München Klinik Bogenhausen

STUDY DESIGN: A histologic study on age-related changes of the human lumbar intervertebral disc was conducted. OBJECTIVES: To investigate comprehensively age-related temporospatial histologic changes in human lumbar intervertebral disc, and to develop a practicable and reliable classification system for age-related histologic disc alteration. SUMMARY OF THE BACKGROUND DATA: No comprehensive microscopic analysis of age-related disc changes is available. There is no conceptual morphologic framework for classifying age-related disc changes as a reference basis for more sophisticated molecular biologic analyses of the causative factors of disc aging or premature aging (degeneration). METHODS: A total of 180 complete sagittal lumbar motion segment slices obtained from 44 deceased individuals (fetal to 88 years of age) were analyzed with regard to 11 histologic variables for the intervertebral disc and endplate, respectively. In addition, 30 surgical specimens (3 regions each) were investigated with regard to five histologic variables. Based on the semiquantitative analyses of 20,250 histologic variable assessments, a classification system was developed and tested in terms of validity, practicability, and reliability. The classification system was applied to cadaveric and surgical disc specimens not included in the development of the classification system, and the scores were assessed by two additional independent raters. RESULTS: A semiquantitative analyses provided clear histologic evidence for the detrimental effect of a diminished blood supply on the endplate, resulting in the tissue breakdown beginning in the nucleus pulposus and starting in the second life decade. Significant temporospatial variations in the presence and abundance of histologic disc alterations were observed across levels, regions, macroscopic degeneration grades, and age groups. A practicable classification system for age-related histologic disc alterations was developed, resulting in moderate to excellent reliability (kappa values, 0.49-0.98) depending on the histologic variable. Application of the classification system to cadaveric and surgical specimens demonstrated a significant correlation with age ( < 0.0001) and macroscopic grade of degeneration ( < 0001). However, substantial data scatter caution against reliance on traditional macroscopic disc grading and favor a histology-based classification system as a reference standard. CONCLUSIONS: Histologic disc alterations can reliably be graded based on the proposed classification system providing a morphologic framework for more sophisticated molecular biologic analyses of factors leading to age-related disc changes. Diminished blood supply to the intervertebral disc in the first half of the second life decade appears to initiate tissue breakdown.

IMPORTANCE: Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE: To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS: Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES: The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS: Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE: Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00334828.

BACKGROUND: The rate of death, including sudden cardiac death, is highest early after a myocardial infarction. Yet current guidelines do not recommend the use of an implantable cardioverter-defibrillator (ICD) within 40 days after a myocardial infarction for the prevention of sudden cardiac death. We tested the hypothesis that patients at increased risk who are treated early with an ICD will live longer than those who receive optimal medical therapy alone. METHODS: This randomized, prospective, open-label, investigator-initiated, multicenter trial registered 62,944 unselected patients with myocardial infarction. Of this total, 898 patients were enrolled 5 to 31 days after the event if they met certain clinical criteria: a reduced left ventricular ejection fraction (< or = 40%) and a heart rate of 90 or more beats per minute on the first available electrocardiogram (ECG) (criterion 1: 602 patients), nonsustained ventricular tachycardia (> or = 150 beats per minute) during Holter monitoring (criterion 2: 208 patients), or both criteria (88 patients). Of the 898 patients, 445 were randomly assigned to treatment with an ICD and 453 to medical therapy alone. RESULTS: During a mean follow-up of 37 months, 233 patients died: 116 patients in the ICD group and 117 patients in the control group. Overall mortality was not reduced in the ICD group (hazard ratio, 1.04; 95% confidence interval [CI], 0.81 to 1.35; P=0.78). There were fewer sudden cardiac deaths in the ICD group than in the control group (27 vs. 60; hazard ratio, 0.55; 95% CI, 0.31 to 1.00; P=0.049), but the number of nonsudden cardiac deaths was higher (68 vs. 39; hazard ratio, 1.92; 95% CI, 1.29 to 2.84; P=0.001). Hazard ratios were similar among the three groups of patients categorized according to the enrollment criteria they met (criterion 1, criterion 2, or both). CONCLUSIONS: Prophylactic ICD therapy did not reduce overall mortality among patients with acute myocardial infarction and clinical features that placed them at increased risk. (ClinicalTrials.gov number, NCT00157768.)

BACKGROUND: New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed by the Food and Drug Administration. METHODS: In this multicenter, noninferiority trial with minimal exclusion criteria, we randomly assigned 2292 patients to undergo treatment with coronary stents releasing either zotarolimus or everolimus. Twenty percent of patients were randomly selected for repeat angiography at 13 months. The primary end point was target-lesion failure, defined as a composite of death from cardiac causes, any myocardial infarction (not clearly attributable to a nontarget vessel), or clinically indicated target-lesion revascularization within 12 months. The secondary angiographic end point was the extent of in-stent stenosis at 13 months. RESULTS: At least one off-label criterion for stent placement was present in 66% of patients. The zotarolimus-eluting stent was noninferior to the everolimus-eluting stent with respect to the primary end point, which occurred in 8.2% and 8.3% of patients, respectively (P<0.001 for noninferiority). There were no significant between-group differences in the rate of death from cardiac causes, any myocardial infarction, or revascularization. The rate of stent thrombosis was 2.3% in the zotarolimus-stent group and 1.5% in the everolimus-stent group (P=0.17). The zotarolimus-eluting stent was also noninferior regarding the degree (+/-SD) of in-stent stenosis (21.65+/-14.42% for zotarolimus vs. 19.76+/-14.64% for everolimus, P=0.04 for noninferiority). In-stent late lumen loss was 0.27+/-0.43 mm in the zotarolimus-stent group versus 0.19+/-0.40 mm in the everolimus-stent group (P=0.08). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS: At 13 months, the new-generation zotarolimus-eluting stent was found to be noninferior to the everolimus-eluting stent in a population of patients who had minimal exclusion criteria. (ClinicalTrials.gov number, NCT00617084.)

AIMS: To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens. METHODS: Internet survey of 1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin-treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA. RESULTS: One third (33.2%) of patients reported insulin omission/non-adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non-adherence and 5.7 days per month of prandial insulin omission/non-adherence. Patients and providers indicated the same five most common reasons for insulin omission/non-adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin-treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives. CONCLUSIONS: Glucose control is inadequate among insulin-treated patients, in part attributable to insulin omission/non-adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia.

BACKGROUND: Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES: The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS: Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS: A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS: FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

BACKGROUND: The standard treatment for patients with symptomatic multivessel coronary artery disease is coronary-artery bypass grafting (CABG). Percutaneous transluminal coronary angioplasty (PTCA) is widely used as an alternative approach to revascularization, but a systematic comparison of the two procedures is needed. We compared the outcomes in patients one year after complete revascularization with CABG or PTCA. METHODS: A total of 8981 patients with multivessel coronary disease were screened at eight clinical sites, and 359 patients were randomly assigned to undergo CABG (177 patients) or PTCA (182 patients). Enrollment required that complete revascularization of at least two major vessels supplying different myocardial regions be deemed clinically necessary and technically feasible. RESULTS: Among the patients in the CABG group, an average of 2.2 +/- 0.6 vessels were grafted, and among those in the PTCA group, 1.9 +/- 0.5 vessels were dilated. After CABG, hospitalization was longer (median, 19, as compared with 5 days for PTCA), and Q-wave myocardial infarction in relation to the procedure was more frequent (8.1 percent, as compared with 2.3 percent after PTCA; P = 0.022), whereas in-hospital mortality did not differ significantly between the two groups (2.5 percent in the CABG group and 1.1 percent in the PTCA group). At discharge 93 percent of the patients in the CABG group were free of angina, as compared with 82 percent of those in the PTCA group (P = 0.005). During the first year of follow-up, further interventions were necessary in 44 percent of the patients in the PTCA group (repeated PTCA in 23 percent, CABG in 18 percent, and both in 3 percent) but in only 6 percent of the patients in the CABG group (repeated CABG in 1 percent and PTCA in 5 percent; P < 0.001). Seventy-four percent of the patients in the CABG group and 71 percent of those in the PTCA group were free of angina one year after treatment. Exercise capacity improved similarly in both groups. However, 22 percent of the CABG group, as compared with only 12 percent of the PTCA group, did not require antianginal medication (P = 0.041). CONCLUSIONS: In selected patients with multivessel coronary disease, PTCA and CABG as initial treatments resulted in equivalent improvement in angina after one year. However, in order to achieve similar clinical outcomes, the patients treated with PTCA were more likely to require further interventions and antianginal drugs, whereas the patients treated with CABG were more likely to sustain an acute myocardial infarction at the time of the procedure.

BACKGROUND: Accelerated graft vessel disease (GVD) represents the most serious long-term complication of heart transplantation. A possible cause underlying this progressive coronary vascular disease is believed to be post-transplantation hypercholesterolemia. METHODS AND RESULTS: In a 4-year prospective randomized study with heart transplant recipients, the efficacy of primary antihypercholesterolemic therapy with simvastatin was compared with that of general dietary therapy. The aim of the treatment was to maintain post-transplantation LDL-cholesterol levels at <120 mg/dL. Seventy-two heart transplant recipients receiving standard triple immunosuppression were randomly assigned to an active-treatment group (low-cholesterol diet and simvastatin, n=35) or a control group (general dietary measures, n=37). In the course of 4 years after transplantation, the simvastatin group had significantly lower LDL-cholesterol concentrations than the control group (mean+/-SD, 115+/-14 versus 156+/-17 mg/dL,P=.002), a significantly better long-term survival (88.6% versus 70.3%,P=.05), and a lower incidence of GVD in the coronary angiographic findings (16.6% versus 42.3%,P=.045). The incidence of graft rejections did not differ between the two groups, although there was a tendency toward a lower number of serious rejections in the simvastatin group (2.8% versus 13.5%, P=.1). Intracoronary ultrasound performed after 4 years in a subgroup of 27 patients (simvastatin, 10; control, 17) showed less intimal thickening in patients with LDL-cholesterol levels of <110 mg/dL (170+/-84 versus 370+/-171 microm, P=.04) and a lower intimal index (13.8+/-7.1% versus 27.9+/-12.1%,P=.04). CONCLUSIONS: In comparison with dietary measures alone, the combination of a low-cholesterol diet and simvastatin after heart transplantation led to a significant reduction in cholesterol levels, a significantly higher long-term survival rate, and a lower incidence of GVD.

OBJECTIVE: The beneficial effect of decompressive craniectomy in the treatment of head trauma patients is controversial. The aim of our study was to assess the value of unilateral decompressive craniectomy in patients with severe traumatic brain injury. METHODS: We retrospectively investigated 49 patients who underwent decompressive craniectomy. Intracranial pressure, cerebral perfusion pressure, therapy intensity level, and cranial computed tomographic scan features (midline shift, visibility of ventricles, gyral pattern, and mesencephalic cisterns) were evaluated before and after craniectomy. The gain of intracranial space was calculated from cranial computed tomographic scans. Patient outcome was graded using the Glasgow Outcome Scale. RESULTS: Thirty-one patients (63.3%) underwent rapid surgical decompression within 4.5 +/- 3.8 hours after trauma; in 18 patients (36.7%), delayed surgical decompression was performed 56.2 +/- 57.0 hours after injury. Patients younger than 50 years or patients who underwent rapid surgical decompression had a significantly better outcome than older patients or patients who underwent delayed surgical decompression. Craniectomy significantly decreased midline shift and improved visibility of the mesencephalic cisterns. The state of the mesencephalic cisterns correlated with the distance of the lower border of the craniectomy to the temporal cranial base. Alterations in intracranial pressure, cerebral perfusion pressure, and therapy intensity level were not significant. The overall mortality of the patients corresponded to the reports of the Traumatic Coma Data Bank (1991). CONCLUSION: Although there was a significant decrease in midline shift after craniectomy, this did not translate into decompressive craniectomy demonstrating a beneficial effect on patient outcome.

Misuse of tools and objects by patients with left brain damage is generally recognized as a manifestation of apraxia, caused by parietal lobe damage. The use of tools and objects can, however, be subdivided in several components. The purpose of our study was to find out which of these are dependent on parietal lobe function. Thirty-eight patients with left brain damage and aphasia were examined using tests to assess the retrieval of functional knowledge from semantic memory (Functional Associations), mechanical problem solving (Novel Tools) and use of everyday tools and objects (Common Tools). Voxel-wise analysis of magnetic resonance images revealed two regions where lesions had a significant impact on the test results. One extended rostrally from the central region and ventrally through the middle frontal cortex to the dorsal margin of the inferior frontal gyrus. The other reached dorsally and caudally from the supramarginal gyrus, through the inferior, to superior parietal lobe. Whereas the frontal lesions had an adverse influence on all experimental tests as well as on the subtests of the Aachen Aphasia test, parietal lesions impaired Novel and Common Tools, but did not have an adverse effect on the Functional Associates. An association between Functional Associations and temporal lesions became apparent when patients with only a selective deficit in the test were considered, but did not show up in the whole group analysis. The parietal influence was as strong for the selection as for the use of either novel or common tools, although choice of appropriate manual configuration and movements was more important for use than for selection. We conclude that the contribution of the parietal lobe to tool use concerns general principles of tool use rather than knowledge about the prototypical use of common tools and objects, and the comprehension of mechanical interactions of the tool with other tools, recipients or material rather than the selection of grip formation and manual movements.

OBJECTIVES: Previous attempts at meta-analysis and systematic review have not provided clear recommendations for the clinical application of thermal ablation in metastatic colorectal cancer. Many authors believe that the probability of gathering randomised controlled trial (RCT) data is low. Our aim is to provide a consensus document making recommendations on the appropriate application of thermal ablation in patients with colorectal liver metastases. METHODS: This consensus paper was discussed by an expert panel at The Interventional Oncology Sans Frontières 2013. A literature review was presented. Tumour characteristics, ablation technique and different clinical applications were considered and the level of consensus was documented. RESULTS: Specific recommendations are made with regard to metastasis size, number, and location and ablation technique. Mean 31 % 5-year survival post-ablation in selected patients has resulted in acceptance of this therapy for those with technically inoperable but limited liver disease and those with limited liver reserve or co-morbidities that render them inoperable. CONCLUSIONS: In the absence of RCT data, it is our aim that this consensus document will facilitate judicious selection of the patients most likely to benefit from thermal ablation and provide a unified interventional oncological perspective for the use of this technology. KEY POINTS: • Best results require due consideration of tumour size, number, volume and location. • Ablation technology, imaging guidance and intra-procedural imaging assessment must be optimised. • Accepted applications include inoperable disease due to tumour distribution or inadequate liver reserve. • Other current indications include concurrent co-morbidity, patient choice and the test-of-time approach. • Future applications may include resectable disease, e.g. for small solitary tumours.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibodies have been recently described in children with acute disseminating encephalomyelitis (ADEM), but the clinical and neuroradiological characterisation of this subgroup is lacking. OBJECTIVE: To compare the clinical and neuroradiological features of paediatric ADEM with and without MOG antibodies. METHODS: Clinical course, cerebrospinal fluid (CSF)-, MRI studies, outcome and MOG status of 33 paediatric ADEM prospectively studied were reviewed. RESULTS: MOG antibodies (median 1:2560; range 1:160-1:20 480) were detected in 19 children with ADEM. The majority of children showed a decline of serum MOG-IgG titres over time. Children with MOG antibodies did not differ in their age at presentation, sex ratio, the presence of oligoclonal bands, clinical symptoms or initial severity, apart from a higher CSF cell count (p=0.038), compared with children without MOG antibodies. In addition, further relapsing demyelinating episodes associated with MOG antibodies were observed only in children with MOG antibodies. All 19 children with MOG antibodies had a uniform MRI pattern, characterised by large, hazy and bilateral lesions and the absence of atypical MRI features (eg, mainly small lesions, well-defined lesions), which was significantly different compared to that of children without MOG antibodies (p=0.003; and p=0.032, respectively). In addition, children with MOG antibodies had involvement of more anatomical areas (p=0.035) including the myelon characterised by a longitudinally extensive transverse myelitis (p=0.003), more often a complete resolution of lesions (p=0.036) and a better outcome (p=0.038). CONCLUSIONS: Patients with ADEM with MOG antibodies in our cohort had a uniform MRI characterised by large, bilateral and widespread lesions with an increased frequency of longitudinal extensive transverse myelitis and a favourable clinical outcome in contrast to children lacking MOG antibodies.

Evidence suggests a correlation between the gut microbiota composition and weight loss caused by caloric restriction. Laparoscopic sleeve gastrectomy (LSG), a surgical intervention for obesity, is classified as predominantly restrictive procedure. In this study we investigated functional weight loss mechanisms with regard to gut microbial changes and energy harvest induced by LSG and a very low calorie diet in ten obese subjects (n = 5 per group) demonstrating identical weight loss during a follow-up period of six months. For gut microbiome analysis next generation sequencing was performed and faeces were analyzed for targeted metabolomics. The energy-reabsorbing potential of the gut microbiota decreased following LSG, indicated by the Bacteroidetes/Firmicutes ratio, but increased during diet. Changes in butyrate-producing bacterial species were responsible for the Firmicutes changes in both groups. No alteration of faecal butyrate was observed, but the microbial capacity for butyrate fermentation decreased following LSG and increased following dietetic intervention. LSG resulted in enhanced faecal excretion of nonesterified fatty acids and bile acids. LSG, but not dietetic restriction, improved the obesity-associated gut microbiota composition towards a lean microbiome phenotype. Moreover, LSG increased malabsorption due to loss in energy-rich faecal substrates and impairment of bile acid circulation. This trial is registered with ClinicalTrials.gov NCT01344525.

OBJECTIVE: PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. RESEARCH DESIGN AND METHODS: PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. RESULTS: More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025). CONCLUSIONS: Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.

Bone and soft tissue samples from 85 ancient Egyptian mummies were analyzed for the presence of ancient Mycobacterium tuberculosis complex DNA (aDNA) and further characterized by spoligotyping. The specimens were obtained from individuals from different tomb complexes in Thebes West, Upper Egypt, which were used for upper social class burials between the Middle Kingdom (since ca. 2050 BC) and the Late Period (until ca. 500 BC). A total of 25 samples provided a specific positive signal for the amplification of a 123-bp fragment of the repetitive element IS6110, indicating the presence of M. tuberculosis DNA. Further PCR-based tests for the identification of subspecies failed due to lack of specific amplification products in the historic tissue samples. Of these 25 positive specimens, 12 could be successfully characterized by spoligotyping. The spoligotyping signatures were compared to those in an international database. They all show either an M. tuberculosis or an M. africanum pattern, but none revealed an M. bovis-specific pattern. The results from a Middle Kingdom tomb (used exclusively between ca. 2050 and 1650 BC) suggest that these samples bear an M. africanum-type specific spoligotyping signature. The samples from later periods provided patterns typical for M. tuberculosis. This study clearly demonstrates that spoligotyping can be applied to historic tissue samples. In addition, our results do not support the theory that M. tuberculosis originated from the M. bovis type but, rather, suggest that human M. tuberculosis may have originated from a precursor complex probably related to M. africanum.

Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined. This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib–gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers. Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59–1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit. Galunisertib–gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.

OBJECTIVE: The BrainLab VectorVision neuronavigation system was used in 131 cases of different brain pathological conditions. The neuronavigation system was used without problems in 125 cases. These cases included 114 microsurgical operations, 4 endoscopic procedures, 4 frameless stereotactic biopsies, and 3 catheter placements. METHODS: The BrainLab VectorVision neuronavigation system is an intraoperative, image-guided, frameless, localization system. The system consists of a computer workstation for registration of images and physical spaces, an intraoperative localization device, and a computer image display. The system provides real-time responses regarding the locations of surgical instruments. VectorVision is based on passive reflections of infrared flashes. Universal adapters with reflective markers for surgical instruments, endoscopes, and the operating microscope are used. RESULTS: In six cases, the system could not be used because of system failure or mishandling. In 125 neurosurgical cases, the neuronavigation system was useful, with a target-localizing accuracy of 4+/-1.4 mm (mean+/-standard deviation). For small cerebral lesions, we never performed an exploration with negative results. CONCLUSION: The BrainLab neuronavigation system has been shown to be very helpful and user-friendly for routine neurosurgical interventions. Its advantage lies in its mobility, based on wireless reflective adapters for surgical instruments, endoscopes, and the operating microscope.

BACKGROUND: The Hartrampf perfusion zones of the lower abdominal flap are generally accepted. They were empirically based on the clinical impression of the perfusion in the first 16 unipedicled transverse rectus abdominis musculocutaneous flaps and have been uncritically adopted for the free transverse rectus abdominis musculocutaneous and the free deep inferior epigastric perforator (DIEP) flap. Scientific data proving the validity of these perfusion zones do not exist. The objective of this study was to evaluate and quantitatively assess the perfusion zones of the DIEP flap. METHODS: In a clinical, prospective study of 15 patients undergoing DIEP flap breast reconstruction, tissue perfusion was intraoperatively assessed using the method of laser-induced fluorescence of indocyanine green. RESULTS: Perfusion of zones I, II, and III was seen 25, 41, and 32 seconds, respectively, after injection, and the perfusion index constituted 76, 25, and 47 percent (median) of normal tissue. Perfusion of zone IV was completely absent in five patients (33 percent); in the remaining patients, it was dramatically decreased (5 percent) and occurred with a delay of 67 seconds. CONCLUSIONS: On the basis of the results of this study, the Hartrampf concept of a centrally perfused skin ellipse with declining perfusion of its peripheral ends is wrong and should be revised. Instead, one should think of the lower abdominal flap as two halves separated by the midline. The ipsilateral half has an axial pattern of perfusion; the contralateral half shows a random-pattern, individually variable blood supply. Therefore, the classic Hartrampf zones should be rearranged, switching zones II and III.

Abstract We developed a specific problem-solving training (PST) and tested it in a small group study. The primary objective of the PST was to provide patients with techniques enabling them to reduce the complexity of a multistage problem by breaking it down to more manageable portions. Thirty-seven “poor” problem solvers were alternately allocated (i.e. in the sequence of their admission) to either a 6-week, 25-session PST (n = 20) or to a memory training (MT; n = 17) of comparable intensity and duration. Treatment effects were evaluated using standard German intelligence tests, the tower-of-Hanoi puzzle, a specifically designed planning test, and a rating of nine aspects of everyday problem-solving behaviour. Data revealed significant prepost effects of the PST in the planning test scores, in all behavioural ratings, and in some intelligence subtests. In comparison, the same tests indicated only minor improvement of the MT.

BACKGROUND: Randomized clinical trials have demonstrated that the use of statins in heart transplant patients lowers cholesterol levels and significantly reduces mortality and the development of transplant vasculopathy. The aim of the present study was to test these effects and the safety of statin therapy over an 8-year period. METHODS AND RESULTS: In 1991, a prospective, randomized, unmasked study was initiated to compare the efficacy of simvastatin, started on the fourth postoperative day (n=35), with that of dietary therapy alone (n=37). Because of significantly improved survival and a lower incidence of transplant vasculopathy, most patients in both groups received statins as open-label prescriptions after 4 years. After 8 years, the Kaplan-Meier survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P<0.006 by log rank; hazard ratio, 0.24; 95% CI, 0.08 to 0.71). Deaths in the simvastatin and control groups were due to transplant vasculopathy (1 versus 4; P<0.2), severe transplant rejection (1 versus 5; P<0.1), malignancies (0 versus 3; P<0.1), and other causes (2 versus 3; P<0.7). The incidence of transplant vasculopathy confirmed by angiography was 24.4% in the simvastatin group versus 54.7% in the control group (P<0.02 by log rank). There was no difference in organ function between the 2 groups. No severe adverse effects of the therapy were observed up to the end of the 8-year observation period. CONCLUSIONS: Simvastatin therapy initiated early after heart transplantation leads to significantly better 8-year survival rates and a significantly lower incidence of transplant vasculopathy without impairment of organ function or severe adverse effects.