The protective effect of anterior cruciate ligament reconstruction on articular cartilage: a systematic review of animal studies.

OBJECTIVE: It is unclear if anterior cruciate ligament (ACL) reconstruction can prevent the onset of degenerative changes in the knee. Previous studies were inconclusive on this subject. The aim of this study was to systematically review all studies on the effect of ACL reconstruction on articular cartilage in animals. DESIGN: Pubmed and Embase were searched to identify all original articles concerning the effect of ACL reconstruction on articular cartilage compared with both its positive (ACL transection) and negative (sham and/or non-operated) control in animals. Subsequently a Risk of bias and meta analysis was conducted based on five outcomes (gross macroscopic assessment, medical imaging, histological histochemical grading, histomophometrics and biomechanical characterization) related to articular cartilage. RESULTS: From the 19 included studies, 29 independent comparisons could be identified which underwent ACL reconstruction with an average timing of data collection of 23 weeks (range 1-104 weeks). Due to limited data availability meta-analysis could only be conducted for gross macroscopic damage. ACL reconstruction caused significant gross macroscopic damage compared with intact controls (SMD 2.0 [0.88; 3.13]). These findings were supported by individual studies reporting on histomorphometrics, histology and imaging. No significant gross macroscopic damage was found when ACL reconstruction was compared with ACL transection (SMD -0.64 [-1.85; 0.57]). CONCLUSION: This systematic review with an average follow up of included studies of 23 weeks (range 1-104 weeks) demonstrates that, in animals, ACL reconstruction does not protect articular cartilage from degenerative changes. The consistency of the direction of effect, provides some reassurance that the direction of effect in humans might be the same.

Systematic review of experimental studies on intestinal anastomosis.

BACKGROUND: The contribution of animal research to a reduction in clinical intestinal anastomotic leakage is unknown, despite numerous experimental studies. In view of the current societal call to replace, reduce and refine animal experiments, this study examined the quality of animal research related to anastomotic healing and leakage. METHODS: Animal studies on intestinal anastomotic healing were retrieved systematically from PubMed and Embase. Study objective, conclusion and animal model were recorded. Reporting quality and internal validity (reporting of randomization and blinding) were assessed. RESULTS: A total of 1342 studies were identified, with a rising publication rate. The objectives of most studies were therapeutic interventions (64·8 per cent) and identification of risk factors (27·5 per cent). Of 350 articles studying experimental therapies, 298 (85·1 per cent) reported a positive effect on anastomotic healing. On average, 44·7 per cent of relevant study characteristics were not reported, in particular details on anastomotic complications (31·6 per cent), use of antibiotics (75·7 per cent), sterile surgery (83·4 per cent) and postoperative analgesia (91·4 per cent). The proportion of studies with randomization, blinding of surgery and blinding of primary outcome assessment has increased in the past two decades but remains insufficient, being included in only 62·4, 4·9 and 8·5 per cent of publications respectively. Animal models varied widely in terms of species, method to compromise healing, intestinal segment and outcome measures used. CONCLUSION: Animal research on anastomotic leakage is of poor quality and still increasing, contrary to societal aims. Reporting and study quality must improve if results are to impact on patients.

Remote Ischemic Preconditioning To Reduce Contrast-Induced Nephropathy: A Randomized Controlled Trial.

BACKGROUND: Despite the increasing use of pre- and post-hydration protocols and low osmolar instead of high osmolar iodine containing contrast media, the incidence of contrast induced nephropathy (CIN) is still significant. There is evidence that contrast media cause ischemia reperfusion injury of the renal medulla. Remote ischemic preconditioning (RIPC) is a non-invasive, safe, and low cost method to reduce ischemia reperfusion injury. The aim of this study is to investigate whether RIPC, as an adjunct to standard preventive measures, reduces contrast induced acute kidney injury in patients at risk of CIN. METHODS: The RIPCIN study is a multicenter, single blinded, randomized controlled trial in which 76 patients at risk of CIN received standard hydration combined with RIPC or hydration with sham preconditioning. RIPC was applied by four cycles of 5 min ischemia and 5 min reperfusion of the forearm. The primary outcome measure was the change in serum creatinine from baseline to 48 to 72 hours after contrast administration. RESULTS: With regard to the primary endpoint, no significant effect of RIPC was found. CIN occurred in four patients (2 sham and 2 RIPC). A pre-defined subgroup analysis of patients with a Mehran risk score ≥11, showed a significantly reduced change in serum creatinine from baseline to 48 to 72 hours in patients allocated to the RIPC group (Δ creatinine -3.3 ± 9.8 µmol/L) compared with the sham group (Δ creatinine +17.8 ± 20.1 µmol/L). CONCLUSION: RIPC, as an adjunct to standard preventive measures, does not improve serum creatinine levels after contrast administration in patients at risk of CIN according to the Dutch guideline. However, the present data indicate that RIPC might have beneficial effects in patients at a high or very high risk of CIN (Mehran score ≥ 11). The RIPCIN study is registered at: http://www.controlled-trials.com/ISRCTN76496973.

Low-pressure pneumoperitoneum during laparoscopic donor nephrectomy to optimize live donors' comfort.

Nowadays, laparoscopic donor nephrectomy (LDN) has become the gold standard to procure live donor kidneys. As the relationship between donor and recipient loosens, it becomes of even greater importance to optimize safety and comfort of the surgical procedure. Low-pressure pneumoperitoneum has been shown to reduce pain scores after laparoscopic cholecystectomy. Live kidney donors may also benefit from the use of low pressure during LDN. To evaluate feasibility and efficacy to reduce post-operative pain, we performed a randomized blinded study. Twenty donors were randomly assigned to standard (14 mmHg) or low (7 mmHg) pressure during LDN. One conversion from low to standard pressure was indicated by protocol due to lack of progression. Intention-to-treat analysis showed that low pressure resulted in a significantly longer skin-to-skin time (149 ± 86 vs. 111 ± 19 min), higher urine output during pneumoperitoneum (23 ± 35 vs. 11 ± 20 mL/h), lower cumulative overall pain score after 72 h (9.4 ± 3.2 vs. 13.5 ± 4.5), lower deep intra-abdominal pain score (11 ± 3.3 vs. 7.5 ± 3.1), and a lower cumulative overall referred pain score (1.8 ± 1.9 vs. 4.2 ± 3). Donor serum creatinine levels, complications, and quality of life dimensions were not significantly different. Our data show that low-pressure pneumoperitoneum during LDN is feasible and may contribute to increase live donors' comfort during the early post-operative phase.

Outcome and risk factors for recurrence of early onset fracture-related infections treated with debridement, antibiotics and implant retention: Results of a large retrospective multicentre cohort study.

INTRODUCTION: Early Fracture-Related Infections (FRIs) are a common entity in hospitals treating trauma patients and are often treated with a Debridement, Antibiotics and Implant Retention (DAIR) procedure. Aims of this study were to 1) evaluate the recurrence rate after DAIR procedures for early onset FRI, 2) establish the number of surgical procedures to gain control of the initial infection and 3) identify independent predictors for recurrence in this cohort. METHODS: A retrospective multicentre cohort study was conducted in two level 1 trauma centres. Consecutive patients who underwent a DAIR procedure between January 1st 2015 and July 1st 2020 for confirmed FRI with an onset of <6 weeks after the latest osseous operation were included. Recorded data included patient demographics, treatment characteristics and follow-up. Univariate and multivariate logistic regression analyses were performed to assess predictors for recurrent FRI. RESULTS: A total of 141 patients with early FRI were included in this study with a median age of 54.0 years (interquartile range (IQR) 34.5-64.0). The recurrence rate of FRI was 13% (n = 19) at one year follow-up and 18% (n = 25) at 23.1 months (IQR 15.3-36.4) follow-up. Infection control was achieved in 94% (n = 127/135) of cases. In total, 73 patients (52%) underwent at least two surgical procedures to treat the ongoing initial episode of FRI, of whom 54 patients (74%) required two to three procedures and 17 patients (23%) four to five procedures. Predictors for recurrent FRI were use of an intramedullary nail during index operation (odds ratio (OR) 4.0 (95% confidence interval (CI) 1.1-13.8)), need for additional surgical procedures to treat ongoing infection during the treatment period following the first presentation of early FRI (OR 1.9 (95% CI 1.1-3.5)) and a decreased Injury Severity Score (ISS) (inverted OR 1.1 (95% CI 1.0-1.1)). CONCLUSION: The recurrence rate after treatment of early onset FRI in patients treated with a DAIR procedure was 18% at 23.1 months follow-up. At least two surgical procedures to gain control of the initial infection were needed in 52% of patients. Independent predictors for recurrent FRI were the use of an intramedullary nail during index operation, need for additional surgical procedures and a decreased ISS.

What is the benefit of treatment with multiple lines of chemotherapy for patients with metastatic breast cancer? A retrospective cohort study.

BACKGROUND: Despite the extensive clinical experience, it is still under debate to what extent patients with metastatic breast cancer (MBC) benefit from multiple lines of chemotherapy beyond standard first or second line treatment. Selection of patients with MBC who will benefit from treatment is crucial to improve outcome and reduce unnecessary toxicity. In this retrospective study, systemic treatment outcome for patients with metastatic MBC is being evaluated. We evaluated to what extent the clinical benefit of prior chemotherapy can predict the success of a subsequent treatment line. METHODS: Ninety-one patients treated with chemotherapy for MBC between January 2005 and January 2009 were included in this study. Clinical characteristics of patients, choices of chemotherapy and response at first evaluation of every treatment line was evaluated based on radiologic and clinical data. RESULTS: Patients received multiple systemic cytotoxic and biological (combination) therapies. 30% of these patients received more than five consecutive systemic (combination) treatments. First line chemotherapy was mostly anthracycline-based, followed by taxanes, capecitabine and vinorelbine. The response rate (RR, complete response plus partial response according to RECIST 1.1) decreased from 20% (95% CI 11-28%) upon first line of treatment to 0% upon the fourth line. The clinical benefit rate (combining RR and stable disease) decreased from 85% (95% CI 78-93%) in the first to 54% (95% CI 26-67) upon the fourth line. 24% of the patients with clinical benefit at first evaluation did not receive a subsequent line of treatment when progressive disease occurred, while sixty-one percent of the patients with progressive disease at first evaluation of a treatment did not receive a subsequent line of chemotherapy. When applied, the efficacy of a subsequent line of treatment was similar for patients independent of previous treatment benefit. CONCLUSION: The clinical benefit at first evaluation from systemic treatment in MBC does not predict for subsequent treatment benefit in this retrospective analysis. The fact that 61% of patients did not receive subsequent treatment after previous treatment failure suggests that either clinical judgement is of critical value in selection of patients to prevent them from unnecessary toxicity or, alternatively indicates that based on the assumption that prior treatment failure predicts for lack of benefit undertreatment of patients occurs. Therefore, a more adequate clinical judgement tool or predictive biomarkers for response are urgently needed to improve treatment outcome.

Is Germany a model for managers?

Most American managers have a hard time making sense of Germany. The country has a fraction of the resources and less than one-third the population of the United States. Labor costs are substantially higher, paid vacations are at least three times as long, and strong unions are deeply involved at all levels of business, from the local plant to the corporate boardroom. Yet German companies manage to produce internationally competitive products in key manufacturing sectors, making Germany the greatest competitive threat to the United States after Japan. The seemingly paradoxical nature of the German economy typically evokes one of two diametrically opposed responses. The first is to celebrate the German economy as a "model" worth emulating--indeed, as the answer to declining U.S. competitiveness. The alternative, more skeptical response is to question Germany's staying power in a new, more competitive global economy. According to Kirsten Wever and Christopher Allen, the problem with both points of view is that they miss the forest for the trees. Observers are so preoccupied with praising--or blaming--individual components of the German economy that they fail to see the dynamic logic that ties these components together into a coherent system. In their review of recent research on the German business system, Wever and Allen argue that managers can learn an important lesson from Germany. In the global economy, competition isn't just between companies but between entire socioeconomic systems. Germany's ability to design a cohesive economic and social system that adapts continuously to changing requirements goes a long way toward explaining that country's competitive success.

[Anaesthesia and intracellular distribution of cerebral hexokinase (author's transl)]. / Narkose und intrazelluläre Verteilung der cerebralen Hexokinase.

The purpose of the present investigation was to demonstrate how the intracellular distribution of hexokinase was influenced by anaesthetics. The experiments were carried out using mice in vivo and the isolated perfused rat brain. Thiopentone (100 mg/kg i.p.) produced an increase of soluble hexokinase activity in brains of mice which were removed from the skull in 45 s to 120 s. A solubilization of hexokinase activity was demonstrable in the surgical stage of anaesthesia, when the animals awoke redistribution to control values was measurable. A dose dependent influence of thiopentone on hexokinase distribution was demonstrated in the isolated perfused rat brain. When the thiopentone concentration in the perfusion medium was increased (0.05-0.8 mM) the soluble hexokinase activity was elevated while the EEG activity was reduced up to isoelectricity.

Key enzymes of glycolysis in brain as influenced by thiopental.

It has been demonstrated in previous work that hexokinase is solubilized from the mitochondrial membrane in anesthesia. In the present investigation this effect was strongly correlated with the surgical stage of anesthesia by the application of thiopental to rats (80 mg/kg), mice (100 mg/kg) and guinea pigs (32 mg/kg). The solubilization of hexokinase was demonstrable, too, in different areas of rat brains under thiopental treatment (80 mg/kg). In order to elevate the cerebral concentration of glucose 6-phosphate, which is the most potent substrate for the solubilization of bound hexokinase, male Sprague-Dawley rats were pretreated with the antimetabolite 6-aminonicotinamide (6-AN). After i.p. injection of 6-AN (35 mg/kg) we measured an increased activity of soluble brain hexokinase in the same order of magnitude as it was determined in anesthesia. Thiopental application did not show a further significant increase. A solubilization of hexokinase activity by 6-AN was not measurable in vitro. Furthermore, we examined the other key enzymes in the glycolytic pathway. We found a competitive inhibition of phosphofrucktokinase activity by thiopental, but no inhibition of hexokinase and pyruvate-kinase activity.

Influence of thiopental on intracellular distribution of hexokinase activity in various tumor cells.

In earlier work it has been shown that mitochondrially bound brain hexokinase is solubilized by anesthetics. This effect was reevaluated using cultured cells. For the present experiments Ehrlich ascites, Harding-Passey melanoma, C-1300-neuroblastoma and C-6-glioma cells were used. The great portion of hexokinase activity bound to the mitochondria of these cells was similar to that in rat brain. After incubation with thiopental the soluble hexokinase activity was increased in all cells studied. Using neuroblastoma and glioma cells the thiopental effect was demonstrated to be dose-dependent. Thus, cultured tumor cells seem to be useful for studying the relationship of the intracellular distribution of hexokinase activity, energy metabolism and the effect of anesthetics.