial populations and reducing biomass in complex environments such as wastewater treatment plants is vast. Here, we present relevant ecological concepts and recent findings on micropredators, and propose that an integrative approach to predation at the microscale should be developed enabling the exploitation of this potential., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

This paper presents the case report of an 11-year-old boy with an acute dissection with thrombosis of the left vertebral artery and thrombosis of the basilar artery. The patient was treated with acute systemic thrombolysis, followed by intra-arterial thrombolysis, without any clinical improvement, showing left hemiplegia, bilateral clonus, hyperreflexia, and impaired consciousness. MRI indicated persistent thrombosis of the arteria basilaris with edema and ischemia of the right brainstem. Heparinization for 72 hours, followed by a two-week LMWH treatment and subsequent oral warfarin therapy, resulted in a lasting improvement of the symptoms. Vertebral artery dissection after minor trauma is rare in children. While acute basilar artery occlusion as a complication is even more infrequent, it is potentially fatal, which means that prompt diagnosis and treatment are imperative. The lack of class I recommendation guidelines for children regarding treatment of vertebral artery dissection and basilar artery occlusion means that initial and follow-up management both require a multidisciplinary approach to coordinate emergency, critical care, interventional radiology, and child neurology services.

Background: Impaired working memory (WM) is a hallmark of schizophrenia. In addition to classical WM regions such as the dorsolateral prefrontal cortex (DLPFC) and the striatum, dysfunctions in the default-mode network (DMN) contribute to these WM deficits. Unaffected siblings of patients also show WM impairments. However, the nature of the functional deficits underlying these impairments is unclear, mainly because of impaired performance confounding neuroimaging results., Methods: Here, we investigated WM and DMN activity in 23 unaffected siblings of schizophrenia patients and 24 healthy volunteers using fMRI and a Sternberg WM task. WM load was determined prior to scanning to ensure 90% accuracy for all subjects., Results: Siblings showed hyperactivation during the encoding phase of WM in the right medial prefrontal cortex (MPFC) which is the anterior part of the DMN. No differences were found during the maintenance phase. During the retrieval phase, siblings showed hyperactivation in WM regions: DLPFC, inferior parietal cortex and the striatum. Siblings who showed hyperactivity in the MPFC during encoding showed DLPFC and striatum hyperactivation during retrieval., Conclusions: Our finding of hyperactivation in WM and DMN areas indicates that siblings fail to adequately inhibit DMN activity during demanding cognitive tasks and subsequently hyperactivate WM areas. This failure may reflect dopamine hyperactivity in the striatum which prevents adequate DMN suppression needed for effective WM. This study provides support for the notion that aberrant WM and DMN activation patterns may represent candidate endophenotypes for schizophrenia., (© 2013 Elsevier B.V. All rights reserved.)

A lucid interval (LI) is the period of time between regaining consciousness after a short period of unconsciousness, resulting from a head injury and deteriorating after the onset of neurologic signs and symptoms caused by that injury. The incentive for this study was the case of a father who left his 14-week-old infant with the nanny in whose custody the infant had collapsed. The nanny denied involvement in the injury, and the father became a suspect. Of 47 abusive head trauma (AHT) cases, 8 were found to have an LI in the past. The history of the cases were thoroughly analyzed and compared with evidence in the literature. An LI is not compatible with an inertial brain injury. Shaking has either an immediate effect or no effect, which means that an LI occurs only in pure impact or blunt injuries. When "shaking lesions" are found including a retinal hemorrhage while the history mentions an LI, the story most likely is false, regardless of whether the perpetrator confesses. The finding of an LI may change the assessment of an AHT case. Lucid interval is a valuable variable in the diagnostic accuracy of an AHT.

Rlf is a guanine nucleotide exchange factor for the small G-proteins RalA and RalB and couples Ras- to Ral-signalling. Here the crystal structure of the catalytic module of Rlf consisting of a REM- and a CDC25-homology domain is determined. The structure is distinguished by an extended three stranded β-sheet called the flagpole. The flagpole is a conserved element in the RalGDS family of guanine nucleotide exchange factors and stabilises the orientation of the REM-domain relative to the CDC25-homology domain. A proline-rich sequence in the flagpole is unique to Rlf and several proteins that interact with this sequence by SH3 domains are identified. Conformational pre-selection results in a gain of affinity and contributes to the establishment of SH3 domain selectivity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The Ras family of small G-proteins plays an essential role in the regulation of a variety of signal transduction processes, ranging from cell cycle control to the regulation of exocytosis. Signalling by the Ras G-proteins is initiated by the CDC25 homology domain (CDC25-HD) containing guanine nucleotide exchange factors (GEFs); each GEF, with its specific selectivity profile towards G-proteins, commonly acts on only a small subset of the Ras family members. Thus, GEFs play a pivotal part in establishing the activation of the downstream signalling routes. The structural basis for the establishment of selectivity in the GEF-G-protein interaction is only partially understood, and several controversies on the selectivity of GEFs are discussed in the literature. In the present study, we undertook a systematic approach to determine the selectivity of CDC25-HD for members of the Ras family. We generated a data set of 126 pairs using a standardised in vitro approach encompassing purified recombinant proteins, and a comprehensive mutational study analysed the basis of the selectivity. Together, these data highlight the distinct selectivity of various GEFs and allow for predictions of untested combinations of GEFs and G-proteins., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A seven-month-old baby was admitted to a hospital emergency department after collapsing suddenly while staying with his nanny. The baby displayed classic symptoms of shaken baby syndrome, including subdural haemorrhage, cytotoxic cerebral oedema, and bilateral retinal hemorrhages. Child protection services were informed, but both the parents and the nanny denied any involvement. In the subsequent weeks, the baby developed three other episodes of new subdural bleeding and a medico-legal investigation was started into the origin of the repeated subdural bleeding. Eventually, platelet aggregation tests and electron microscopy diagnosed a delta-storage pool disease; that is, a haemostatic disorder involving dense granules of the platelets. Initial minor blunt trauma may have resulted in subdural bleeding, while subsequent retinal haemorrhage could have been facilitated by the underlying haemostatic disorder. Delta-storage pool disease should be considered as a possible mimic of abusive head trauma similar to other rare conditions such as Menkes disease and type 1 glutaric aciduria., (Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

It is generally accepted that terms referring to specific craniocerebral injury mechanisms must be replaced by the more general term abusive head trauma (AHT). Although blunt impact trauma remains an essential part of AHT, it has received far less attention in the literature than shaken-impact injuries. The current article presents 19 confessed cases of a series of 47 highly suspected AHT cases. Of these, 13 were confessed shaken-impact cases, and the other 6 confessed blunt trauma cases. There were no significant differences in the appearance of subdural hematoma, which was present in each case. Retinal hemorrhage, which was present in 10 of the 13 shaken-impact cases in which an ophthalmologic examination was conducted, occurred in 2 of the 6 blunt trauma cases. In 1 case, retinal hemorrhage probably had of metabolic origin. Skull fractures with an overlying subgaleal hematoma and a subdural hematoma below the fracture side were found in 5 of the blunt trauma cases but was also seen in the 2 shaken-impact cases with a skull fracture. The most important finding was a lucid interval (LI) in 3 blunt AHT cases. An LI does not seem to occur in shaking injuries because of the immediate and persistent effect of brain damage that such injuries involve. Therefore, LI makes it important to conduct a detailed investigation of the clinical course in time in suspected AHT cases.

Controlled activation of the complement system, a key component of innate immunity, enables destruction of pathogens with minimal damage to host tissue. Complement factor H (CFH), which inhibits complement activation, and five CFH-related proteins (CFHR1-5) compose a family of structurally related molecules. Combined deletion of CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, we report an autosomal dominant complement-mediated GN associated with abnormal increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal copies of these genes, affected individuals carry a unique hybrid CFHR3-1 gene. In addition to identifying an association between these genetic observations and complement-mediated kidney disease, these results provide insight into the protective role of the combined deletion of CFHR3 and CFHR1 in IgA nephropathy.

ACTIBIND and its human homologue RNASET2 are T2 ribonucleases (RNases). RNases are ubiquitous and efficient enzymes that hydrolyze RNA to 3' mononucleotides and also possess antitumorigenic and antiangiogenic activities. Previously, we have shown that ACTIBIND and RNASET2 bind actin and interfere with the cytoskeletal network structure, thereby inhibiting cell motility and invasiveness in cancer and in endothelial cells. We also showed that ACTIBIND binds actin in a molar ratio of 1:2. Here, we further characterize ACTIBIND and determine its crystal structure at 1.8 Å resolution, which enables us to propose two structural elements that create binding sites to actin. We suggest that each of these binding sites is composed of one cysteine residue and one conserved amino acid region. These binding sites possibly interfere with the cytoskeleton network structure and as such may be responsible for the antitumorigenic and antiangiogenic activities of ACTIBIND and its human analogue RNASET2.

Emergency and forensic physicians may find themselves sometimes on the same medical battleground but with different primary aims and hence often ignore or do not recognize each other's needs. The emergency physician interacts with law enforcement agencies with greater frequency than any other hospital physician and hence needs expertise with legal issues. Awareness of the forensic relevance of certain medical observations by emergency physicians, knowledge of emergency medicine methodology and techniques and of resuscitation-related injuries by forensic physicians may lead to a higher standard in both forensic and emergency medicine, a better serving of the criminal justice system, and most importantly safeguarding the rights of victims of criminal assault. It is this achievable mutual symbiosis that we would like to refer to as the concept of 'forensic emergency medicine'.

Objective: To evaluate the feasibility of infants' weaning of opioids and sedatives at home., Design: Retrospective observational study., Setting: Level 3 pediatric intensive care unit., Patients: Neonates treated for congenital diaphragmatic hernia (CDH) with extra corporeal membrane oxygenation (ECMO)., Intervention: Eligible infants were discharged early and further weaned of analgesics and/or sedatives at home., Results: Of the 30 neonates treated for CDH with ECMO from 2003 to 2005, 15 survived. Five of these were weaned at home, on the guidance of telephone contact once a week. The mean infusion rates of morphine and midazolam for these children were significantly higher than those for other infants. Weaning at home took 11, 42, 107, 173, and 180 days, respectively, in the resultant mean savings on hospitalization costs per patient amounted to Euro150, 000., Conclusions: The results indicate that home weaning reduced the length of hospital stay by a median of 107 days for the five infants in this study, and thereby considerably reduced healthcare costs. Parents need to be informed clearly about possible withdrawal symptoms and should consent in this strategy. The strategy of final weaning with the aid of weekly telephone consultations with a consultant pediatric intensivist was feasible for these parents.

We consider a recently suggested "equation of state" for natively folded proteins, and verify its validity for a set of about 5800 proteins. The equation is based on a fractal viewpoint of proteins, on a generalization of the Landau-Peierls instability, and on a marginal stability criterion. The latter allows for coexistence of stability and flexibility of proteins, which is required for their proper function. The equation of state relates the protein fractal dimension d(f), its spectral dimension d(s), and the number of amino acids N. Using structural data from the protein data bank (PDB) and the Gaussian network model (GNM), we compute d(f) and d(s) for the entire set and demonstrate that the equation of state is well obeyed. Addressing the fractal properties and making use of the equation of state may help to engineer biologically inspired catalysts.

The castor bean plant (Ricinus communis L.) or wonder tree is cultivated in many countries as an ornamental annual plant in gardens. The highest concentration of the lectin ricin is present in the seeds and pods. Ricin is considered as one of the most toxic natural poisons. Ricinine is a piperidine alkaloidal toxin present in castor bean and is described as a biomarker for the exposure to ricin. A case report is presented of a 49-year-old man who committed suicide by intravenous and subcutaneous injection of a castor bean extract. He was brought to the emergency department 24 h after injecting himself. On admission, the patient was conscious and he presented with a history of nausea, vomiting, diarrhoea, dyspnoea, vertigo and muscular pain. Despite symptomatic and supportive intensive care, the man died 9 h after admission due to multiorgan failure. A body external examination was performed. Blood, urine, vitreous humour and the castor bean extract were submitted to the laboratory for toxicological analysis. The identification of ricinine in the extract was performed by solid phase extraction in combination with full-scan gas chromatography/mass spectrometry, high-performance liquid chromatography with photodiode array detection and liquid chromatography/mass spectrometry operated in the full-scan mode, respectively. An extraction procedure with Oasis HLB solid phase extraction cartridges was applied. Chromatography was achieved using a Symmetry C18 column using a gradient mode with 0.15% formic acid and 0.15% formic acid in acetonitrile as mobile phase. Exposure to the castor bean extract was confirmed by identification of the biomarker ricinine in blood, urine and vitreous humour using solid phase extraction and liquid chromatography tandem mass spectrometry with electro spray source in positive ionization mode. Multiple reaction monitoring was used for specific detection. To the authors' knowledge, it is the first time that ricinine has been identified in vitreous humour in a case of castor bean poisoning. Based on the clinical symptoms and the results of the toxicological analysis, we concluded that death was caused by intoxication with plant toxins originated from R. communis L.

We determine and compare the crystal structure of two proteases belonging to the subtilisin superfamily: S41, a cold-adapted serine protease produced by Antarctic bacilli, at 1.4 A resolution and Sph, a mesophilic serine protease produced by Bacillus sphaericus, at 0.8 A resolution. The purpose of this comparison was to find out whether multiple calcium ion binding is a molecular factor responsible for the adaptation of S41 to extreme low temperatures. We find that these two subtilisins have the same subtilisin fold with a root mean square between the two structures of 0.54 A. The final models for S41 and Sph include a calcium-loaded state of five ions bound to each of these two subtilisin molecules. None of these calcium-binding sites correlate with the high affinity known binding site (site A) found for other subtilisins. Structural analysis of the five calcium-binding sites found in these two crystal structures indicate that three of the binding sites have two side chains of an acidic residue coordinating the calcium ion, whereas the other two binding sites have either a main-chain carbonyl, or only one acidic residue side chain coordinating the calcium ion. Thus, we conclude that three of the sites are of high affinity toward calcium ions, whereas the other two are of low affinity. Because Sph is a mesophilic subtilisin and S41 is a psychrophilic subtilisin, but both crystal structures were found to bind five calcium ions, we suggest that multiple calcium ion binding is not responsible for the adaptation of S41 to low temperatures., (Copyright 2008 Wiley-Liss, Inc.)

Psoas compartment block (PCB) is a potentially useful but controversial technique for lower limb surgery. We have conducted a systematic review of the efficacy and safety of PCB for anaesthesia and postoperative analgesia for hip and knee surgery. Relevant studies were identified within PubMed, EMBASE, and the Cochrane Library. The main outcome measure for anaesthesia was anaesthetic efficacy. For postoperative analgesia, the severity of postoperative pain was compared. The data were subjected to meta-analysis using relative risks with 95% confidence intervals (95% CI) for dichotomous variables and weighted mean differences with 95% CI for continuous variables. Thirty publications were included. PCB is an effective intervention for analgesia after hip and knee surgery. It appears superior to opioids for pain relief after hip surgery. This analgesic benefit may be extended beyond 8 h by the use of a catheter technique. Compared with Winnie's 3-in-1 block, PCB is associated with more consistent block of the obturator nerve. PCB may be an alternative to postoperative neuraxial block. Although PCB combined with sciatic nerve block and sedation is an effective technique for minor knee surgery, there is currently insufficient data to recommend the use of this approach for hip and major knee surgery. PCB is a safe and effective alternative for analgesia after hip and knee surgery. More research is required to define its role in the intraoperative setting and confirm potentially beneficial effects on variables such as perioperative haemodynamics and blood loss.

Since pain-related fear may contribute to the development and maintenance of chronic low back pain (CLBP), an exposure in vivo treatment (EXP) was developed for CLBP patients. We examined the effectiveness as well as specific mediating mechanisms of EXP versus operant graded activity (GA) directly and 6 months post-treatment in a multi-centre randomized controlled trial. In total, 85 patients suffering from disabling non-specific CLBP reporting at least moderate pain-related fear were randomly allocated to EXP or GA. It was demonstrated that EXP, despite excelling in diminishing pain catastrophizing and perceived harmfulness of activities, was equally effective as GA in improving functional disability and main complaints, although the group difference almost reached statistical significance favouring EXP. Both treatment conditions did not differ in pain intensity and daily activity levels either. Nor was EXP superior to GA in the subgroup of highly fearful patients. Irrespective of treatment, approximately half the patients reported clinically relevant improvements in main complaints and functional disability, although for the latter outcome the group difference was almost significant favouring EXP. Furthermore, the effect of EXP relative to GA on functional disability and main complaints was mediated by decreases in catastrophizing and perceived harmfulness of activities. In sum, this study demonstrates that up to 6 months after treatment EXP is an effective treatment, but not more effective than GA, in moderately to highly fearful CLBP patients, although its superiority in altering pain catastrophizing and perceived harmfulness of activities is clearly established. Possible explanations for these findings are discussed.

After placement of a reverse shoulder endoprosthesis, range of motion is usually still compromised. To what extent this occurs from limitation in motion of the reverse endoprosthesis is, however, unclear. We measured the motion pattern of 16 patients (18 shoulders) during three active and passive range of motion tasks using a six degree-of-freedom electromagnetic tracking device. Despite rotator cuff deficiencies, glenohumeral elevation contributed roughly two-thirds of the total thoracohumeral elevation, which is comparable to healthy subjects. However, patients could not actively use the full range of motion provided by the prosthesis. Although we found considerable interindividual differences in shoulder kinematics, the limitation in glenohumeral range of motion appears related to a lack of generated muscle force and not the design of the prosthesis.

ACTIBIND is a T2 RNase extracellular glycoprotein produced by the mould Aspergillus niger B1 (CMI CC 324626) that possesses anticarcinogenic and antiangiogenic activities. ACTIBIND was found to be an actin-binding protein that interacts with rabbit muscle actin in a 1:2 molar ratio (ACTIBIND:actin) with a binding constant of 16.17 x 10(4) M(-1). Autoclave-treated ACTIBIND (EI-ACTIBIND) lost its RNase activity, but its actin-binding ability was conserved. ACTIBIND crystals were grown using 20% PEG 3350, 0.2 M ammonium dihydrogen phosphate solution at room temperature (293 K). One to four single crystals appeared in each droplet within a few days and grew to approximate dimensions of 0.5 x 0.5 x 0.5 mm after about two weeks. Diffraction studies of these crystals at low temperature (100 K) indicated that they belong to the P3(1)21 space group, with unit-cell parameters a = 78, b = 78, c = 104 A.

A cognitive behavioural account of chronic low back pain (CLBP) proposes that the relationship between pain catastrophizing and functional disability is mediated by fear of movement/(re)injury. Several clinical studies already demonstrated the contribution of pain catastrophizing and fear of movement/(re)injury in the development and maintenance of CLBP. This study included people with low back pain (LBP) in the general population, and aimed to investigate whether fear of movement/(re)injury mediated the relationship between pain catastrophizing and functional disability, by examining several prerequisites for mediation. Data from the Dutch population-based Musculoskeletal Complaints and Consequences Cohort (DMC(3)) study were used, including 152 people suffering from LBP who completed both a follow-up questionnaire and a baseline questionnaire 6 months previously. This study was unable to demonstrate that the relationship between pain catastrophizing and functional disability was mediated by fear of movement/(re)injury, since the prerequisite that pain catastrophizing and functional disability were related, was not fulfilled. However, pain catastrophizing was significantly related to fear of movement/(re)injury 6 months later, above and beyond other contributing variables such as fear of movement/(re)injury already present at baseline. On its turn, fear of movement/(re)injury was related to functional disability, in addition to pain intensity. Although this study leaves some indistinctness concerning the actual relationships between pain catastrophizing, fear of movement/(re)injury, and functional disability, it does provide some evidence for the contributing role of these factors in LBP in the general population.

Research studies focusing on the fear-avoidance model have expanded considerably since the review by Vlaeyen and Linton (Vlaeyen J. W. S. & Linton, S. J. (2000). Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain, 85(3), 317--332). The fear-avoidance model is a cognitive-behavioral account that explains why a minority of acute low back pain sufferers develop a chronic pain problem. This paper reviews the current state of scientific evidence for the individual components of the model: pain severity, pain catastrophizing, attention to pain, escape/avoidance behavior, disability, disuse, and vulnerabilities. Furthermore, support for the contribution of pain-related fear in the inception of low back pain, the development of chronic low back pain from an acute episode, and the maintenance of enduring pain, will be highlighted. Finally, available evidence on recent clinical applications is provided, and unresolved issues that need further exploration are discussed.

Fear of movement/(re)injury is assumed to contribute to the development and maintenance of chronic low back pain (CLBP) in a subgroup of patients. Studying fear of movement/(re)injury with implicit attitude measures, without the awareness of the patient, might be a valuable addition to self-report questionnaires. The aims of the current study were to investigate whether CLBP patients demonstrate more implicit fear of movement/(re)injury than healthy controls, and whether 2 implicit measures are related to each other, and to an explicit self-report measure of fear of movement/(re)injury. A group of 66 CLBP patients and 30 healthy controls took part in this study. In addition to self-report questionnaires, fear of movement/(re)injury was implicitly assessed by the Extrinsic Affective Simon Task (EAST) and the Go-No-Go-Association Task (GNAT) that aimed to determine the association between back-stressing movements and the evaluation "threatening". On both implicit tasks it was found that neither CLBP patients nor healthy controls demonstrated implicit fear of movement/(re)injury, and that CLBP patients did not differ from healthy controls in their level of implicit fear of movement/(re)injury. In general, no associations were found between the EAST and the GNAT, or between implicitly measured and self-reported fear of movement/(re)injury. One major caveat in drawing inferences from these findings is the poor reliability of these implicit measures. Research towards the psychometric properties of these measures should first be expanded before modifying, and applying, them to more complex domains such as fear of movement/(re)injury.

Two women, 33 and 31 years of age, were referred to a surgeon for the removal of a previously implanted hormonal contraceptive after the general practitioner had attempted this without success. However, no foreign body could be detected in either patient by surgery, echography and MRI and by X-ray, echography and MRI, respectively. They were then referred to a gynaecologist. In the first patient, a low level of etonogestrel confirmed that there was no contraceptive in her body. Subcutaneous contraceptives are sometimes implanted incorrectly. If the rod is not palpable at the site of insertion, then the etonogestrel level should be determined first of all. If the hormone level indicates that a rod is indeed present, then echography or MRI may be considered to localise it before resorting to surgical exploration. Many problems can be prevented by proper implantation.

Two men aged 34 and 41 years, respectively, displayed hyperactive and chaotic behaviour. On the basis of the symptoms and their effect on the patients' functioning during childhood and adulthood, the diagnosis of attention deficit/hyperactivity disorder (ADHD) was made. The patients became calmer with methylphenidate treatment, but a few months later they chose to stop taking the medication and to accept their hyperactive behaviour. To establish the diagnosis of ADHD in adults, it is essential that some of the symptoms started before seven years of age and that the symptoms and resulting impairment persist over time from childhood into adulthood. To investigate this, it is necessary to obtain heteroanamnestic information from the parents or other people who knew the patient at that age. Treatment with medication and psychoeducation is effective and can prevent further suffering.

The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.

Objectives: The purpose of this study was to identify trends and factors associated with outcomes of persistent truncus arteriosus (PTA)., Background: Although there have been significant improvements, PTA continues to be associated with significant morbidity and mortality., Methods: We undertook a review of all consecutive cases of PTA (n = 205) presenting at our institution from 1953 to 1997. Data were collected regarding demographics, anatomy, management (surgical palliation and repair) and outcomes (mortality and reoperation)., Results: Significant trends (p < or = 0.001) related to groups defined by year of birth were as follows: number of cases (1953-1967, n = 13; 1968-1977, n = 42; 1978-1987, n = 69; 1988-1997, n = 81), median age at first assessment (8 months, 42 days, 7 days and 2 days, respectively), proportion who did not have any surgery (58%, 27%, 22% and 11%), proportion who had an initial palliative procedure (25%, 37%, 6% and 2%), proportion who underwent PTA repair (31%, 59%, 72% and 88%), median age at PTA repair (11.2 years, 1.1 years, 1.6 months and 12 days) and proportion dying before hospital discharge after repair (50%, 63%, 56% and 41%). Since 1995, mortality before hospital discharge after repair has further decreased to 2/11 (18%). Increasing time to initial conduit replacement in hospital survivors was significantly related to larger sized conduit at repair (p = 0.02) and use of pulmonary homografts (vs. aortic homografts or xenografts; p = 0.002). Interventional catheterization to address conduit obstructions significantly increased conduit longevity., Conclusions: Significant improvements in PTA outcomes are evident with trends toward earlier age at assessment and complete repair.

We treated 100 patients having osteomyelitis with debridement and gentamicin-PMMA beads and followed them for 5 (1-12) years. 66 of the infections were chronic, in 18 cases combined with arthritis and in 3 cases with pseudarthrosis. They underwent 117 "treatment periods", consisting of one or more operations (total 152), in most cases with an interval of 2 weeks. No systemic antibiotics were necessary besides the local antibiotic treatment in 52 of the treatment periods. Healing was achieved in 92 patients, in 78 after a single treatment period which included 1-5 operations, in 14 after two or three treatment periods. Healing was more difficult to achieve when the infection was chronic, especially with a duration of more than 6 years or when caused by elective surgery. Local antibiotic treatment with gentamicin PMMA beads has the advantage that the wound can be closed primarily and that a higher local antibiotic concentration in the tissues can be achieved, often making systemic antibiotic treatment unnecessary.

To determine cis-acting elements controlling the rat B-50/GAP-43 gene expression, the genomic DNA encoding exon 1 and the 5' flanking sequence was isolated. Sequence analysis of 1 kb 5' untranslated region (UTR) revealed the presence of a (GA)-repeat and a (GT)-repeat. The size of the (GA)-repeat varied due to both an instability of phage lambda lambda DNA in E. coli and genomic variation between rats. Transcription initiation sites were mapped in 8-day-old rat brain poly(A)+ mRNA. Primer extension indicated multiple transcription start sites at -159 and -339/-342 nt upstream of the translation start site; reverse transcriptase coupled PCR showed that the most 5' transcription start site is located between -465 and -440. Northern blotting demonstrated that approximately 90% of the B-50 mRNAs initiates at approximately -50. Promoter analysis by transient transfection assays in undifferentiated and retinoic acid-differentiated P19-EC cells revealed that the rat B-50 gene contains two promoters. P1 (located between -750 and -407) contains commonly observed promoter elements such as a TATA box and CCAAT boxes. P2 (located between -233 and -1) neither contains TATA boxes, CCAAT boxes nor consensus sequences of house-keeping gene promoters like GC-boxes. The activity of P1 is inhibited at neuroectodermal differentiation of P19-EC cells whereas the activity of P2 is stimulated. In 8 day old rat brain the majority of the B-50 mRNA transcripts are derived from P2. It is concluded that at this developmental stage P2 is the most important promoter.

An autopsy study was performed on temporal lobe samples from 20 non-demented patients with amyotrophic lateral sclerosis (ALS), 17 age-matched non-demented controls and 4 Alzheimer's disease (AD) patients. Formalin fixed, paraffin embedded sections from the hippocampus with adjacent parahippocampal gyrus and from the superior temporal gyrus were stained with conventional and immunohistochemical stains. Immunohistochemical staining for the A4 protein was enhanced by pretreatment with 0.25% pepsin before 100% formic acid. The incidence and severity of AD-like pathological changes were similar in ALS patients and non-demented controls. In both groups, pathological changes increased with age. This study does not support the hypothesis that ALS and AD share an etiopathogenetic background.

In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration of enalaprilat only slightly increased the effect of bradykinin on coronary flow. In nitrate-tolerant hearts of rats pretreated with isosorbide dinitrate (15 mg daily), the increase in coronary flow by nitroglycerin and bradykinin was significantly less when compared to control hearts. The effect of captopril was not affected by pretreatment. The involvement of endothelium-derived relaxing factor (EDRF) in the effect of captopril was apparent from experiments with L-arginine, the precursor of EDRF, and L-NMMA, the "false" precursor of EDRF. L-Arginine increased the effect of captopril, whereas L-NMMA showed a competitive antagonism for the effect of captopril on coronary flow in the isolated rat heart. Clinically, the effect of captopril was studied in 10 patients with stable, exercise-induced angina pectoris that had been treated for 3 weeks with slow-release isosorbide dinitrate (20 mg four times daily). At day 7, a baseline exercise test was obtained. Subsequently, patients with chest pain and at least 1-mm ST-segment depression on the ECG during exercise were included. They received on day 14 and 21 either captopril (25 mg) or placebo 1 h before exercise testing in a randomized, double-blind, crossover design. Captopril significantly improved the combined score of maximal ST-segment depression, maximal workload, and time to angina when compared to placebo. No differences in the pressure-rate index at rest and during exercise were seen. These results indicate that the sulfhydryl group of certain angiotensin converting enzyme inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF. In the clinical situation, this may lead to an improved exercise performance in patients with stable angina pectoris during chronic nitrate treatment, independent of its systemic vascular effects.

Rat Kupffer cells contain the three major cytoskeletal components: microfilaments (MF), microtubules (MT), and intermediate filaments (IF) of the vimentin type. Previous cytomagnetometric data obtained from alveolar macrophages and rat Kupffer cells in culture provided evidence that actin filaments contribute to the movements of lysosomes. The lysosomal transport in living cells was affected, when the MFs were selectively disturbed, whereas the depolymerization of the MTs had no effect on the lysosomal movement measured by cytomagnetometric means. Immunofluorescence and ultrastructural studies of isolated and cultured rat Kupffer cells, presented in this paper, will investigate the relationship between lysosomes and the cytoskeleton. The principal filamentous structure in the peripheral cytoplasm of Kupffer cells in a dense meshwork of actin filaments. The dimension of the meshes combined with the dimensions of lysosomes implies the necessity of either (i) disintegration of the actin filament cross-links, (ii) depolarymerization and redistribution of MF's, or (iii) a displacement of actin filaments by the lysosomes during the organelle transport. The presence of microtubules in cytoplasmic protrusions and their track from the periphery to the perinuclear region during interphase might play a role in the transport mechanism of lysosomes, the more so because microtubules could often be demonstrated in closest association with lysosomes even in the first phase of endocytosis. The distribution pattern of vimentin, found as a dense interconnected framework surrounding the lysosomes like a basket, could play a role in positioning the organelles. The dynamic functions of MF's and MT's and their multifunctionality led to an adaptive and flexible organization of these filaments which may both be involved in lysosomal motion.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the contribution of each of the two adenovirus type 5 (Ad5) major early region 1b (E1b) proteins in cell transformation and in lytic infection. An Ad5 E1 plasmid, in which the reading frame for the 19-kDa E1b protein was abolished by a stop codon close to the initiation codon, transformed primary baby rat kidney (BRK) cells with an efficiency of about half of that of a wild type Ad5 E1 plasmid, whereas a plasmid with a mutation in the gene for the 58-kDa E1b protein transformed the same primary cells with only one-third of the wild type efficiency. Plasmids containing region E1a only or a plasmid carrying mutations in the genes for major E1b proteins all transformed primary cells with an efficiency of approximately 5% of wild type. To test the effect of the E1b mutations in virion-mediated cell transformation, the mutant E1b regions were introduced into intact viral genomes by overlap recombination and were subsequently used in a transformation assay on BRK cells. The 19 and 58-kDa mutant viruses were found to transform BRK cells with 11 and 25% of the efficiency of wild type virus, respectively. These results suggest that the 19-kDa E1b protein is essential for virus-mediated cell transformation, in agreement with results of others, but not for plasmid-mediated cell transformation. In lytic infection, the 19-kDa mutant virus was some 30-fold reduced in yield on HeLa cells, whereas the 58-kDa mutant virus was 3000-fold reduced in its ability to grow on HeLa cells at low multiplicity of infection, but showed a marked multiplicity-dependent leakiness. The 58-kDa mutant virus was not defective when its growth was assayed on human embryonic kidney (HEK) cells. This may indicate that cellular proteins are expressed in HEK cells that are functionally homologous to the 58-kDa E1b protein.