Role of antibiotic treatment after surgical debridement of superficial hand infections in 180 patients.

Considering the rising prevalence of antimicrobial resistance and the lack of recommendations on antibiotic treatment, the present study evaluated the necessity of local and systemic antibiotic therapy in addition to surgical debridement in superficial hand infections. Superficial hand infections were defined as not involving tendons, joints or bone. Data were analyzed for 180 patients, assigned to three study groups according to postoperative antimicrobial treatment. Patients in group I were treated with both systemic and local antibiotics; in group II antimicrobial therapy was limited to local antibiotics in the form of subcutaneous gentamicin bead chains; group III did not receive any antibiotic treatment after surgical debridement. Patients were followed up at two weeks and at three months. Immobilization time and length of stay were longer in group I, but there were no significant differences between the groups in terms of revision rate or recovery of hand function assessed by measurement of finger mobility, grip strength and the Disabilities of the Arm, Shoulder and Hand score at follow-up. Antibiotic treatment of hand infections should be considered carefully and reserved for specific indications: e.g., severe infections and selected patients such as those with diabetes or immunocompromising diseases.

The pharmacodynamic effects of combined administration of flibanserin and alcohol.

WHAT IS KNOWN AND OBJECTIVE: Flibanserin is a serotonin 5-HT1A agonist and 5-HT2A antagonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Because of the increased risk of hypotension- and syncope-related adverse events (AEs) observed with coadministration of flibanserin and alcohol, alcohol use is contraindicated. To provide a more comprehensive understanding of the interaction between flibanserin and alcohol, the results of a dedicated phase 1 alcohol-interaction study and a pooled analysis of phase 3 studies of premenopausal women with HSDD are presented. METHODS: In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4 ). Pooled data from five phase 3 studies of patients receiving flibanserin 100 mg once daily (n=1543), or placebo (n=1905), were analysed. RESULTS: In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use. WHAT IS NEW AND CONCLUSION: Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear.

Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters.

Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.

Tryptophan Metabolism Along the Kynurenine Pathway Downstream of Toll-like Receptor Stimulation in Peripheral Monocytes.

Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll-like receptors (TLRs), representing the first line of immune defence against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of this study was to investigate whether stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analysed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan. Stimulation of TLR-2, TLR-3, TLR-4, TLR-7/8 and TLR-9 was found to induce the production of kynurenine, but only stimulation of TLR-3 increased levels of further downstream metabolites, such as KYNA and QUIN. Stimulation of TLR-1, TLR-5 and TLR-6 did not induce the kynurenine pathway. Taken together, this study provides novel evidence demonstrating that TLR activation induces a pattern of downstream tryptophan degradation along the kynurenine pathway in monocytes. The results of this study may implicate that TLRs can be used as new drug targets for the regulation of aberrant tryptophan metabolism along this pathway, a potential therapeutic strategy that may be of importance in several disorders.

Repeated LPS Injection Induces Distinct Changes in the Kynurenine Pathway in Mice.

The immune system has been recognized as a potential contributor to psychiatric disorders. In animals, lipopolysaccharide (LPS) is used to induce inflammation and behaviors analogous to some of the symptoms in these disorders. Recent data indicate that the kynurenine pathway contributes to LPS-induced aberrant behaviors. However, data are inconclusive regarding optimal LPS dose and treatment strategy. Here, we therefore aimed to evaluate the effects of single versus repeated administration of LPS on the kynurenine pathway. Adult C57BL6 mice were given 0.83 mg/kg LPS as a single or a repeated injection (LPS + LPS) and sacrificed after 24, 48, 72, or 120 h. Mice receiving LPS + LPS had significantly elevated brain kynurenine levels at 24 and 48 h, and elevated serum kynurenine at 24, 48 and 72 h. Brain kynurenic acid and quinolinic acid were significantly increased at 24 and 48 h in mice receiving LPS + LPS, whereas serum kynurenic acid levels were significantly decreased at 24 h. The increase of brain kynurenic acid by LPS + LPS was likely unrelated to the higher total dose as a separate group of mice receiving 1.66 mg/kg LPS as single injection 24 h prior to sacrifice did not show increased brain kynurenic acid. Serum quinolinic acid levels were not affected by LPS + LPS compared to vehicle. Animals given repeated injections of LPS showed a more robust induction of the kynurenine pathway in contrast to animals receiving a single injection. These results may be valuable in light of data showing the importance of the kynurenine pathway in psychiatric disorders.

Susceptibility of Lenticels within the Stem Depression of Tomato Fruit to Bacterial Soft Rot.

The postharvest development of bacterial soft rot in tomato fruit caused by Pectobacterium carotovorum is herein linked with inoculation of lenticel-like apertures located around the stem attachment. Stem scars misted with aqueous cell suspensions of P. carotovorum (1 × 106 CFU/ml) or briefly (5 s) immersed in the suspension were likely to become infected during subsequent storage, with a disease incidence exceeding 70% within 7 days at 24°C. Water soaking was initially observed beneath the fruit surface at the juncture of radial walls of endocarp tissues and a corky ring around the stem attachment. If fruit were swirled for 1 min in chlorine at 150 ppm, pH 6.5, within 5 s after inoculation, lesions did not occur. However, if the chlorine treatment was delayed by 120 s, lesions occasionally developed. A 60-min delay usually assured that decay would occur before fruit ripened (within 5 days). Delaying the chlorine wash by 18 h, as would occur if commercial harvests were held overnight prior to packing operations, led to the same incidence of bacterial soft rot as observed among control fruit. Inoculation of fruit with attached stems did not lead to as much decay during storage compared with stemless fruit, suggesting that an intact calyx physically reduced lenticel exposure to external aqueous cell suspensions. Tomato fruit exposed to uncontrolled free moisture during or shortly after harvest have a high potential for postharvest decays and the likely site for infection development is the area surrounding the stem attachment.

A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria.

Symptoms of attention deficit-hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU ASCEND study evaluated the effects of sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to sapropterin therapy. In the 38 individuals with sapropterin-responsive PKU and ADHD symptoms at baseline, sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to sapropterin therapy noted in a large cohort of individuals with PKU indicate that these symptoms are potentially reversible when blood Phe levels are reduced.

Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI.

Bile salt export pump (BSEP) inhibition has been proposed to be an important mechanism for drug-induced liver injury (DILI). Modeling can prioritize knowledge gaps concerning bile acid (BA) homeostasis and thus help guide experimentation. A submodel of BA homeostasis in rats and humans was constructed within DILIsym, a mechanistic model of DILI. In vivo experiments in rats with glibenclamide were conducted, and data from these experiments were used to validate the model. The behavior of DILIsym was analyzed in the presence of a simulated theoretical BSEP inhibitor. BSEP inhibition in humans is predicted to increase liver concentrations of conjugated chenodeoxycholic acid (CDCA) and sulfate-conjugated lithocholic acid (LCA) while the concentration of other liver BAs remains constant or decreases. On the basis of a sensitivity analysis, the most important unknowns are the level of BSEP expression, the amount of intestinal synthesis of LCA, and the magnitude of farnesoid-X nuclear receptor (FXR)-mediated regulation.

[Development of diagnosis-related groups in different surgical disciplines]. / Entwicklung der Fallpauschalenvergütung in verschiedenen chirurgischen Fachgebieten.

BACKGROUND: Since the introduction of Diagnosis-Re-lat-ed Groups (DRGs) in Germany, the variables of remuneration have continuously changed. Subjectively, reimbursement by DRG has a negative connotation among all specialities. We analysed the development of reimbursement and length of stay in different surgical specialties. MATERIAL AND METHODS: By grouping the top-10-diagnoses and therapies in hand surgery, trauma surgery, general surgery as well as cardiothoracic and vascular surgery between 2004 and 2010, DRGs were obtained, compared and the data deduced. RESULTS: While the lower threshold of length of stay remained almost the same, mean value and upper threshold became shorter in most of the top-10-diagnoses. During the observation period, total reimbursement increased by 30 % in hand surgery, 20 % in general surgery and 17 % in cardiothoracic and vascular surgery, while in trauma surgery it decreased by 1 %. This corresponds to mean annual growth rates of 4.47 %, 3.08 %, 2.68 % and - 0.15 %, respectively. No correlation was found between the 4 disciplines and macro-economic parameters. CONCLUSION: Reductions of mean and upper thresholds of length of stay are present in all surgical disciplines. Total reimbursements developed partially in a contradictory manner. Negative growth involves the danger that hospital investments cannot be realised, especially in the presence of high personnel costs.

[Benign subcutaneous emphysema caused by a bellows mechanism of the first interdigital space]. / Benigne subkutane Emphysembildung durch einen Falten-Blasebalg-Mechanismus der ersten Zwischenfingerfalte.

We report 2 cases of subcutaneous emphysema after stab wounds of the first interdigital space. The first diagnosis of a gas gangrene was not confirmed. We hypothese an air incorporation caused by a bellows mechanism. An escape of the air may not be possible due to an one-way valve mechanism. The aim of this report is to describe criteria to distinguish benign emphysema from emphysema caused by infection.

Reimbursement for tissue reconstruction by pedicled and free flaps across five European countries. The importance of autologous breast reconstruction.

AIM: Case payment mechanisms have become the principle means of remunerating hospitals in many countries. We analysed the reimbursement for different types of autologous tissue transfer in five European countries. METHODS: We looked at common surgical options for breast reconstruction and flaps at other body regions. The principle diagnosis was systematically modified and processed with national grouper software to identify the relevant Diagnosis-Related Groups. RESULTS: The mean difference in payment was 4509 € in breast reconstruction versus only 2599 € in other locations. According to the underlying diagnosis for reconstruction, procedures after resection of malignant breast cancer showed higher reimbursement (mean 8319 €) than of other body parts (mean 6454 €). Sweden had the highest mean reimbursement (9589 €) followed by Austria (8032 €), Germany (7259 €), Italy (6667 €) and the UK (6037 €). Austria, Italy and the UK showed significant differences of reimbursement between pedicled flaps of the breast and other parts of the body. CONCLUSION: International data for the benchmarking and refinement of a national compensation system can be a useful instrument in identifying ways of improving each system. Across a spectrum of European countries, reimbursement for the reconstruction of the breast and other body parts was analysed and characteristics were identified. As rationalisation of healthcare becomes widespread in European countries, the need for individualised reimbursement which correlates accordingly is becoming ever more important.

Innovative solutions to novel drug development in mental health.

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.

Coelioscopic orchiectomy can be effectively and safely accomplished in chelonians.

Coelioscopic orchiectomy was performed in 27 male turtles (25 juvenile to adult red-eared sliders (Trachemys scripta elegans), one adult eastern painted turtle (Chrysems picta picta), and one juvenile male yellow-spotted Amazon River turtle (Podocnemis unifilis)). Orchiectomy was conducted under coelioscopic visualisation using ligation and transection of the mesorchium, or transection of the mesorchium with monopolar radiosurgical scissors. In 22 cases, bilateral orchiectomy was performed through a single incision; five turtles required bilateral incisions. All turtles recovered from anaesthesia. Nine turtles died within one year of surgery from conditions believed to be unrelated to surgery. One turtle was lost to follow-up. Seventeen turtles remain clinically healthy one to three years postoperatively. Coelioscopic orchiectomy provides a minimally invasive method for sterilisation of male chelonians and provides excellent visualisation during surgery. This technique is a useful model for the development of additional minimally invasive surgical techniques for chelonians.

Inhibition of Ephrin B3-mediated survival signaling contributes to increased cell death response of non-small cell lung carcinoma cells after combined treatment with ionizing radiation and PKC 412.

Radiation therapy is frequently used to treat non-small cell lung cancers (NSCLCs). We have previously shown that a combination of ionizing radiation (IR) and the staurosporine analog PKC 412, but not Ro 31-8220, increases cell death in NSCLC cells. To identify genes involved in the enhancement of cell death, a total gene profiling in response to co-administration of (i) PKC 412 with IR, or (ii) Ro 31-8220 with IR was implemented. These combined treatments caused upregulation of 140 and 179 genes and downregulation of 253 and 425 genes, respectively. Certain genes were selected and verified by real-time quantitative PCR and, of these genes, robust suppression of Ephrin B3 expression was suggested as a possible cell death-inducing mechanism of combined treatment with IR and PKC 412. Indeed, silencing of Ephrin B3 using siRNA in NSCLC cells resulted in a major alteration of their morphology with an elongated phenotype, decreased proliferation and increased cell death signaling. Moreover, silencing of Ephrin B3 in combination with IR caused a decrease in IR-mediated G(2)-arrest, induced cellular senescence, inhibited MAPK ERK and p38 phosphorylation, and caused an upregulation of p27(kip1) expression. Finally, silencing of Ephrin B3 in combination with IR sensitized U-1810 cells to IR-induced apoptosis. In conclusion, we identify and describe Ephrin B3 as a putative signaling molecule involved in the response of NSCLC cells to combined treatment with PKC 412 and ionizing radiation.

A European comparison of reimbursement in breast reconstruction.

AIMS: Case payment mechanisms have become the principal means of remunerating hospitals in most developed countries. The purpose of this study was to make an international comparison of reimbursement for breast reconstructive surgery. METHODS: We analysed remuneration for unilateral and bilateral female breast reconstruction (pedicled flaps, free flaps, alloplastic procedures) across five different European countries. National grouper software was used to identify Diagnosis Related Groups from which the proceeds were derived. RESULTS: The mean reimbursement was € 5593 for pedicled flaps, € 9149 for free flaps and € 4037 for implant-based reconstructions. The highest payments were in Sweden and the lowest in Italy. When adjusting payments by purchasing power parities, the relation among the countries did not change. The Austrian system makes a clear distinction between one-stage and two-stage delayed reconstructive interventions whereas reimbursement in other countries favoured a two-stage approach. Only one of five national reimbursement systems distinguishes between unilateral and bilateral reconstructions. CONCLUSIONS: Across a spectrum of European countries, reimbursement for breast reconstruction was based on similar procedure-specific systems, although there was a wide variation in tariffs and consideration of other factors such as underlying diagnosis. As delivery of healthcare becomes more rationalised, there is a need for individualised reimbursement which correlates directly with activity. Drawing on the experience of different healthcare systems may lead to development of a more robust and fair system of reimbursement.

What do web-use skill differences imply for online health information searches?

BACKGROUND: Online health information is of variable and often low scientific quality. In particular, elderly less-educated populations are said to struggle in accessing quality online information (digital divide). Little is known about (1) how their online behavior differs from that of younger, more-educated, and more-frequent Web users, and (2) how the older population may be supported in accessing good-quality online health information. OBJECTIVE: To specify the digital divide between skilled and less-skilled Web users, we assessed qualitative differences in technical skills, cognitive strategies, and attitudes toward online health information. Based on these findings, we identified educational and technological interventions to help Web users find and access good-quality online health information. METHODS: We asked 22 native German-speaking adults to search for health information online. The skilled cohort consisted of 10 participants who were younger than 30 years of age, had a higher level of education, and were more experienced using the Web than 12 participants in the less-skilled cohort, who were at least 50 years of age. We observed online health information searches to specify differences in technical skills and analyzed concurrent verbal protocols to identify health information seekers' cognitive strategies and attitudes. RESULTS: Our main findings relate to (1) attitudes: health information seekers in both cohorts doubted the quality of information retrieved online; among poorly skilled seekers, this was mainly because they doubted their skills to navigate vast amounts of information; once a website was accessed, quality concerns disappeared in both cohorts, (2) technical skills: skilled Web users effectively filtered information according to search intentions and data sources; less-skilled users were easily distracted by unrelated information, and (3) cognitive strategies: skilled Web users searched to inform themselves; less-skilled users searched to confirm their health-related opinions such as "vaccinations are harmful." Independent of Web-use skills, most participants stopped a search once they had found the first piece of evidence satisfying search intentions, rather than according to quality criteria. CONCLUSIONS: Findings related to Web-use skills differences suggest two classes of interventions to facilitate access to good-quality online health information. Challenges related to findings (1) and (2) should be remedied by improving people's basic Web-use skills. In particular, Web users should be taught how to avoid information overload by generating specific search terms and to avoid low-quality information by requesting results from trusted websites only. Problems related to finding (3) may be remedied by visually labeling search engine results according to quality criteria.

Psychotherapy as an epigenetic 'drug': psychiatric therapeutics target symptoms linked to malfunctioning brain circuits with psychotherapy as well as with drugs.

WHAT IS KNOWN AND OBJECTIVE: Psychotherapy has traditionally competed with psychopharmacology. As drugs have become the more dominant treatment in psychiatry and primary care, this approach is increasingly criticized as limited in scope, lacking in robust outcomes and too heavily influenced by the pharmaceutical industry. Our objective is to show that recent advances in neurobiology are clarifying that learning and environmental experiences, such as psychotherapy, change brain circuits as do drugs. The leading notion of how therapeutic effects occur in psychiatric disorders is that they happen when symptoms are reduced by improving the efficiency of information processing in hypothetically malfunctioning brain circuits. COMMENT: With this formulation of psychiatric symptoms and their relief, it is not surprising that both psychotherapy and psychopharmacology can be clinically effective for treating psychiatric disorders, or indeed that combining them can be therapeutically synergistic. Psychotherapy, including a new spinoff of cognitive behavioural therapy called trial-based therapy, like many other forms of learning, can hypothetically induce epigenetic changes in brain circuits that can enhance the efficiency of information processing in malfunctioning neurons to improve symptoms in psychiatric disorders, just like drugs. WHAT IS NEW AND CONCLUSION: Psychotherapies can be conceptualized as epigenetic 'drugs', or at least as therapeutic agents that act epigenetically in a manner similar or complementary to drugs. These findings are leading to a paradigm shift in psychiatry such that psychotherapy is experiencing a come-back as various standardized, brief, goal-directed psychotherapies are being integrated with drug treatment of psychiatric disorders by psychopharmacologists who have traditionally relied on a drugs-only approach.

An international opinion research survey of the etiology, diagnosis, therapy and outcome of Kienböck's disease (KD).

OBJECTIVES: Every fourth publication on Kienböck's disease (KD) is based for the most part on rather divergent expert opinion. We therefore surveyed expert opinion on KD in three European countries: (1) for the suspected aetiologies; (2) routinely used diagnostic tools; (3) recommended treatment and (4) expected outcome. METHODS: A questionnaire consisting of 16 questions was handed out at the national meetings for surgery of the hand in Germany (DE), France (FR) in 2009 and in the United Kingdom (UK) in 2010. RESULTS: Among the 126 surgeons who participated in the survey, 82 had a national diploma for surgery of the hand. None of the most commonly discussed etiopathological hypotheses were estimated as being very likely. Hand/arm vibration exposure was considered less likely among respondents in France and the UK than among respondents in Germany. Treatment recommendations are very heterogeneous for stage IIIB according to Lichtman. CONCLUSIONS: Expert opinions on diagnostic criteria, the pathogenesis and the choice of treatment are not consistent and may vary from one country to another.