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.

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.

[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.

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.

[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.

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.

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.

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.

In vivo behavior of murine epidermal cell lines derived from initiated and noninitiated skin.

The in vivo behavior of cell cultures derived from normal and carcinogen-treated mouse epidermis was studied by implanting the cultures in a s.c. vascularized bed protected by a silicone chamber. Cells derived from normal adult mouse epidermis as well as cells derived from tumor-promoter-treated skin were unable to grow in these systems. Conversely, cell lines derived from skin initiated with single doses of N-methyl-N'-nitro-N-nitrosoguanidine or 9,10-dimethyl-1,2-benzanthracene proliferated in these chambers, reforming an epithelial structure. The type of structure in the chambers varied, ranging from formation of almost normal epithelia to atypical invasive behavior. The variable in vivo behavior among the different cell lines may be attributed to the initiation agent, the number of passages of the cultures, random genetic events, the strain of mouse, or a combination of these factors. Most of the cell types used in this study and all the cell lines that were able to grow in these chambers were selected for resistance to Ca-induced terminal differentiation. However, resistance to terminal differentiation according to the Ca2+ switch does not always correlate with the ability to grow in the chambers, since cell lines derived from spontaneous foci of resistance failed to grow in this system. These studies showed some of the possibilities of the SC silicone chambers to study the histogenic potential of cell lines derived from carcinogen-treated epidermis. This system also appears suitable to study the complex relationship between epidermal cells and specialized (dermal) stroma.

Enhanced malignant progression of mouse skin tumors by the free-radical generator benzoyl peroxide.

Chemical carcinogenesis in mouse skin can be divided into the processes of initiation, promotion, and progression. The free-radical generator benzoyl peroxide is moderately active during the promotion stage. Repetitive treatment of mouse benign skin tumors (papillomas) with benzoyl peroxide (20 mg, twice weekly) increased the number of cumulative carcinomas per group by 325% and the number of keratoacanthomas by 44% compared to tumor-bearing Sencar mice treated with the promoter 12-O-tetradecanoylphorbol-13-acetate. The lack of increase in the number of cumulative papillomas per group due to benzoyl peroxide treatment suggests that benzoyl peroxide enhanced the progression of preexisting papillomas. The ability of benzoyl peroxide to enhance the progression of benign tumors to cancer should be considered when determining the human risk from exposure to this widely used chemical agent; in addition, biological assays specifically testing malignant progression may be essential and beneficial for determining an agent's carcinogenic risk.

Nucleotide sequence of rat vascular cell adhesion molecule-1 cDNA.

Vascular cell adhesion molecule 1 (VCAM-1) is an inducible transmembrane protein which is expressed by vascular endothelium following cytokine activation. VCAM-1 mediated the adhesion of certain blood leukocytes and tumor cells via the interaction with its counter-receptor, the integrin VLA4. When initially cloned from interleukin-1 (IL-1) stimulated human umbilical vein endothelial cells, VCAM-1 was reported to contain six immunoglobulin-like domains. However, subsequent cDNA clones and structural analysis of the human gene evealed an alternatively spliced seventh immunoglobulin domain. This seven domain form appears to be the predominant transcript in IL-1 activated endothelium. In this report, the cloning and nucleotide sequence of rat VCAM-1 is described.

Comparative toxicity of non-steroidal anti-inflammatory agents.

Comparative toxicity of non-steroidal anti-inflammatory drugs was assessed using the Stanford Toxicity Index consisting of weighted symptoms, laboratory abnormalities and hospitalizations in 2976 consecutively enrolled rheumatoid arthritis patients from eight data bank centers with 27,936 patient-years of observation. Scores ranged from 1.77 (SE 0.20) for aspirin to 5.94 (SE 0.92) for meclofenamate, with many differences between drugs being 2- to 3-fold and highly statistically significant. Results are consistent with our prior data, persist when assessed by several different scoring algorithms, are consistent across data bank centers and are consistent with data of others. There are major and reproducible differences in the overall toxicity of different non-steroidal anti-inflammatory drugs.

The Health Assessment Questionnaire (HAQ).

Patient-reported outcomes (PROs) provide intrinsic knowledge about a patient's health, functional status, symptoms, treatment preferences, satisfaction, and quality of life. They have become an established approach for assessing health outcomes. The Health Assessment Questionnaire (HAQ), introduced in 1980, is among the first PRO instruments designed to represent a model of patient-oriented outcome assessment. The HAQ is based on five patient-centered dimensions: disability, pain, medication effects, costs of care, and mortality. It has been validated by mail, in the office, by telephone, and by comparison with paraprofessional and physician judgments as a reliable instrument, and has been significantly correlated with other PRO instruments. Typically, one of two HAQ versions is used: the Full HAQ, which assesses all five dimensions, and the Short or 2-page HAQ, which contains only the HAQ disability index (HAQ-DI) and the HAQ's patient global and pain visual analog scales (VAS). The HAQ-DI and the global and pain VAS (i.e., the short HAQ) have essentially retained their original content since their inception, while the Full HAQ undergoes periodic revision to address issues of contemporary scientific interest. The HAQ-DI has been translated or culturally adapted into more than 60 different languages or dialects and has become part of the National Institutes of Health "Road-map" Project, the Patient-Reported Outcomes Measurement Information System (PROMIS).

The Arthritis, Rheumatism and Aging Medical Information System (ARAMIS): still young at 30 years.

Chronic diseases such as atherosclerosis, arthritis, diabetes, and cancer are among major public health concerns. To understand their cumulative risk factors and antecedents, a chronic disease databank consisting of time-oriented, multidisciplinary longitudinal data, prospectively collected on consecutive patients and describing their clinical courses, provides a systematic anthology of patient reported outcome (PRO) data. ARAMIS, which began in the mid-1970s, was the first large-scale chronic disease data bank system. Outcomes data are collected using the Health Assessment Questionnaire (HAQ), a well established PRO instrument that collects patient-centered data in the areas of disability, pain and other symptoms, adverse effects of treatment, economic impact, and mortality. More than 900 peer-reviewed studies have emanated from ARAMIS since its inception. In the earlier days, and even today, ARAMIS had to invent its own tools for the study of these new sciences. ARAMIS has made dominant contributions to the understanding of PROs and to helping improve treatment and health outcomes in rheumatoid arthritis (RA), osteoarthritis (OA), scleroderma, lupus, aging, and drug side effects. It continues to traverse terrain with participation in the NIH "Roadmap" project, the Patient Reported Outcome Measurement Information System (PROMIS). PROMIS is designed to provide improved assessment of health status across all chronic illnesses as part of an improved infrastructure for clinical research. As initiator of the rich history of chronic disease data banks with "rolling" consecutive open patient cohorts, ARAMIS has enabled the study of real-world PROs in rheumatology, with a wealth of resultant improved approaches to treatment, outcome, cost effectiveness, and quality of life.

The promise of PROMIS: using item response theory to improve assessment of patient-reported outcomes.

PROMIS (Patient-Reported-Outcomes Measurement Information System) is an NIH Roadmap network project intended to improve the reliability, validity, and precision of PROs and to provide definitive new instruments that will exceed the capabilities of classic instruments and enable improved outcome measurement for clinical research across all NIH institutes. Item response theory (IRT) measurement models now permit us to transition conventional health status assessment into an era of item banking and computerized adaptive testing (CAT). Item banking uses IRT measurement models and methods to develop item banks from large pools of items from many available questionnaires. IRT allows the reduction and improvement of items and assembles domains of items which are unidimensional and not excessively redundant. CAT provides a model-driven algorithm and software to iteratively select the most informative remaining item in a domain until a desired degree of precision is obtained. Through these approaches the number of patients required for a clinical trial may be reduced while holding statistical power constant. PROMIS tools, expected to improve precision and enable assessment at the individual patient level which should broaden the appeal of PROs, will begin to be available to the general medical community in 2008.

High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener's granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide.

The objective of this study was to evaluate the feasibility and safety of high-dose azathioprine pulse (HAP) therapy in the induction of remission in patients with active Wegener's granulomatosis (WG) or progressive lupus nephritis (LN) refractory to or intolerant of cyclophosphamide. Four patients with antineutrophil cytoplasmic antibody (ANCA)-associated WG and two patients with progressive LN were treated with HAP (1200-1800 mg) applied monthly as continuous intravenous infusions at 50 mg/h. Patients received a total of 50 courses of intravenous azathioprine (AZA) therapy. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS) and the Systemic Lupus Erythematosus Activity Index (SLEDAI). As only partial remission was induced in patients with progressive LN on this regimen, an additional 18 cycles were applied in these patients in which oral AZA at 100 mg/day in weeks 2 and 3 was added between two intravenous courses. A hereditary defect in thiopurine methyltransferase activity was excluded before initiation of treatment. High-dose azathioprine pulse and the intensified HAP treatment were well tolerated. Complete remission was achieved in two patients with WG suffering from three relapses of disease on application of 2-6 courses of HAP. Remission was maintained for 16-24 months. The remaining two patients with WG were withdrawn after 2-3 courses due to unchanged disease activity. In two patients with LN, partial remission was noted on 6-9 courses of HAP; however, the patients relapsed despite therapy with methotrexate and mycophenolate mofetil. The intensified HAP regimen led to partial or complete remission in both LN patients which was confirmed by sequential renal biopsies. Our results suggest that HAP therapy represents a well-tolerated regimen in patients with active WG and LN intolerant of or refractory to cyclophosphamide. As partial or complete remission was observed in four of six patients, further studies seem warranted to assess clinical efficacy in these patients.

Advances in management of rheumatic disease. 1965 to 1985.

Advances in management of the rheumatic diseases over the past 20 years have been substantial. Over this period, survival of patients with systemic lupus erythematosus improved dramatically. Previously fatal renal crisis in scleroderma became treatable. Survival in Wegener's granulomatosis improved from 7% after 2 years to over 90%. Gout became an easily and effectively managed disease. Polymyalgia rheumatica became readily recognized and dramatically treatable. Less quantifiably, the shift toward more aggressive use of an increasing repertoire of "disease-modifying" agents in rheumatoid arthritis gave hope of having altered the natural history of the disease. Replacement of destroyed joints dramatically reduced pain and improved function in appropriately selected individuals. An increasingly broad mission of the National Institutes of Health has provided support for systematic evaluation of clinical management, including the Multi-Purpose Arthritis Centers, the American Rheumatism Association Medical Information System, and the Cooperating Clinics, effectively complementing research in fundamental mechanisms of disease. The role of the concerned clinician and the clinical epidemiologist in identification of new syndromes and new diseases and in innovating approaches to their management has been extremely important; this role appears far from over.

Marginal benefit of renal biopsy in systemic lupus erythematosus.

The predictive information provided by renal biopsy was assessed for four systemic lupus erythematosus (SLE) patient populations and compared with the predictive information from clinical data without benefit of biopsy, both measured against actual outcome. Renal biopsy results, whether studied by light or electron microscopy, contain important prognostic information. However, the prognostic information from renal biopsies in these patient groups is generally less than that of even the simplest clinical classifications; and when combined with clinical information, the total prognostic content is essentially that of the clinical information alone. Thus, judged by presently available data, the renal biopsy in SLE provides mainly redundant prognostic information. The marginal benefit is the difference between what is known before and after a test. Quantitation of predictive accuracy allows assessment of marginal benefit, that is, the increment in accuracy afforded by an additional test. Costly and potentially hazardous procedures, such as renal biopsy, require reassessment in terms of marginal rather than absolute predictive ability.

Progression of functional disability in patients with rheumatoid arthritis. Associations with rheumatology subspecialty care.

BACKGROUND: To determine whether patients with rheumatoid arthritis and their physicians make appropriate decisions regarding referral to rheumatologists and the need for continuing rheumatology care, we examined the relationship between the progression of functional disability in these patients and their use of rheumatology subspecialty care over time. METHODS: A cohort of 282 patients with rheumatoid arthritis was followed prospectively for up to 10 years. Participants were categorized into three subgroups based on the pattern of care received from rheumatologists over the study period: patients who were never treated by a rheumatologist; patients treated by a rheumatologist only intermittently; and patients treated by a rheumatologist at least once during each 6-month study period. The outcome was the rate of progression of functional disability, measured using the Health Assessment Questionnaire Disability Index. RESULTS: Among the 52 patients who had not been referred to a rheumatologist, 30 (58%) had rates of progression of functional disability that were stable or improving over time (rate < 0.01 Disability Index units per year), while 22 (42%) had rates that were worsening (rate > or = 0.01 Disability Index units per year). Among patients treated by rheumatologists, the average rate of progression was substantially lower among the 69 patients who were treated regularly by a rheumatologist than among 161 patients treated by rheumatologists intermittently (0.008 Disability Index units per year vs 0.020 Disability Index units per year). This difference was associated with more intensive use of second-line antirheumatic medications, and more frequent joint surgeries, among patients treated by rheumatologists on a regular basis. CONCLUSIONS: Most patients with rheumatoid arthritis in this community cohort were treated by a rheumatologist, but 42% of those not referred had progressively increasing functional disability. Among patients treated by rheumatologists, those who had continuing care from rheumatologists experienced lower rates of progression of functional disability than those who had only intermittent care. These results suggest that use of rheumatology subspecialty care is associated with better health outcomes in rheumatoid arthritis.