Three-year follow-up of the grip concept: an open, prospective, observational registry study on biomechanically calculated abdominal wall repair for complex incisional hernias.

PURPOSE: We studied the effectiveness of biomechanically calculated abdominal wall reconstructions for incisional hernias of varying complexity in an open, prospective observational registry trial. METHODS: From July 1st, 2017 to December 31st, 2020, four hospitals affiliated with the University of Heidelberg recruited 198 patients with complex incisional hernias. Hernias were repaired using biomechanically calculated reconstructions and materials classified on their gripping force towards cyclic load. This approach determines the required strength preoperatively based on the hernia size, using the Critical Resistance to Impacts related to Pressure. The surgeon is supported in reliably determining the Gained Resistance, which is based on the mesh-defect-area-ratio, as well as other mesh and suture factors, and the tissue stability. Tissue stability is defined as a maximum distension of 1.5 cm upon a Valsalva maneuver. In complex cases, a CT scan of the abdomen can be used to assess unstable tissue areas both at rest and during Valsalva's maneuver. RESULTS: Larger and stronger gripping meshes were required for more complex cases to achieve a durable repair, especially for larger hernia sizes. To achieve durable repairs, the number of fixation points increased while the mesh-defect area ratio decreased. Performing these repairs required more operating room time. The complication rate remained low. Less than 1% of recurrences and low pain levels were observed after 3 years. CONCLUSIONS: Biomechanical stability, defined as the resistance to cyclic load, is crucial in preventing postoperative complications, including recurrences and chronic pain.

Elevated levels of soluble total and hyperphosphorylated tau result in early behavioral deficits and distinct changes in brain pathology in a new tau transgenic mouse model.

Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr(181), Ser(199), Thr(231) and Thr(235)), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser(396) and Ser(404) in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.

Biomechanics applied to incisional hernia repair - Considering the critical and the gained resistance towards impacts related to pressure.

BACKGROUND: Incisional hernia repair is burdened with recurrence, pain and disability. The repair is usually carried out with a textile mesh fixed between the layers of the abdominal wall. METHODS: We developed a bench test with low cyclic loading. The test uses dynamic intermittent strain resembling coughs. We applied preoperative computed tomography of the abdomen at rest and during Valsalva's maneuver to the individual patient to analyze tissue elasticity. FINDINGS: The mesh, its placements and overlap, the type and distribution of fixation elements, the elasticity of the tissue of the individual and the closure of the abdominal defect-all aspects influence the reconstruction necessary. Each influence can be attributed to a relative numerical quantity which can be summed up into a characterizing value. The elasticity of the tissues within the abdominal wall of the individual patient can be assessed with low-dose computed tomography of the abdomen with Valsalva's maneuver. We established a procedure to integrate the results into a surgical concept. We demonstrate potential computer algorithms using non-rigid b-spline registration and artificial intelligence to further improve the evaluation process. INTERPRETATION: The bench test yields relative values for the characterization of hernia, mesh and fixation. It can be applied to patient care using established procedures. The clinical application in the first ninety-six patients shows no recurrences and reduced pain levels after one year. The concept has been spread to other surgical groups with the same results in another fifty patients. Future efforts will make the abdominal wall reconstruction more predictable.

Coherent electro-optical detection of terahertz radiation from an optical parametric oscillator.

We report the realization of coherent electro-optical detection of nanosecond terahertz (THz) pulses from an optical parametric oscillator, which is pumped by a Q-switched nanosecond Nd:YVO4 laser at 1064 nm and emits at approximately 1.5 THz. The beam profile and wavefront of the THz beam at focus are electro-optically characterized toward the realization of a real-time THz camera. A peak dynamic range of approximately 37 dB/radical Hz is achieved with single-pixel detection.

Early results from a randomized clinical trial of colon J pouch versus transverse coloplasty pouch after low anterior resection for rectal cancer.

BACKGROUND: Patients with primary rectal cancer undergoing low anterior resection are often reconstructed using a pouch procedure. The aim of this trial was to compare colon J pouch (CJP) with transverse coloplasty pouch (TCP) reconstruction with regard to functional results, perioperative mortality and morbidity. As there is considerable uncertainty over the true anastomotic leak rate in patients with a TCP, the study analysed short-term outcome data. METHODS: Elective patients suitable for either procedure after sphincter-saving low anterior resection were eligible. Randomization took place during surgery. The primary endpoint was the rate of late evacuation problems after 2 years; secondary endpoints were anastomotic leak rate, perioperative morbidity and mortality. RESULTS: Between 21 October 2002 and 5 December 2005, 149 patients were randomized. All 76 patients randomized to TCP had the procedure compared with 68 of the 73 patients (93 percent) randomized to CJP. Both groups were comparable with regard to demographic and clinical characteristics. Surgical complications (CJP: 19 percent; TCP: 18 percent) and the overall anastomotic leak rate (8 percent) were equally distributed in both groups. CONCLUSION: This trial demonstrated a comparable early outcome for TCP and CJP. This contradicts previous reports suggesting a higher leak rate after TCP. REGISTRATION NUMBER: ISRCTN78983587 (http://www.controlled-trials.com).

Understanding memory effects in Li-ion batteries: evidence of a kinetic origin in TiO2 upon hydrogen annealing.

Memory effects in Li-ion battery materials have been explained on the basis of the thermodynamics of many-particles body, however the role of the (de-)intercalation kinetics is not yet clear. We demonstrate that kinetic aspects, specifically Li-ion mobility, are determining the magnitude of the memory effect in TiO2 by studying samples with different levels of oxygen vacancies.

Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01.

PURPOSE: Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected International Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m(2) body-surface area intravenously in the first chemotherapy course, then 450 mg/m(2) x 5 days; 12 cycles, plus leucovorin 100 mg/m(2) (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred eighty (96.9%) of 702 patients enrolled onto this study were eligible. After a median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P =.037) and significantly decreased overall mortality (P =.0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P =.0059) and disease-free survival (P =.03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSION: After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.

A temperature-sensitive brain tumor suppressor mutation of Drosophila melanogaster: developmental studies and molecular localization of the gene.

The recessive-lethal, temperature-sensitive (ts) mutation of the tumor suppressor gene lethal(3)malignant brain tumor (l(3)mbt) causes in a single step the malignant transformation of the adult optic neuroblasts and ganglion mother cells in the larval brain at the restrictive temperature of 29 degrees C. The transformed cells are differentiation-incompetent and grow autonomously in a lethal and invasive fashion in situ in the brain as well as after transplantation in vivo into wild-type adult hosts. The imaginal discs show epithelial overgrowth. At the permissive temperature of 22 degrees C development is completely normal. The ts-period of gene activity responsible for 100% brain tumor suppression and normal imaginal disc development encompasses the first six hours of embryonic development. The l(3)mbt gene function is, however, also required thereafter for the proper differentiation of the brain and the imaginal discs. The l(3)mbt gene is located cytologically in the salivary gland chromosome bands 97E8-F11, and in molecular terms in 29 kb of DNA detected via a P-element insertional deletion.

The Drosophila melanogaster tumor suppressor gene lethal(3)malignant brain tumor encodes a proline-rich protein with a novel zinc finger.

The lethal(3)malignant brain tumor [t(3)mbt] gene causes, when mutated, malignant growth of the adult optic neuroblasts and ganglion mother cells in the larval brain and imaginal disc overgrowth. Via overlapping deficiencies a genomic region of approximately 6.0 kb was identified, containing l(3)mbt+ gene sequences. The l(3)mbt+ gene encodes seven transcripts of 5.8 kb, 5.65 kb, 5.35 kb, 5.25 kb, 5.0 kb, 4.4 kb and 1.8 kb. The putative MBT163 protein, encompassing 1477 amino acids, is proline-rich and contains a novel zinc finger. In situ hybridizations of whole mount embryos and larval tissues revealed l(3)mbt+ RNA ubiquitously present in stage 1 embryos and throughout embryonic development in most tissues. In third instar larvae l(3)mbt+ RNA is detected in the adult optic anlagen and the imaginal discs, the tissues directly affected by l(3)mbt mutations, but also in tissues, showing normal development in the mutant, such as the gut, the goblet cells and the hematopoietic organs.

Large-area electro-optic ZnTe terahertz emitters.

We present a detailed experimental and theoretical study of terahertz (THz) generation and beam propagation in an optoelectronic THz system consisting of a large-area (ZnTe) electro-optic emitter and a standard electro-optic detector, and provide a comparison to typical biased GaAs emitters. As predicted by theory, in the absence of saturation the generated THz pulse energy is inversely proportional to the area of the optical pump beam incident on the emitter, although the detected on-axis electric field amplitude of the subsequently focused THz beam is practically independent of this area. This latter result promotes the use of larger emitter crystals in amplifier-laser-based THz systems in order to minimize saturation effects. Moreover, the generation of an initially larger THz beam also provides improved spatial resolution at intermediate foci between emitter and detector.

Drosophila differentiation genes instrumental in tumor suppression.

Tumor suppressor genes of Drosophila are developmental genes which, in the homozygously mutated state, induce in one step malignant or benign neoplastic transformation of specific cell types. They act early in development and by this set the stage for cell specific differentiation of imaginal discs, adult optic neuroblasts, blood and gonial cells. The structure, expression and possible function of the following four tumor suppressor genes are discussed: tumorous imaginal disc, lethal (3) malignant brain tumor, lethal (3) malignant blood neoplasm-1 and benign (2) gonial cell neoplasm.

Is there a place for "dose-dense" weekly schedules of the taxoids?

The recommended weekly dose and the maximum tolerated weekly dose of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) have yet to be determined. We report that a weekly dose of up to 40 mg/m2 docetaxel for 6 weeks is active in pretreated patients with metastatic breast cancer. From a preliminary study, this dose-dense schedule appears to induce less hematologic toxicity than a schedule of 100 mg/m2 every 3 weeks while achieving similar response rates and may represent a valuable alternative involving a shorter treatment time in the palliative therapy of advanced disease in higher-risk patients. The dose-dense weekly administration of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) also appears to be active, although the toxicity profiles of the two taxanes may differ.

Schedule- and dose-intensified paclitaxel as weekly 1-hour infusion in pretreated solid tumors: results of a phase I/II trial.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been studied primarily on a 3-week schedule as a 3-, 24-, or 96-hour infusion at doses ranging from 135 to 250 mg/m2. The observed toxicity profile seems to be both dose and schedule dependent. Dose densification of paclitaxel given weekly over 6 weeks on a split-dose schedule for an overall increase in dose intensity was thought to improve the therapeutic index of paclitaxel in a variety of advanced malignancies and to be suitable for outpatient administration. For this study, chemotherapy consisted of a weekly 1-hour infusion of paclitaxel at a starting dose of 40 mg/m2/wk for 6 weeks, followed by a 2- to 3-week interval. Paclitaxel dosage was escalated in 10 mg/m2/wk increments in subsequent patients, to a maximum dosage of 90 mg/m2/wk. Intravenous dexamethasone, cimetidine, clemastine, and ondansetron were administered immediately before the paclitaxel infusion. Fifty patients participated in the study. The male to female ratio was 21 to 29, the median age was 53.2 years (age range, 33 to 74), and the median performance status was 1. All patients were chemotherapeutically pretreated. Overall response included five complete responses (10%), 15 partial responses (30%), 19 no change (38%), and 11 disease progressions (22%). Median dose intensity was 410 mg/m2/6 wk (range, 200 to 540 mg/m2/6 wk). Hematologic toxicity was mild, with no grade 3 or 4 toxicity up to 90 mg/m2/wk. No hypersensitivity reactions or neurologic or cardiac toxicities were documented. Dose-densified, weekly paclitaxel is concluded to be active in a variety of pretreated tumor entities. The overall low hematologic and peripheral toxicity profile suggests that further dose intensification of weekly paclitaxel and/or combination with other cytotoxic agents (eg, cisplatin/carboplatin, ifosfamide, etoposide) may be warranted. Paclitaxel can be given safely in the outpatient setting. Paclitaxel 90 mg/m2/wk is recommended for single-agent treatment. Dose-densified paclitaxel may be considered a valuable and promising alternative to standard 3-week treatment, with further options possible in combination chemotherapy.

Genetic and molecular analysis of six tumor suppressor genes in Drosophila melanogaster.

Six Drosophila melanogaster tumor suppressor genes causing malignant or benign tumors in specific cell types are described. The wild-type alleles of these genes are instrumental in the differentiation of particular cell types. In the homozygous state, recessive mutations in the genes interrupt the differentiation of the cells and thus cause their uncontrolled, autonomous, lethal proliferation. The tumors show all major characteristics of malignant and benign neoplastic growth. Genomic sequences of four of the genes have been identified and are currently being characterized.

Terahertz dark-field imaging of biomedical tissue.

We investigate dark-field imaging in the terahertz (THz) fre-quency regime with the intention to enhance image contrast through the analysis of scattering and diffraction signatures. A gold-on-TPX test structure and an archived biomedical tissue sample are examined in conventional and dark-field transmission geometry. In particular, the capability of the technique for tumor detection is addressed.

Glutamate-stimulated secretion of amyloid precursor protein from cortical rat brain slices.

The aim of this study was to determine whether L-glutamate, a major excitatory transmitter in the cerebral cortex, modulates the proteolytic cleavage of the amyloid precursor protein (APP) in the brain through specific receptor activation. Native rat brain cerebral cortical slices were stimulated either with L-glutamate or various glutamate receptor agonists, and the soluble APP derivatives released into the incubation medium were assayed by Western blot analysis. Immunoprecipitation with specific antibodies revealed that in the medium only secretory forms of APP lacking intact C-terminus were present, whereas in the brain slices both C- and N-terminal intact APP products were detectable. L-glutamate induced the release of secretory APP from cortical slices in a concentration-dependent but biphasic manner, with the highest release at 50 microM L-glutamate and smaller effects at higher glutamate concentrations. To determine whether the effect of L-glutamate is mediated through distinct glutamate receptor subtypes, brain slices were incubated in the presence of various specific glutamate receptor agonists. Activation of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor with 50 nM (RS)-bromohomoibotenic acid resulted in a reduced release of secretory APP by 17% +/- 3 (P < 0.01, one tailed Student's t-test) compared to the incubation without any drug. Stimulation of the metabotropic glutamate receptor with 50 nM (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG-I) led to an enhanced release of secretory APP by 39% +/- 3 (P < 0.001), whereas activation of the N-methyl-D-aspartate (NMDA) receptor with 50 nM (1R,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1R,3R)-ACPD) did not significantly change the secretion of APP compared to the incubation without any drug. The data suggest that: (i) cortical glutamatergic neurotransmission is involved in APP metabolism; and (ii) the stimulation of APP cleavage in cerebral cortical brain slices is mainly mediated by the metabotropic but not the NMDA glutamate receptor subtype, whereas the AMPA receptor subtype seems to inhibit the secretory path of APP processing.

Inhibition of the neuronal insulin receptor. An in vivo model for sporadic Alzheimer disease?

It has been hypothesized that a central even in the early pathogenesis of sporadic Alzheimer disease (SAD) is the dysfunction of the neuronal insulin receptor signal transduction. To prove this, this receptor was inhibited by a triplicate icv application of STZ. Insulin binding sites were upregulated as in SAD. With respect to glucose transport proteins, detailed investigations are necessary.

Expression of fructose-1,6-bisphosphatase mRNA isoforms in normal and basal forebrain cholinergic lesioned rat brain.

Fructose-1,6-bisphosphatase is one of the key enzymes in the gluconeogenic pathway predominantly occurring in liver, kidney and muscle. In the brain, fructose-1,6-bisphosphatase has been suggested to be an astrocyte-specific enzyme but the functional importance of glyconeogenesis in the brain is still unclear. To further elucidate the cellular source of fructose-1,6-bisphosphatase in the brain, non-radioactive in situ hybridizations were performed using digoxigenin-labeled RNA probes based on the sequence of recently cloned rat liver and muscle fructose-1,6-bisphosphatase cDNAs. In situ hybridization using a riboprobe for the liver isoform revealed a location of the hybridization signal mainly in neurons, while rat muscle fructose-1,6-bisphosphatase mRNA was detected in both neurons and astrocytes in the hippocampal formation and in layer I of the cerebral cortex.RT-PCR using RNA preparations of rat astrocytes, neurons, and adult whole brain demonstrated a localization of liver fructose-1,6-bisphosphatase mRNA isoform in neurons but not in astrocytes. The muscle fructose-1,6-bisphosphatase mRNA isoform could be detected by RT-PCR in total rat brain, astrocytic, and neuronal mRNA preparations. The isoforms of fructose-1,6-bisphosphatase mRNA seemingly demonstrate a distinct cellular expression pattern in rat brain suggesting a role of glyconeogenesis in both neurons and glial cells.

Glucose metabolism in cholinoceptive cortical rat brain regions after basal forebrain cholinergic lesion.

To address the question whether the changes in cortical glucose metabolism observed in patients with Alzheimer's disease are interrelated with, or consequences of, basal forebrain cholinergic cell loss, an experimental approach was employed to produce cortical cholinergic dysfunction in rat brain by administration of the cholinergic immunotoxin 192IgG-saporin. [14C]D-glucose utilization in brain homogenates, D-glucose-displaceable [3H]cytochalasin B binding to glucose transporters (GLUT). Northern and Western analyses, as well as in vivo [14C]2-deoxyglucose autoradiography were used to quantify the regional glucose metabolism. Basal forebrain cholinergic lesion resulted in transient increases in glucose transporter binding in cortical regions displaying reduced acetylcholinesterase activity, already detectable seven days after lesion with peak values around 30 days post lesion. Western analysis revealed that the changes in total glucose transporter binding are mainly due to changes in the GLUT3 subtype only, while the levels of GLUT1 and GLUT3 mRNA (Northern analysis) were not affected by cholinergic lesion. Both immunocytochemistry and in situ hybridization demonstrated preferential localizations of GLUT1 on brain capillaries and GLUT3 on neurons, respectively. A lesion-induced transient decrease in [14C]D-glucose utilization seven days post lesion was detected in the lesion site, whereas cholinoceptive cortical regions were not affected. In vivo [14C]deoxyglucose uptake was transiently increased in cholinoceptive cortical regions and in the lesion site being highest between three to seven days after lesion. The cholinergic lesion-induced transient up-regulation of cortical glucose transporters and deoxyglucose uptake reflects an increased glucose demand in regions depleted by acetylcholine suggesting functional links between cortical cholinergic activity and glucose metabolism in cholinoceptive target regions.

Angioocclusive chemotherapy in melanoma: rationale and technical considerations.

To date, systemic chemotherapy for melanoma metastases appears to be of only limited benefit since tumoricidal drug concentrations can hardly overcome primary or secondary drug resistance of melanoma cells. Recently, intraarterial infusion techniques with or without regional venous drug hemofiltration have been shown to provide high cytotoxic levels at the target region, thus subsequently using persistent (chemo-embolization) or transient (microspheres, liposomes) blocking techniques may optimize the pharmacological advantage of regional drug delivery. In a pilot series in metastatic liver cancer a significant increase of drug concentration within the target tissue could be achieved while systemic levels were found to be reduced during angio-occlusion. The rationale of angio-occlusive approaches in melanoma offers the possibility of focusing the anti-tumor action directly at the target so that improved response rates can be expected.