Lagrangian Supersaturation Fluctuations at the Cloud Edge.

Evaporation of cloud droplets accelerates when turbulence mixes dry air into the cloud, affecting droplet-size distributions in atmospheric clouds, combustion sprays, and jets of exhaled droplets. The challenge is to model local correlations between droplet numbers, sizes, and supersaturation, which determine supersaturation fluctuations along droplet paths (Lagrangian fluctuations). We derived a statistical model that accounts for these correlations. Its predictions are in quantitative agreement with results of direct numerical simulations, and explain the key mechanisms at play.

[Surgical treatment of intracaval tumor relapse after radical tumor nephrectomy in locally advanced renal cell carcinoma]. / Chirurgische Therapie des intrakavalen Tumorrezidivs nach radikaler Tumornephrektomie lokal fortgeschrittener Nierenzellkarzinome.

BACKGROUND: About 4-10% of patients with renal cell carcinoma (RCC) demonstrate intracaval tumor thrombi at the time of diagnosis. Furthermore, 2-3% of patients might develop local relapses of which intracaval recurrences represent a rare event with fewer than 15 cases reported in the literature. We report the diagnosis, surgical technique, perioperative complications, and oncological outcome in an additional 6 cases. PATIENTS AND METHODS: Between 2008 and 2019, 6 patients were treated with isolated intracaval relapse of RCC. All patients had undergone radical nephrectomy with thrombectomy in the past. The mean time between first surgery and relapse was 45.2 (6-114) months and the mean age of patients was 75 (70-80) years: 2, 3 and 1 patient demonstrated thrombus level II, III, and IV, respectively. A thoracoabdominal and a transperitoneal surgical approach was chosen in 4 and 2 patients, respectively. Perioperative complications were reported according to the Clavien-Dindo classification. Relapse-free, cancer-specific and overall survival were calculated with the Kaplan-Meier method. RESULTS: The cava thrombus could be resected completely in all cases. The mean time of surgery was 330 (260-510) min and the mean blood loss was 1500 (300-6500) ml. Clavien-Dindo grade II and IV complications developed in 2 and 1 patients, respectively. The 90-day readmission rate and mortality were 0%. After a mean follow-up of 32.3 (6-96) months, 5 patients are relapse-free and 1 patient developed pulmonary and hepatic metastases managed by immuno-oncological therapy. One patient died 27 months postoperatively due to multiple myeloma. CONCLUSION: Secondary thrombectomy for isolated intracaval tumor thrombus relapse represents a challenging surgery which is associated with a high oncological control rate and tolerable surgery-related morbidity. This type of surgery should be performed in centres with significant expertise in radical nephrectomy for locally advanced disease and thrombus surgery.

[Consequences of autopsies for the living : Causes of death in the clinical diagnosis "septic and toxic shock"]. / Konsequenzen von Autopsiebefunden für die Lebenden : Todesursachenfeststellungen bei der klinischen Diagnose "septisch-toxischer Schock".

BACKGROUND: There is reason to believe that the diagnosis of septic and toxic shock, as indicated on the death certificate, cannot be confirmed as the cause of death without autopsy and subsequent histological analysis. The external examination of the corpse can therefore not represent the sole basis for a reliable statement about the infection status of a corpse, e. g. as a prerequisite for embalming. MATERIAL AND METHODS: The validity of autopsy in determining septic and toxic shock as the cause of death is demonstrated in 7 exemplary cases. RESULTS: Decades of experience in a university pathology institute have shown that an external examination of the corpse alone is not suitable for certifying the cause of death if an infectious disease is suspected. Consequently, only autopsy with subsequent histological analysis provides reliable statements on the etiopathogenesis of the underlying process. Possible problems and discrepancies between clinical and pathological diagnoses are discussed on the basis of several cases with or without autoptic confirmation of the septic shock. The case of a missionary from Africa infected with Lassa virus serves to point out the seriousness of the threat an undiagnosed infection may represent to the attending staff. CONCLUSION: During the treatment of patients suspected to have an infectious cause of fever of unknown origin, compliance with the usual safety regulations, including adequate disinfecting measures, is essential. In cases with fatal outcome, not infrequently under the clinical picture of a septic and toxic shock, autopsy should be regularly performed to confirm the type of infection and the infectious cause of death. Rapid and open communication between the professional groups involved plays a crucial role in this process.

Neutral processes forming large clones during colonization of new areas.

In species reproducing both sexually and asexually clones are often more common in recently established populations. Earlier studies have suggested that this pattern arises due to natural selection favouring generally or locally successful genotypes in new environments. Alternatively, as we show here, this pattern may result from neutral processes during species' range expansions. We model a dioecious species expanding into a new area in which all individuals are capable of both sexual and asexual reproduction, and all individuals have equal survival rates and dispersal distances. Even under conditions that favour sexual recruitment in the long run, colonization starts with an asexual wave. After colonization is completed, a sexual wave erodes clonal dominance. If individuals reproduce more than one season, and with only local dispersal, a few large clones typically dominate for thousands of reproductive seasons. Adding occasional long-distance dispersal, more dominant clones emerge, but they persist for a shorter period of time. The general mechanism involved is simple: edge effects at the expansion front favour asexual (uniparental) recruitment where potential mates are rare. Specifically, our model shows that neutral processes (with respect to genotype fitness) during the population expansion, such as random dispersal and demographic stochasticity, produce genotype patterns that differ from the patterns arising in a selection model. The comparison with empirical data from a post-glacially established seaweed species (Fucus radicans) shows that in this case, a neutral mechanism is strongly supported.

ETS-dependent p16INK4a and p21waf1/cip1 gene expression upon endothelin-1 stimulation in malignant versus and non-malignant proximal tubule cells.

AIM: Cellular senescence, leading to cell death through prevention of regular cell renewal, is associated with the upregulation of the tumor suppressor gene p16(INK4a). While this mechanism has been described as leading to progressive nephron loss, p16(INK4a) upregulation in renal cell carcinoma has been linked to a disease-specific improved patient survival rate. While in both conditions endothelin-1 is also upregulated, the signaling pathway connecting ET-1 to p16(INK4a) has not been characterized until this study. MAIN METHODS: Cell culture, qRT-PCR, Western Blot, immunoprecipitation (IP), proximity ligation assay (PLA), and non-radioactive electrophoretic mobility shift assay (EMSA). KEY FINDINGS: In malignant renal proximal tumor cells (Caki-1), an activation of p16(INK4a) and p21(waf1/cip1) was observed. An increased expression of E-26 transformation-specific (ETS) transcription factors was detectable. Using specific antibodies, a complex formation between ETS1 and extracellular signal-regulated kinase-2 (ERK2) was shown. A further complex partner was Mxi2. EMSA with supershift analysis for ETS1 and Mxi2 indicated the involvement of both factors in the protein-DNA interaction. After specifically blocking the endothelin receptors, ETS1 expression was significantly downregulated. However, the endothelin B receptor dependent downregulation was stronger than that of the A receptor. In contrast, primary proximal tubule cells showed a nuclear decrease after ET-1 stimulation. This indicates that other ETS members may be involved in the observed p16(INK4a) upregulation (as described in the literature). SIGNIFICANCE: ETS1, ERK2 and Mxi2 are important complex partners initiating increased p16(INK4a) and p21w(af1/cip1) activation in renal tumor cells.

Disability outcomes and dose escalation with etanercept, adalimumab, and infliximab in rheumatoid arthritis patients: a US-based retrospective comparative effectiveness study.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic disease that if left untreated may substantially impair physical functioning. Etanercept, infliximab, and adalimumab are tumor necrosis factor (TNF) blockers whose FDA-approved indications in the US include moderate to severe RA. TNF-blocker dose escalation has been well documented in the literature; however, the comparative effectiveness of these agents remains uncertain. OBJECTIVE: To compare the effectiveness and dose escalation rates of etanercept, adalimumab, and infliximab in US community settings. We hypothesized that etanercept would be equivalent to infliximab and adalimumab in patient-reported disability 9-15 months after therapy initiation, and that fewer etanercept patients would experience dose escalation. METHODS: This is a retrospective analysis of the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS). Adult patients with no biologic use 6 months before TNF-blocker initiation (index) and with Health Assessment Questionnaire Disability Index (HAQ-DI) scores at index and 9-15 months after index were analyzed (218 etanercept, 93 infliximab, and 40 adalimumab). RESULTS: HAQ-DI change scores at 9-15 months did not differ by treatment (-0.12, -0.10, and -0.08 points for etanercept, infliximab, and adalimumab, respectively; p = 0.52). Dose increases were observed in 1.4% of etanercept, 10.8% of infliximab (p < 0.001), and 12.5% of adalimumab patients (p = 0.004). HAQ-DI change was associated with pre-index HAQ-DI score (p < 0.0001) and disease duration (p = 0.001). CONCLUSIONS: Fewer etanercept patients escalated dose than infliximab or adalimumab patients, but improvements in functional disability were similar. These differences may have been influenced by package labeling, mode of administration, or other factors. RA treatment with infliximab and adalimumab in community settings, characterized by dose escalation, did not yield greater disability improvements compared to etanercept, which remained at a relatively stable dose. Uncontrolled treatment selection in this observational design may have influenced outcomes, and prior methotrexate treatment may partly explain disability improvements smaller than typically observed in clinical trials.

Recovery of whisking function after manual stimulation of denervated vibrissal muscles requires brain-derived neurotrophic factor and its receptor tyrosine kinase B.

Functional recovery following facial nerve injury is poor. Neuromuscular junctions (NMJs) are "bridged" by terminal Schwann cells and numerous regenerating axonal sprouts. We have shown that this poly-innervation of NMJs can be reduced by manual stimulation (MS) with restoration of whisking function. In addition, we have recently reported that insulin-like growth factor-1 (IGF-1) is required to mediate the beneficial effects of MS. Here we extend our findings to brain derived neurotrophic factor (BDNF). We then examined the effect of MS after facial-facial anastomosis (FFA) in heterozygous mice deficient in BDNF (BDNF(+/-)) or in its receptor TrkB (TrkB(+/-)). We quantified vibrissal motor performance and the percentage of NMJ bridged by S100-positive terminal Schwann cells. In intact BDNF(+/-) or TrkB(+/-) mice and their wild type (WT) littermates, there were no differences in vibrissal whisking nor in the percentage of bridged NMJ (0% in each genotype). After FFA and handling alone (i.e. no MS) in WT animals, vibrissal whisking amplitude was reduced (60% lower than intact) and the percentage of bridged NMJ increased (27% more than intact). MS improved both the amplitude of vibrissal whisking (not significantly different from intact) and the percentage of bridged NMJ (11% more than intact). After FFA and handling in BDNF(+/-) or TrkB(+/-) mice, whisking amplitude was again reduced (53% and 60% lower than intact) and proportion of bridged NMJ increased (24% and 29% more than intact). However, MS failed to improve outcome in both heterozygous strains (whisking amplitude 55% and 58% lower than intact; proportion of bridged NMJ 27% and 18% more than intact). We conclude that BDNF and TRkB are required to mediate the effects of MS on target muscle reinnervation and recovery of whisking function.

Recovery of whisking function promoted by manual stimulation of the vibrissal muscles after facial nerve injury requires insulin-like growth factor 1 (IGF-1).

Recently, we showed that manual stimulation (MS) of denervated vibrissal muscles enhanced functional recovery following facial nerve cut and suture (FFA) by reducing poly-innervation at the neuro-muscular junctions (NMJ). Although the cellular correlates of poly-innervation are established, with terminal Schwann cells (TSC) processes attracting axon sprouts to "bridge" adjacent NMJ, molecular correlates are poorly understood. Since quantitative RT-PCR revealed a rapid increase of IGF-1 mRNA in denervated muscles, we examined the effect of daily MS for 2 months after FFA in IGF-1(+/-) heterozygous mice; controls were wild-type (WT) littermates including intact animals. We quantified vibrissal motor performance and the percentage of NMJ bridged by S100-positive TSC. There were no differences between intact WT and IGF-1(+/-) mice for vibrissal whisking amplitude (48 degrees and 49 degrees ) or the percentage of bridged NMJ (0%). After FFA and handling alone (i.e. no MS) in WT animals, vibrissal whisking amplitude was reduced (60% lower than intact) and the percentage of bridged NMJ increased (42% more than intact). MS improved both the amplitude of vibrissal whisking (not significantly different from intact) and the percentage of bridged NMJ (12% more than intact). After FFA and handling in IGF-1(+/-) mice, the pattern was similar (whisking amplitude 57% lower than intact; proportion of bridged NMJ 42% more than intact). However, MS did not improve outcome (whisking amplitude 47% lower than intact; proportion of bridged NMJ 40% more than intact). We conclude that IGF-I is required to mediate the effects of MS on target muscle reinnervation and recovery of whisking function.

Immunohistochemical study of remodeling of myocardial lymphatic and blood microvascular structures in terminal heart failure: differences between ischemic and dilated cardiomyopathy.

This study investigated (cardiac) remodeling of the myocardial microvasculature in patients with terminal heart failure due to ischemic (ICM) and dilative (DCM) cardiomyopathy. Seventeen transmural left-ventricular (LV) biopsies (9 ICM and 8 DCM), taken from heart transplant recipients at transplantation (n=4) or during ventricular assist device implantation (n=13) were investigated by immunohistostaining for VEGFR-1 and VEGFR-2 as capillary markers and VEGFR-3, D2-40, PROX-1 and LYVE-1 as lymphatic markers. Results were compared to LV biopsies from 7 donor hearts (control). Compared to control, DCM hearts showed a significantly higher density of LYVE-1 positive lymphatics (p < 0.05), whereas no difference was seen for other markers. ICM hearts showed a significantly higher density of D2-40 positive lymphatics (p < 0.01) and a lower density of VEGFR-2 capillaries compared to control (p < 0.05). In comparison to normal donor hearts, ICM and DCM hearts showed a significantly different pattern of microvascular receptor expression. As distinct patterns were seen in ICM and DCM, the effect of microvascular remodeling may be substantially different between two clinically important causes of cardiomyopathy. Further research should be aimed at defining the impact of extracellular matrix composition and VEGF-related angiogenesis on the myocardial microvasculature at various stages of heart failure.

Hepatic steatosis in organ donors: disparity between surgery and histology?

BACKGROUND: In times of organ shortage, use of marginal cadaveric livers has become increasingly important to reduce pressing organ demand and rising death rates while awaiting donations. Indisputably, fatty change in donor livers is a risk factor for poor initial function after orthotopic transplantation. However, identifying and rejecting marginal from good donor livers is one of the most difficult surgical tasks. Unfortunately, a liver biopsy with rapid histological diagnosis is rarely performed to identify marginal livers. METHODS: From 2005 to 2008, we investigated 36 livers of organ donors, which were explanted but not transplanted or underwent liver wedge biopsy during organ donation. All livers underwent standard surgical procedures and were allocated by Eurotransplant International Foundation. After unsuccessful allocation, explanted livers were photographically documented, formalin-fixed, and analyzed histopathologically. RESULTS: Seven livers were classified as good organ quality by the surgeon (19.4%); 15 were acceptable (41.6%); and 14 poor (39%). In 63.8% of livers, a frozen section was performed; 6/36 cases (16.7%) showed macrovesicular and microvesicular steatosis of less than 30%. In addition, all six cases fulfilled two or less extended donor criteria, as defined by the German Medical Association. CONCLUSION: More marginal livers from cadaveric organ donors could have been transplanted. To extend the transplant pool of liver grafts, liver biopsies should be performed in all cases of acceptable and poor livers. If frozen section analysis is performed, a wedge liver biopsy should be taken from at least two different segments of the liver to validate the histological results.

Intraoral molluscum contagiosum imitating a squamous-cell carcinoma in an immunocompetent person--case report and review of the literature.

A case of intraoral molluscum contagiosum involving the right distal alveolar bridge of an immunocompetent person is reported. A review of the literature, with only five previously published cases, revealed that involvement of the oral soft tissues is rare.

Dynamics and predictive modelling of Vibrio spp. in the Neuse River Estuary, North Carolina, USA.

Vibrio spp. are naturally occurring bacteria in marine and estuarine environments around the world. The genus includes several human and animal pathogens that can negatively impact human health, seafood and aquaculture. Vibrio spp. populations are capable of rapid adaptation in response to changing environmental conditions, making them dynamic over short-term and seasonal scales. Temperature, vertical mixing, tidal flushing, climate, precipitation and nutrient loading can change the estuarine environment and subsequently alter microbial community structure, including Vibrio spp., affecting estuarine water quality and public health. To describe these dynamics, Vibrio spp. concentrations and a range of microbial, physical and chemical measures were monitored every 2 weeks and after storm events for 19 months in the Neuse River Estuary (NRE). Results showed clear seasonal and geographic trends in Vibrio spp. abundance. Multiple regression analysis revealed a strong relationship to temperature and salinity, with additional minor influences of chlorophyll a and dissolved organic carbon. Similar models based on easily measured environmental parameters should be pursued for individual Vibrio species in the NRE and other estuarine environments. Predictive models provide useful information for managers, researchers and modellers of estuarine ecosystems.

Sediment-water exchange of Vibrio sp. and fecal indicator bacteria: implications for persistence and transport in the Neuse River Estuary, North Carolina, USA.

In estuaries, frequent resuspension and deposition of sediment complicate bacterial transport model development by transporting particle-attached bacteria and possibly inducing bacterial responses, such as growth, degradation, or changes in attachment. In order to better characterize these dynamics, observations were made in the Neuse River Estuary (NRE) using the combination of an in situ sampler to monitor the water column and sediment cores to monitor sediment concentrations. Two allochthonous bacteria, Escherichia coli (EC) and Enterococcus sp. (ENT), were selected as proxies for fecal contamination from stormwater runoff. Vibrio sp. (VIB), native to the NRE, was also observed as an autochthonous bacterial group that includes potentially pathogenic species. Two sampling periods were identified as dominated by different suspension types: runoff and resuspension. Despite this difference, several bacterial measures remained comparable between sampling periods. In bottom water, VIB concentration was correlated with salinity and ENT concentration was correlated with turbidity. Differences were observed for EC, where higher concentrations were found in hypoxic waters and sediment during the resuspension period. In the sediment, EC and VIB concentrations significantly increased following the passage of Hurricane Ophelia in September 2005. Throughout this study, all bacterial groups showed evidence of persistence in sediment, suggesting that sediment resuspension represents a significant source of bacteria to the water column.

Evaluation of a preliminary physical function item bank supported the expected advantages of the Patient-Reported Outcomes Measurement Information System (PROMIS).

OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS) was initiated to improve precision, reduce respondent burden, and enhance the comparability of health outcomes measures. We used item response theory (IRT) to construct and evaluate a preliminary item bank for physical function assuming four subdomains. STUDY DESIGN AND SETTING: Data from seven samples (N=17,726) using 136 items from nine questionnaires were evaluated. A generalized partial credit model was used to estimate item parameters, which were normed to a mean of 50 (SD=10) in the US population. Item bank properties were evaluated through Computerized Adaptive Test (CAT) simulations. RESULTS: IRT requirements were fulfilled by 70 items covering activities of daily living, lower extremity, and central body functions. The original item context partly affected parameter stability. Items on upper body function, and need for aid or devices did not fit the IRT model. In simulations, a 10-item CAT eliminated floor and decreased ceiling effects, achieving a small standard error (< 2.2) across scores from 20 to 50 (reliability >0.95 for a representative US sample). This precision was not achieved over a similar range by any comparable fixed length item sets. CONCLUSION: The methods of the PROMIS project are likely to substantially improve measures of physical function and to increase the efficiency of their administration using CAT.

More relevant, precise, and efficient items for assessment of physical function and disability: moving beyond the classic instruments.

OBJECTIVES: Patient reported outcomes (PROs) have become standard study endpoints. However, little attention has been given to using item improvement to advance PRO performance which could improve precision, clarity, patient relevance, and information content of "physical function/disability" items and thus the performance of resulting instruments. METHODS: The present study included 1860 physical function/disability items from 165 instruments. Item formulations were assessed by frequency of use, modified Delphi consensus, respondent judgement of clarity and importance, and item response theory (IRT). Data from 1100 rheumatoid arthritis, osteoarthritis, and normal ageing subjects, using qualitative item review, focus groups, cognitive interviews, and patient survey were used to achieve a unique item pool that was clear, reliable, sensitive to change, readily translatable, devoid of floor and ceiling limitations, contained unidimensional subdomains, and had maximal information content. RESULTS: A "present tense" time frame was used most frequently, better understood, more readily translated, and more directly estimated the latent trait of disability. Items in the "past tense" had 80-90% false negatives (p<0.001). The best items were brief, clear, and contained a single construct. Responses with four to five options were preferred by both experts and respondents. The term physical function may be preferable to the term disability because of fewer floor effects. IRT analyses of "disability" suggest four independent subdomains (mobility, dexterity, axial, and compound) with factor loadings of 0.81-0.99. CONCLUSIONS: Major improvement in performance of items and instruments is possible, and may have the effect of substantially reducing sample size requirements for clinical trials.