Weight loss induced alleviation of sleep-disordered breathing is associated with improvement of non-alcoholic fatty liver disease.

INTRODUCTION: Sleep-disordered breathing (SDB) and non-alcoholic fatty liver disease (NAFLD) are both common comorbidities in obese patients. Structured weight loss programs are effective and can reduce the incidence and severity of obesity-related comorbidities. The objective of the present analysis is to test whether weight loss induced alleviation of SDB is a predictor for improvement of NAFLD. METHODS: Obese participants underwent a standardized non-surgical 3 months weight reduction program (800 kilocalories per day with low carbohydrate and fat content). Abdominal sonography for NAFLD (grade 0 to 3) and monitoring for SDB (defined as apnea-hypopnea index [AHI] ≥ 15/h) were performed at baseline and after 3 months. Alleviation of SDB was defined as a shift from AHI≥ 15/h to <15/h. RESULTS: 48 patients (48% female, age 42 ± 12 years, body-mass index 40.3 ± 8.1 kg/m2, AHI 14 ± 17/h, 85% NAFLD grade ≥1) participated in the weight loss program. In contrast to the no SDB group, in patients with SDB weight loss of 27.1 ±0 .9 kg (8.4 ± 2.8 kg/m2) after three months was paralleled by a reduction in AHI (-22 ± 17/h), prevalence of SDB (from 31% to 13%), and oxidized low-density lipoprotein (-13 ± 11 U/l). In individuals with preexisting SDB NAFLD grade improved more (2 versus 1, p<0.001) and was at a lower degree at 3 months than in those without SDB (0 versus 1, p = 0.015). In multivariable analysis models, SDB at baseline was associated with improvement of NAFLD grade (B 0.908; 95% CI 0.125, 1.691; p = 0.024), independently of age, sex, and BMI (each p>0.05, respectively). Decreasing BMI (B 0.16 [95%-CI 0.08; 0.23], p<0.001) and alleviation of SDB (B 0.90 [95%-CI 0.21; 1.58], p = 0.012) were independently associated with improvement of NAFLD grade. CONCLUSION: Preexisting SDB and weight loss induced alleviation of SDB are predictors for improvement in NAFLD grade, independent of the extent of weight loss. SDB may contribute to the pathogenesis of NAFLD via SDB-induced oxidative stress and inflammation, but the causal mechanism remains unclear.

Multimodal ultrasound imaging with conventional B-mode, elastography, and parametric analysis of contrast-enhanced ultrasound (CEUS): A novel approach to assess small bowel manifestation in severe COVID-19 disease.

The aim was to describe the small bowel morphology with conventional B-mode and elastography and additionally to evaluate dynamic effects of COVID-19 associated small bowel microvascularization using CEUS with color coded perfusion parameters.Thirteen patients with severe COVID-19 acute respiratory distress syndrome (ARDS) were investigated. 13 patients required intensive care treatment with mechanical ventilation. Five patients required extracorporeal membrane oxygenation (ECMO). Contrast-enhanced ultrasound (CEUS) was performed by an experienced investigator as a bolus injection of up to 2.4 ml sulfur hexafluoride microbubbles via a central venous catheter. In the parametric analysis of CEUS, the flare of microbubbles over time is visualized with colors. This is the first work using parametric analysis of CEUS to detect perfusion differences in the small bowel.Parametric analysis of CEUS in the intestinal phase was carried out, using DICOM loops for 20 seconds. In 5 patients, parametric analysis revealed intraindividual differences in contrast agent behavior in the small bowel region. Analogous to the computed tomography (CT) images parametric analysis showed regions of simultaneous hyper- and hypoperfusion of the small intestine in a subgroup of patients. In 5 patients, the parametric image of transmural global contrast enhancement was visualized.Our results using CEUS to investigate small bowel affection in COVID-19 suggest that in severe COVID-19 ARDS systemic inflammation and concomitant micro embolisms may lead to disruption of the epithelial barrier of the small intestine.This is the first study using parametric analysis of CEUS to evaluate the extent of small bowel involvement in severe COVID-19 disease and to detect microemboli. In summary, we show that in COVID-19 the small bowel may also be an important interaction site. This is in line with the fact that enterocytes have been shown to a plenitude of angiotensin converting enzyme (ACE)-2 receptors as entry sites of the virus.

Neoadjuvant concurrent chemoradiotherapy with and without hyperthermia in retroperitoneal sarcomas: feasibility, efficacy, toxicity, and long-term outcome.

PURPOSE: Retroperitoneal (RPS) sarcomas are associated with poor local and abdominal tumor control. However, the benefit of preoperative radio- or chemotherapy alone for these entities is currently unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency toward early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation. METHODS: From 2000-2019, 27 patients with intermediate- or high-grade RPS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45-75 Gy) and two cycles of chemotherapy (doxorubicin 50 mg/m2 BSA/d3 q28 and ifosfamide 1.5 g/m2 BSA/d1­5 q28) in neoadjuvant intent. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) additionally received deep regional hyperthermia. RESULTS: The median follow-up time was 53 months (±56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free survival was 74.6% (±10.1%) and 66.3% (±11.9%), distant metastasis-free survival was 67.2% (±9.7%) and 59.7% (±11.1%), and overall survival was 60.3% (±10.5%) and 60.3% (±10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%), and anemia (11%). There were no treatment-related deaths. CONCLUSION: Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal sarcomas is feasible and provided high local control of intermediate- and high-grade sarcoma.

High resolution flow (HR Flow) and Glazing Flow in cases of hepatic flow changes: Comparison to color-coded Doppler sonography (CCDS).

AIM: To evaluate the possibilities of flow detection using high resolution flow (HR Flow) and Glazing Flow technique in patients with liver parenchymal changes and flow changes in comparison to color-coded Doppler sonography (CCDS). MATERIAL AND METHODS: All examinations were performed using a multi frequency matrix convex probe with high resolution technique (SC6-1U/Resona7, Mindray, Shenzhen, China) by one experienced examiner to evaluate the venous, portal venous and arterial liver flow with digital documentation of the dynamic flow parameters like peak systolic flow, end-diastolic flow and resistance index. For liver parenchymal stiffness changes shear wave elastography was performed with at least 10 measurements. By two independent readers an elevation was performed to evaluate the image quality and the degree of flow artefacts, from 0 = not available to 5 points with excellent image quality without flow artefacts. RESULTS: All 40 patients (24 men, 16 women, age 27-83 years, mean 56±5 years) showed morphology changes from B-Mode of the liver parenchyma to inhomogeneous tissue with higher stiffness evaluated by the shear wave elastography (1.45 m/s up to 2.79 m/s±1.79 m/s, considering F1 up to F4 fibrosis) and in 15 cases histopathologically proven liver cirrhosis. In 9 cases after non-acute thrombosis flow reduction of the portal vein was the reason for the diameter less than 5 mm. Flow parameters for the venous flow were between 8 cm/s up to 29 cm/s, mean 14±4 cm/s, for the hepatic portal vein 5 cm/s up to 57 cm/s, mean 17±5 cm/s, for the hepatic artery systolic flow between 50 cm/s up to 127±33 cm/s, end-diastolic flow from 22 cm/s up to 47±8 cm/s. Resistance index for the hepatic artery was between 0.41 up to 0.73, mean 0.67±0.25. The image quality for CCDS over all cases was evaluated for CCDS between 1 up to 4. The mean quality was 2.5±0.5, for HR Flow in combination with Glazing Flow 3±0.5, with significant differences for the 2 readers (P < 0.01). CONCLUSION: Combination of HR Flow with Glazing Flow could be helpful to evaluate morphological und hemodynamic changes of liver arterial flow, portal venous and venous flow. Reduction of flow artefacts in combination with a higher image quality could be helpful for optimizing the digital measurements also for follow up examinations.

Interstitial lung opacities in patients with severe COVID-19 pneumonia by bedside high-resolution ultrasound in association to CO2 retention.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can cause acute respiratory distress syndrome (ARDS). OBJECTIVE: This single centre cross-section study aimed to grade the severity of pneumonia by bed-side lung ultrasound (LUS). METHODS: A scoring system discriminates 5 levels of lung opacities: A-lines (0 points),≥3 B-line (1 point), coalescent B-lines (2 points), marked pleural disruptions (3 points), consolidations (4 points). LUS (convex 1-5 MHz probe) was performed at 6 defined regions for each hemithorax either in supine or prone position. A lung aeration score (LAS, maximum 4 points) was allocated for each patient by calculating the arithmetic mean of the examined lung areas. Score levels were correlated with ventilation parameters and laboratory markers. RESULTS: LAS of 20 patients with ARDS reached from 2.58 to 3.83 and was highest in the lateral right lobe (Mean 3.67). Ferritin levels (Mean 1885µg/l; r = 0.467; p = 0.051) showed moderate correlation in spearman roh calculation. PaCO2 level (Mean 46.75 mmHg; r = 0.632; p = 0.005) correlated significantly with LAS, while duration of ventilation, Horovitz index, CRP, LDH and IL-6 did not. CONCUSIONS: The proposed LAS describes severity of lung opacities in COVID-19 patients and correlates with CO2 retention in patients with ARDS.

Contrast enhanced ultrasound (CEUS) with parametric imaging and time intensity curve analysis (TIC) for evaluation of the success of prostate arterial embolization (PAE) in cases of prostate hyperplasia.

AIM: To evaluate the use of dynamic contrast enhanced ultrasound (CEUS) with parametric color-coded imaging and time intensity curve analysis (TIC) for planning and follow-up after prostate arterial embolization (PAE). MATERIAL/METHOD: Before and after selective iliacal embolization by PAE with a follow up of 6 months 18 male patients (43-78 years, mean 63±3.5 years) with histopathological proven benign prostate hyperplasia were examined by one experienced examiner. A multifrequency high resolution probe (1-6 MHz) was used for transabdominal ultrasound and CEUS with bolus injections of 2.4 ml sulphur-hexafluoride microbubbles. Independent evaluation of color-coded parametric imaging before and after PAE by in PACS stored DICOM loops from arterial phase (10-15 s) up to 1min were performed. Criteria for successful treatment were reduction of early arterial enhancement by changes of time to peak (TTP) and area under the curve (AUC) by measurements in 8 regions of interest (ROI) of 5 mm in diameter at the margin and in the center and changes from hyperenhancement in parametric imaging (perfusion evaluation of arterial enhancement over 15 s) from red and yellow to blue and green by partial infarctions. Reference imaging method was the contrast high resolution 3 tesla magnetic resonance tomography (MRI) using 3D vibe sequences before and after PAE and for the follow up after 3 and 6 months. RESULTS: PAE was technically and clinically successful in all 18 patients with less clinical symptoms and reduction of the gland volume. In all cases color-coded CEUS parametric imaging was able to evaluate partial infarction after embolization with changes from red and yellow to green and blue colors in the embolization areas. Relevant changes could be evaluated for TIC-analysis of CEUS with reduced arterial enhancement in the arterial phase and prolonged enhancement of up to 1 min with significant changes (p = 0.0024). The area under the curve (AUC) decreased from 676±255.04 rU (160 rU-1049 rU) before PAE to 370.43±255.19 rU (45 rU-858 rU) after PAE. Time to peak (TTP) did not change significantly (p = 0.6877); TTP before PAE was 25.82±9.04 s (12.3 s-42.5 s) and after PAE 24.43±9.10 s (12-39 s). Prostate volume decreased significantly (p = 0.0045) from 86.93±34.98 ml (30-139 ml) before PAE to 50.57±26.26 ml (19-117 ml) after PAE. There were no major complications and, in most cases (14/18) a volume reduction of the benign prostate hyperplasia occurred. CONCLUSION: Performed by an experienced examiner CEUS with parametric imaging and TIC-analysis is highly useful to further establish prostatic artery embolization (PAE) as a successful minimal invasive treatment of benign prostatic hyperplasia.

Penile bulb sparing in prostate cancer radiotherapy : Dose analysis of an in-house MRI system to improve contouring.

OBJECTIVE: This study aimed to assess the reduction in dose to the penile bulb (PB) achieved by MRI-based contouring following drinking and endorectal balloon (ERB) instructions. PATIENTS AND METHODS: A total of 17 prostate cancer patients were treated with intensity-modulated radiation therapy (IMRT) and interstitial brachytherapy (IBT). CT and MRI datasets were acquired back-to-back based on a 65 cm3 air-filled ERB and drinking instructions. After rigid co-registration of the imaging data, the CT-based planning target volume (PTV) used for treatment planning was retrospectively compared to an MRI-based adaptive PTV and the dose to the PB was determined in each case. The adapted PTV encompassed a caudally cropped CT-based PTV which was defined on the basis of the MRI-based prostate contour plus an additional 5 mm safety margin. RESULTS: In the seven-field IMRT treatment plans, the MRI-based adapted PTV achieved mean (Dmean) and maximum (Dmax) doses to the PB which were significantly lower (by 7.6 Gy and 10.9 Gy, respectively; p <0.05) than those of the CT-contoured PTV. For 6 patients, the estimated PB Dmax (seven-field IMRT and IBT) for the adapted PTV was <70 Gy, whereas only 1 patient fulfilled this criterium with the CT-based PTV. CONCLUSION: MRI-based contouring and seven-field IMRT-based treatment planning achieved dose sparing to the PB. Whereas the comparison of MRI and CT contouring only relates to external beam radiotherapy (EBRT) sparing, considering EBRT and IBT shows the improvement in PB sparing for the total treatment.

Acquired temozolomide resistance in human glioblastoma cell line U251 is caused by mismatch repair deficiency and can be overcome by lomustine

Purpose. Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. While the alkylating agent temozolomide (TMZ) has prolonged overall survival, resistance evolution represents an important clinical problem. Therefore, we studied the effectiveness of radiotherapy and CCNU in an in vitro model of acquired TMZ resistance. Methods. We studied the MGMT-methylated GBM cell line U251 and its in vitro derived TMZ-resistant subline, U251/TMZ-R. Cytotoxicity of TMZ, CCNU, and radiation was tested. Both cell lines were analyzed for MGMT promotor status and expression of mismatch repair genes (MMR). The influence of MMR inhibition by cadmium chloride (CdCl2) on the effects of both drugs was evaluated. Results. During the resistance evolution process in vitro, U251/TMZ-R developed MMR deficiency, but MGMT status did not change. U251/TMZ-R cells were more resistant to TMZ than parental U251 cells (cell viability: 92.0% in U251/TMZ-R/69.2% in U251; p = 0.032) yet more sensitive to CCNU (56.4%/80.8%; p = 0.023). The effectiveness of radiotherapy was not reduced in the TMZ-resistant cell line. Combination of CCNU and TMZ showed promising results for both cell lines and overcame resistance. CdCl2-induced MMR deficiency increased cytotoxicity of CCNU. Conclusion. Our results confirm MMR deficiency as a crucial process for resistance evolution to TMZ. MMR-deficient TMZ-resistant GBM cells were particularly sensitive to CCNU and to combined CCNU/TMZ. Effectiveness of radiotherapy was preserved in TMZ-resistant cells. Consequently, CCNU might be preferentially considered as a treatment option for recurrent MGMT-methylated GBM and may even be suitable for prevention of resistance evolution in primary treatment (AU)

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Acquired temozolomide resistance in human glioblastoma cell line U251 is caused by mismatch repair deficiency and can be overcome by lomustine.

PURPOSE: Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. While the alkylating agent temozolomide (TMZ) has prolonged overall survival, resistance evolution represents an important clinical problem. Therefore, we studied the effectiveness of radiotherapy and CCNU in an in vitro model of acquired TMZ resistance. METHODS: We studied the MGMT-methylated GBM cell line U251 and its in vitro derived TMZ-resistant subline, U251/TMZ-R. Cytotoxicity of TMZ, CCNU, and radiation was tested. Both cell lines were analyzed for MGMT promotor status and expression of mismatch repair genes (MMR). The influence of MMR inhibition by cadmium chloride (CdCl2) on the effects of both drugs was evaluated. RESULTS: During the resistance evolution process in vitro, U251/TMZ-R developed MMR deficiency, but MGMT status did not change. U251/TMZ-R cells were more resistant to TMZ than parental U251 cells (cell viability: 92.0% in U251/TMZ-R/69.2% in U251; p = 0.032) yet more sensitive to CCNU (56.4%/80.8%; p = 0.023). The effectiveness of radiotherapy was not reduced in the TMZ-resistant cell line. Combination of CCNU and TMZ showed promising results for both cell lines and overcame resistance. CdCl2-induced MMR deficiency increased cytotoxicity of CCNU. CONCLUSION: Our results confirm MMR deficiency as a crucial process for resistance evolution to TMZ. MMR-deficient TMZ-resistant GBM cells were particularly sensitive to CCNU and to combined CCNU/TMZ. Effectiveness of radiotherapy was preserved in TMZ-resistant cells. Consequently, CCNU might be preferentially considered as a treatment option for recurrent MGMT-methylated GBM and may even be suitable for prevention of resistance evolution in primary treatment.

Clinically significant CMV (re)activation during or after radiotherapy/chemotherapy of the brain : Correlation with neurological deterioration and improvement upon antiviral treatment.

INTRODUCTION: For both patients with high-grade gliomas and multiple cerebral metastases, radio(chemo)therapy is the standard therapy. Neurological decline during treatment is rarely attributed to infections of the brain but to tumor progression or side effects of radiotherapy. CASE REPORTS: We present 4 cases of cytomegalovirus (CMV) viremia associated with neurological deterioration, which occurred during or shortly after radiotherapy and/or chemotherapy of the brain (brain metastases 2, high-grade glioma 1, carcinoma infiltrating brain 1). In all cases, neurological decline was sudden and unexpected, and causes such as increased intracranial pressure or tumor progression could be excluded radiologically. Treatment with dexamethasone and mannitol had no or only very short-term effects. General infections were either excluded or receding before the neurological symptoms occurred. All patients presented with decreasing levels of thrombocytes. In all cases, CMV (re)activation could be proven using blood test for CMV-DNA. The anti-CMV-IgG status suggested reactivation rather than a primary infection. One patient died within 72 h of onset of the symptoms (results of CMV tests were received postmortem). Diagnosis of 3 patients allowed successful administration of antiviral treatment, which greatly improved the general and neurological conditions of the patients within 48 h. DISCUSSION: Neurological deterioration during RT is hardly ever attributed to viral infections. These cases suggest that CMV reactivation and subsequent infection might actually be causative and has to be considered and treated. CONCLUSION: Further prospective studies verifying and investigating this observation in terms of frequency and clinical relevance seem indicated.

Phosotynthesis in hemiepiphytic species of Clusia and Ficus.

Hemiepiphytic species in the genera Clusia and Ficus were investigated to study their mode of photosynthetic metabolism when growing under natural conditions. Despite growing sympatrically in many areas and having the same growth habit, some Clusia species show Crassulacean acid metabolism (CAM) whereas all species of Ficus investigated are C3. This conclusion is based on diurnal CO2 fixation patterns, diurnal stomatal conductances, diurnal titratable acidity fluctuations, and δ13C isotope ratios. Clusia minor, growing in the savannas adjacent to Barinas, Venezuela, shows all aspects of Crassulacean acid metabolism (CAM) on the basis of nocturnal gas exchange, stomatal conductance, total titratable acidity, and carbon isotope composition when measured during the dry season (February 1986). During the wet season (June 1986), the plants shifted to C3-type gas exchange with all CO2 uptake occurring during the daylight hours. The carbon isotope composition of new growth was-28 to-29‰ typical of C3 plants.

Gastric stress ulcers and gastrointestinal hormones - response to hydrochloric acid and sodium chloride infused intraduodenally. Preliminary report.

Gastric stress ulcers were produced by restraint in nonsecretory rats, and the response of the ulcer index to intraduodenal hydrochloric acid (HCl) or sodium chloride (NaCl) was studied in a three-step dose-response trial. Both substances lowered the ulcer index dose-dependently (Km HCl 0.038 +/- Km NaCl 0.089 +/- 0.009 mM/kg/h, respectively) reaching a nadir in rats receiving HCl. The improvement in ulcerations was associated with elevated plasma secretin, glucose, and lowered gastrin in this protocol. In both experimental procedures plasma vasoactive intestinal peptide (VIP) was higher with the low and intermediate doses as compared with the high dose when a slight venous hyperosmolality was present. Glucagon and insulin remained essentially stable. It is concluded that stress ulcers of the restraint type may be prevented by intraduodenal HCl, suggesting that the interplay of gastrointestinal hormones is deranged by stress and partly restored by acid instillation.

Reduction of gastric stress ulcers by intraduodenal infusion of liquids--observations in a rat model.

The number and severity of gastric stress ulcers (= ulcer index) in rats caused by the restraint technique can be reduced by instilling water, hydrochloric acid or Ringer solution intraduodenally during the stress period. This effect is not caused by lower gastric acid, lower blood gastrin and glucagon and most likely not by an improved gastric mucosal microcirculation.

Urate metabolism and gastric ulcerations in rats as influenced by stress and allopurinol.

Stress and allopurinol (ALL) were investigated in rats with regard to their influence on serum uric acid and glucose concentration, gastric secretion, microcirculation (MBF) and stress ulcer index. There is a non-competitive type of interaction between severe stress and ALL-mediated xanthine oxydase inhibition (= per cent fall in serum uric acid) as compared with control conditions (= mild stress). Vmax is different (84.6 +/- 1.9 and 92.3+/-2.26; P less than 0.05), but not Km (0.39 +/- 0.09 and 0.68 +/- 0.08 mg/kg/h ALL). Serum uric acid is higher in rats with draining gastric fistula than those with closed fistula suggesting that already mild stress is associated with an increase in uricemia in this species. ALL does not significantly alter gastric acid and uric acid secretion but improves markedly gastric ulcer index during mild and severe stress. Since MBF is significantly elevated by ALL during the latter circumstances, a dissociation between MBF and acid secretion is one feature of ALL actions and might become a primary aim in treatment of this disorder.

Anti-stress ulcer and anti-secretory effect of somatostatin in rats -- failure to suppress serum gastrin.

In rats the influence of arresting free motions (= controls; mild stress) and of restraint (= severe stress) without and with additional somatostatin (SRIF) on gastric secretion, mucosal microcirculation and stress ulcer formation was studied. Severe stress alone reduces volume, acid and pepsin secretion, acid concentration, aminopyrine clearance and ratio. The ulcer index is elevated. Under both conditions SRIF inhibits in a dose-dependent manner volume and acid secretion, and ulcer incidence is lower. The interaction between severe stress and the antiulcer component of SRIF is characterized as non-competitive. Under these conditions and a continuous infusion of SRIF (10.0 microgram/kg.h over 8 h) acid concentration, acid and pepsin secretion fall subtotally, ulcer index to 50 percent of vehicle (saline) treated rats, if gastric fistula drains juice outside stomach. Microcirculation and serum gastrin are unchanged. In animals with closed fistula ulcer index is reduced by 85 percent, average gastrin again is unchanged. It is concluded that stress ulcers develop at a low secretory and microcirculatory state of gastric mucosa. The prophylactic effect of SRIF results from direct inhibition of parietal and chief cells and additional yet unknown factors.