Electronic structure of strain-tunable Janus WSSe-ZnO heterostructures from first-principles.

The electronic structure of semiconducting 2D materials such as monolayer transition metal dichalcogenides (TMDs) are known to be tunable via environment and external fields, and van der Waals (vdW) heterostructures consisting of stacks of distinct types of 2D materials offer the possibility to further tune and optimize the electronic properties of 2D materials. In this work, we use density functional theory (DFT) calculations to calculate the structure and electronic properties of a vdW heterostructure of Janus monolayer WSSe with monolayer ZnO, both of which possess out of plane dipole moments. The effects of alignment, biaxial and uniaxial strain, orientation, and electric field on dipole moments and band edge energies of this heterostructure are calculated and examined. We find that the out of plane dipole moment of the ZnO monolayer is highly sensitive to strain, leading to the broad tunability of the heterostructure band edge energies over a range of experimentally-relevant strains. The use of strain-tunable 2D materials to control band offsets and alignment is a general strategy applicable to other vdW heterostructures, one that may be advantageous in the context of clean energy applications, including photocatalytic applications, and beyond.

Interplay between fibrinolysis and complement: plasmin cleavage of iC3b modulates immune responses.

BACKGROUND: The plasmin(ogen) and complement systems are simultaneously activated at sites of tissue injury, participating in hemostasis, wound healing, inflammation and immune surveillance. In particular, the C3 proteolytic fragment, iC3b, and its degradation product C3dg, which is generated by cleavage by factor I (FI) and the cofactor complement receptor CR1, are important in bridging innate and adaptive immunity. Via a thioester (TE) bond, iC3b and C3dg covalently tag pathogens, modulating phagocytosis and adaptive immune responses. OBJECTIVE: To examine plasmin-mediated proteolysis of iC3b, and to evaluate the functional consequences, comparing the effects with products generated by FI/CR1 cleavage of iC3b. METHODS: Dose-dependent and time-dependent plasmin-mediated cleavage of iC3b were characterized by analytical gel electrophoresis. The properties of the resultant TE bond-containing fragments on phagocytosis and induction of pro-inflammatory cytokines were measured in cell culture systems. RESULTS: At low concentrations, plasmin effectively cleaves iC3b, but at numerous previously undescribed sites, giving rise to novel C3c-like and C3dg-like moieties, the latter of which retain the TE bond. When attached to zymosan or erythrocytes and exposed to THP-1 macrophages, the C3dg-like proteins behave almost identically to the bona fide C3dg, yielding less phagocytosis as compared with the opsonin iC3b, and more macrophage secretion of the pro-inflammatory cytokine, IL-12. CONCLUSION: Plasmin cleavage of iC3b provides a complement regulatory pathway that is as efficient as FI/CR1 but does not require a cellular cofactor.

Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo.

Increased expression of HBEGF in estrogen receptor-negative breast tumors is correlated with enhanced metastasis to distant organ sites and more rapid disease recurrence upon removal of the primary tumor. Our previous work has demonstrated a paracrine loop between breast cancer cells and macrophages in which the tumor cells are capable of stimulating macrophages through the secretion of colony-stimulating factor-1 while the tumor-associated macrophages (TAMs), in turn, aid in tumor cell invasion by secreting epidermal growth factor. To determine how the autocrine expression of epidermal growth factor receptor (EGFR) ligands by carcinoma cells would affect this paracrine loop mechanism, and in particular whether tumor cell invasion depends on spatial ligand gradients generated by TAMs, we generated cell lines with increased HBEGF expression. We found that autocrine HBEGF expression enhanced in vivo intravasation and metastasis and resulted in a novel phenomenon in which macrophages were no longer required for in vivo invasion of breast cancer cells. In vitro studies revealed that expression of HBEGF enhanced invadopodium formation, thus providing a mechanism for cell autonomous invasion. The increased invadopodium formation was directly dependent on EGFR signaling, as demonstrated by a rapid decrease in invadopodia upon inhibition of autocrine HBEGF/EGFR signaling as well as inhibition of signaling downstream of EGFR activation. HBEGF expression also resulted in enhanced invadopodium function via upregulation of matrix metalloprotease 2 (MMP2) and MMP9 expression levels. We conclude that high levels of HBEGF expression can short-circuit the tumor cell/macrophage paracrine invasion loop, resulting in enhanced tumor invasion that is independent of macrophage signaling.

Conquering the complex world of human septins: implications for health and disease.

Septins are highly conserved filamentous proteins first characterized in budding yeast and subsequently identified in must eukaryotes. Septins can bind and hydrolyze GTP, which is intrinsically related to their formation of septin hexamers and functional protein interactions. The human septin family is composed of 14 loci, SEPT1-SEPT14, which encode dozens of different septin proteins. Their central GTPase and polybasic domain regions are highly conserved but they diverge in their N-terminus and/or C-terminus. The mechanism by which the different isoforms are generated is not yet well understood, but one can hypothesize that the use of different promoters and/or alternative splicing could give rise to these variants. Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell division, chromosome segregation, protein scaffolding, cellular polarity, motility, membrane dynamics, vesicle trafficking, exocytosis, apoptosis, and DNA damage response. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Alterations of these proteins, by mutation or expression changes, have been associated with a variety of cancers and neurological diseases. The association of septins with cancer results from alterations of expression in solid tumors or translocations in leukemias [mixed lineage leukemia (MLL)]. Expression changes in septins have also been associated with neurological conditions such as Alzheimer's and Parkinson's disease, as well as retinopathies, hepatitis C, spermatogenesis and Listeria infection. Pathogenic mutations of SEPT9 were identified in the autosomal dominant neurological disorder hereditary neuralgic amyotrophy (HNA). Human septin research over the past decade has established their importance in cell biology and human disease. Further functional characterization of septins is crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications.

Quality of ambulatory care after myocardial infarction among Medicare patients by type of insurance and region.

PURPOSE: To evaluate use of effective cardiac medications and rehabilitation after myocardial infarction in the ambulatory setting in health maintenance organizations (HMOs) and fee-for-service care, and by region. SUBJECTS AND METHODS: We surveyed elderly Medicare patients during 1996 and 1997 in California (n = 516), Florida (n = 304), and the Northeast (n = 220; Massachusetts, New York, and Pennsylvania) approximately 18 months after myocardial infarction. We assessed use of cardiac medications and rehabilitation for HMO (n = 520) and fee-for-service (n = 520) patients matched by age, sex, month of infarct, and region. RESULTS: Across all regions, similar proportions of HMO and fee-for-service patients were using aspirin (72%, n = 374 vs. 74%, n = 387), beta-blockers (38%, n = 195 vs. 32%, n = 168), angiotensin-converting enzyme inhibitors (31%, n = 159 vs. 29%, n = 148), cholesterol-lowering agents (28%, n = 146 vs. 30%, n = 157), and calcium channel blockers (31%, n = 162 vs. 31%, n = 159; all P >0.07), except in California where more HMO patients received beta-blockers (36%, n = 93 vs. 26%, n = 66, P = 0.01). In adjusted analyses, use of these drugs did not differ significantly between HMO and fee-for-service patients. Substantial regional differences were evident in the use of beta-blockers (Northeast 46%, n = 102; Florida 34%, n = 102; California 31%, n = 159) and cholesterol-lowering agents (California 35%, n = 182; Florida 24%, n = 73; Northeast 22%, n = 48; each P <0.001). Fee-for-service patients were more likely than HMO patients to receive cardiac rehabilitation in unadjusted (32%, n = 167, vs. 22%, n = 141, P = 0.001) and adjusted analyses. CONCLUSIONS: Both HMO and fee-for-service patients would likely benefit from greater use of beta-blockers and cholesterol-lowering agents. Professional fees for cardiac rehabilitation may promote increased use among fee-for-service patients. Future studies should assess the quality of ambulatory cardiac care in different types of HMOs and the reasons for geographic variations in cardiac drug use.

Successful treatment of rhino-orbital mucormycosis without exenteration: the use of multiple treatment modalities.

PURPOSE: To describe the successful management of rhino-orbital mucormycosis without the use of orbital exenteration. METHOD: Case report. RESULTS: The patient had successful eradication of the fungal infection with retention of normal vision and ocular function. CONCLUSIONS: The use of multiple treatment modalities including aggressive surgical debridement guided by intraoperative frozen section monitoring, intravenous liposomal amphotericin B, intraorbital regular amphotericin B and hyperbaric oxygen may allow complete resolution of orbital phycomycosis and spare the patient from the blindness and disfigurement associated with exenteration.

Appropriateness of coronary angiography after myocardial infarction among Medicare beneficiaries. Managed care versus fee for service.

BACKGROUND: Previous studies have documented that cardiac procedures are performed less frequently in patients enrolled in managed-care plans than in those with fee-for-service coverage. However, it is not known whether this difference is due to less frequent use of cardiac procedures when they are indicated or to less frequent use when they are not indicated. METHODS: We compared the use of coronary angiography after acute myocardial infarction among Medicare beneficiaries who had traditional fee-for-service coverage with the use among Medicare beneficiaries enrolled in managed-care plans. The analysis was adjusted for differences in demographic and clinical characteristics of the patients and for characteristics of the hospitals to which they were admitted. We studied more than 50,000 beneficiaries in seven states and evaluated their care according to guidelines proposed by the American College of Cardiology and the American Heart Association (ACC-AHA). RESULTS: Among the 44 percent of patients in both groups who had ACC-AHA class I indications (those for which angiography is useful and effective), more fee-for-service beneficiaries than managed-care enrollees underwent angiography (46 percent vs. 37 percent, P<0.001). The rate of angiography was very low among patients with class I indications who were admitted to hospitals without angiography facilities (31 percent in the fee-for-service group and 15 percent in the managed-care group, P<0.001). Among patients with class III indications (those for which angiography is not effective), the rate of use was low in both groups (approximately 13 percent). CONCLUSIONS: In situations in which angiography is thought to be useful, it is used less often among Medicare beneficiaries enrolled in managed-care plans than among those with fee-for-service coverage. Moreover, rates of use among patients with class I indications are fairly low in both groups, suggesting that there is room for improving the care of elderly patients with myocardial infarction, especially those admitted to hospitals without angiography facilities.

Polymorphic eruption of pregnancy and herpes gestationis: comparison of granulated cell proteins in tissue and serum.

Polymorphic eruption of pregnancy (PEP) and herpes gestationis (HG) are pregnancy-related dermatoses of unknown aetiology with eosinophil infiltration which, at early stages, may show similar clinical and histopathological features. To determine the relative contributions of eosinophils, neutrophils and mast cells to the pathogenesis of PEP and HG through deposition of granule proteins, we studied tissue and serum from 15 patients with PEP and 10 with HG. Using indirect immunofluorescence with antibodies to human eosinophil granule major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), neutrophil elastase and mast cell tryptase, we determined and compared cellular and extracellular staining patterns in lesional skin biopsy specimens and, using immunoassay, measured MBP, EDN, and ECP in patients' sera. Eosinophil infiltration and extracellular protein deposition of all three eosinophil granule proteins were present in both PEP and HG indicating a pathogenic role for eosinophils in both diseases. Staining for eosinophil granule proteins was especially prominent in urticarial lesions and around blisters in HG. EDN and ECP serum levels in PEP and ECP serum levels in HG were significantly increased compared with those in normal pregnant and normal nonpregnant serum. Neutrophils were more prominent in HG specimens than in PEP specimens; extracellular neutrophil elastase was minimally present and similar in both diseases. Mast cell numbers and extracellular tryptase deposition did not differ between the two diseases and did not differ from mast cell counts in skin of normal pregnant women. This study shows that eosinophil granule proteins are deposited extracellularly in tissue and are increased in serum in both PEP and HG. Moreover, eosinophil involvement in the two diseases is more consistent than neutrophil and mast cell involvement. Comparatively, tissue eosinophil infiltration and extracellular protein deposition is more extensive in HG than in PEP, suggesting that eosinophil involvement is greater in the pathogenesis of HG than PEP and similar to that found in bullous pemphigoid.

The effect of soap distribution on diarrhoea: Nyamithuthu Refugee Camp.

BACKGROUND: In January 1993, Nyamithuthu Camp in Malawi housed 64000 Mozambican refugees. Communicable diseases, primarily diarrhoea, pneumonia, malaria and measles, contribute to substantially higher mortality rates in refugee populations compared to similar non-displaced populations. METHOD: A systematic sample of 402 households in one portion of the camp were surveyed for diarrhoeal risk factors, and then interviewed twice weekly for 4 months regarding new diarrhoea episodes and the presence of soap in the household. Two-hundred grams of soap per person was distributed monthly. RESULTS: Households had soap on average only 38% of the interview days. Soap was used primarily for bathing and washing clothes (86%). Although 81% of mothers reported washing their children's hands, only 28% of those mothers used soap for that purpose. The presence of soap in a household showed a significant protective effect: there were 27% less episodes of diarrhoea in households when soap was present compared to when no soap was present (RR = 0.73, 95% CI: 0.54 < RR < 0.98). Potential confounding factors were assessed and did not appear to be responsible for the association between the presence of soap and reductions in diarrhoea incidence. CONCLUSION: In summary, our findings suggest that the provision of regular and adequate soap rations, even in the absence of a behaviour modification or education programme, can play an important role in reducing diarrhoea in refugee populations. If subsequent study confirms the soap as a cheap and effective measure to reduce diarrhoea, its provision in adequate amounts should be a high priority in refugee settings.

PIP: In January 1993, Nyamithuthu Camp in Malawi housed 64,000 Mozambican refugees. Communicable diseases such as diarrhea, pneumonia, malaria, and measles cause substantially higher mortality rates in refugee populations compared to similar nondisplaced populations. A sample of 402 households in one part of the camp was surveyed for diarrheal risk factors, then interviewed twice weekly for 4 months about new diarrhea episodes and the presence of soap in the household. Each refugee was routinely rationed 240 g of soap in bar form per month. Surveyed households had soap on an average of only 38% of interview days, with soap used mainly for bathing and washing clothes. While 81% of mothers reported washing their children's hands, only 28% of those mothers used soap for that purpose. There were 27% fewer episodes of diarrhea in households where soap was present compared to when soap was not present. No potential confounding factors were found to be responsible for the association between the presence of soap and reductions in the incidence of diarrhea. These findings highlight the importance of regularly providing adequate soap rations in reducing diarrhea in refugee populations.

Localization of eosinophil-derived neurotoxin and eosinophil cationic protein in neutrophilic leukocytes.

Eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are generally regarded as eosinophil-specific proteins. We tested whether EDN and ECP are present in mature neutrophils. By indirect immunofluorescence, both eosinophils and neutrophils stained with antibodies to EDN and ECP. Lysates of purified (<0.1% eosinophil contamination) neutrophils contained EDN, 112+/-4 ng/10(6) cells, and ECP, 163+/-2 ng/10(6) cells, whereas eosinophil major basic protein (MBP) was not detectable. Electron microscopic examination of immunogold-labeled buffy coat cells stained with EDN antibody showed that EDN is localized to neutrophil granules. Finally, EDN mRNA was detected in lysates of highly purified neutrophils (0.001% eosinophil contamination) by the reverse transcription-polymerase chain reaction. We conclude that proteins that are either identical to or immunologically cross-reactive with EDN and ECP are present in neutrophils and that EDN is synthesized and localized to neutrophil granules. Thus, caution must be exercised in interpreting the presence of EDN and ECP as specific markers of eosinophil-associated inflammation in human disease.

Familial eosinophilic cellulitis, dysmorphic habitus, and mental retardation.

BACKGROUND: Eosinophilic cellulitis is a polymorphous, chronic disease characterized by eosinophil infiltration and granulomatous inflammation. OBJECTIVE: Our purpose was to describe the clinical, histologic, and immunohistologic findings in three family members who have had eosinophilic cellulitis since childhood associated with mental retardation and abnormal body habitus. METHODS: Family members were evaluated. Multiple skin biopsy specimens were obtained and examined after hematoxylin-and-eosin staining, by immunofluorescence and by electron microscopy. Blood specimens were analyzed by immunoassays for eosinophil granule proteins and eosinophil active cytokines. RESULTS: Three short-statured, mentally retarded family members with abnormal body habitus in at least two generations had recurrent eosinophilic cellulitis. Peripheral blood and bone marrow eosinophilia was present. Plasma eosinophil granule major basic protein and eosinophil-derived neurotoxin levels were elevated with normal plasma eosinophil cationic protein levels. Eosinophil survival in culture was increased by patients' plasma and was blocked with monoclonal interleukin-5 antibody. The level of plasma interleukin-5 was elevated. Lesional skin biopsy specimens showed massive staining for three eosinophil granule proteins. Electron microscopy showed eosinophil disruption. CONCLUSION: Eosinophilic cellulitis, mental retardation, and abnormal body habitus were likely inherited as a dominant syndrome in this family in which eosinophil involvement was striking.

Sarcoidosis with orbital tumor outside the lacrimal gland: initial manifestation in 2 elderly white women.

Two elderly white women (aged 72 and 87 years) were first seen with painless, unilateral orbital swelling. Orbital scanning revealed masses infiltrating the soft tissue around the eye. Biopsy results showed nodular, noncaseating granulomas consistent with sarcoidosis. One patient's workup revealed systemic manifestations of sarcoidosis at the time of examination with hilar lymphadenopathy noted on gallium scan; the other refused a complete systemic workup. The orbital tumors resolved with systemic prednisone therapy. To our knowledge, our 87-year-old patient is the oldest to be seen with orbital sarcoidosis. These 2 patients demonstrate that this diagnosis must be considered with orbital tumors in the elderly and in unusual locations, such as these which occurred outside the lacrimal gland.

Survival rates for four forms of cancer in the United States and Ontario.

OBJECTIVES: In this study, cancer survival rates for patients diagnosed in Ontario and selected areas within the United States were compared. METHODS: Relative survival rates were computed for patients aged 15 through 84 years diagnosed with any of four forms of cancer (breast, colon, lung, and Hodgkin's disease). The cohorts represented those diagnosed over the years 1978 through 1986 in the Canadian province of Ontario and in nine regions covered by the US National Cancer Institute's Surveillance Epidemiology and End Results program. Patients were followed through the end of 1990. RESULTS: The cumulative relative survival rates were similar for American and Canadian patients. The largest difference was observed for breast cancer, where patients in the United States enjoyed a survival advantage throughout the follow-up period. CONCLUSIONS: Patients in the United States and Ontario with the diseases studied, except for breast cancer, experience very similar survival. The greater use of mammographic screening in the United States could account for that country's higher breast cancer survival rate by promoting earlier and therefore more efficacious treatment, by introducing bias, or by a combination of both treatment and bias factors.

Dermal eosinophils in atopic dermatitis undergo cytolytic degeneration.

BACKGROUND: Immunofluorescent staining for eosinophil granule proteins in lesional skin of patients with atopic dermatitis shows extensive extracellular deposition throughout the upper dermis with relatively few intact eosinophils. OBJECTIVE: This study was carried out to determine whether eosinophil granule protein deposition in atopic dermatitis occurs by classical exocytosis, by piecemeal degranulation, or as a result of cytolysis. METHODS: Skin biopsy specimens from 10 patients with atopic dermatitis were examined by electron microscopy. RESULTS: The biopsy specimens showed varying degrees of dermal eosinophil granule major basic protein deposition by indirect immunofluorescence. Specimens from seven patients showed striking alterations of eosinophils by electron microscopy including intact eosinophils with granule alterations (reversal of core staining and/or core lucency) and with uropod processes. Biopsy specimens from six patients showed evidence of eosinophil degeneration with disruption of nuclear and/or plasma membranes. In four patients' specimens, membrane-bound eosinophil granules were present near degenerating eosinophils or were present in the absence of recognizable eosinophils. Evidence of classical exocytotic degranulation was not observed. Two of the specimens were also examined by immunoelectron microscopy for major basic protein localization. In these, major basic protein appeared to be lost from the granule core and distributed in the eosinophil cytoplasm as granules disintegrated and the cell disrupted. CONCLUSION: These findings support the hypothesis that eosinophils undergo cytolysis with release of granule contents and membrane-bound granules; this is likely the usual mechanism of eosinophil granule protein release in atopic dermatitis.

Deposition of eosinophil granule proteins precedes blister formation in bullous pemphigoid. Comparison with neutrophil and mast cell granule proteins.

Eosinophils, neutrophils, and mast cells have all been implicated in the pathogenesis of bullous pemphigoid (BP). To comparatively characterize the involvement of these cells in BP, 10 lesional skin biopsy specimens were identified retrospectively and studied for tissue localization of eosinophil, neutrophil, and mast cell granule proteins. Subsequently, multiple skin biopsies of lesions in various developmental stages were obtained from 3 patients with untreated BP. Involved and uninvolved skin specimens were also obtained from 2 patients. Using indirect immunofluorescence, retrospectively identified lesions showed eosinophils and extracellular granule protein deposition prominently in areas of blistering. Evolving lesions showed eosinophil granule protein deposition in all stages but was most marked in early erythematous and prebullous (urticarial) lesions and was minimal in uninvolved skin. Vascular cell adhesion molecule-1, E-selectin, and P-selectin were detected on vessels and very late activation antigen-4 was detected on mononuclear cells and eosinophils by immunoperoxidase staining of lesions. Eosinophil granule proteins were increased in the peripheral blood, urine, and blister fluid. Blister fluids caused increased eosinophil survival that was inhibited by antibodies to interleukin-5 and interleukin-3. Although neutrophil and mast cell infiltration was observed, extracellular granule protein deposition from these cells was minimal except in two specimens. These results demonstrate that eosinophils infiltrate and deposit granule proteins early in the development of BP lesions, that eosinophil-activating cytokines are present in blister fluid, and that eosinophil-selective adhesion molecules are present. These studies strongly support a role for eosinophils in blister formation in BP.

Immunohistological comparison of granulated cell proteins in induced immediate urticarial dermographism and delayed pressure urticaria lesions.

Urticarial dermographism and delayed pressure urticaria are two forms of physical urticaria which are well defined clinically and histologically. Previous studies have shown eosinophil granule protein deposition in urticarial reactions, including chronic urticaria, solar urticaria and delayed pressure urticaria. To evaluate and compare the involvement of granulated inflammatory cells in urticarial dermographism and delayed pressure urticaria, we studied sequential biopsies of induced lesions of urticarial dermographism and delayed pressure urticaria by indirect immunofluorescence, to detect eosinophil granule major basic protein (MBP) and neutrophil granule elastase. Biopsies from dermographic lesions at time 0, 5 min, 15 min, 2 h and 24 h, showed few infiltrating eosinophils, with minimal extracellular MBP deposition, and a few infiltrating neutrophils, with minimal neutrophil elastase deposition, throughout the evolution of the lesions. Sequential biopsies of delayed pressure urticaria at time 0, 20 min, 6, 12 and 24 h, showed eosinophil infiltration with extensive MBP deposition beginning at 20 min, and neutrophil infiltration with variable elastase deposition beginning at 20 min. Control tissue specimens from normal volunteers showed neutrophil infiltration and slight degranulation, but no eosinophil infiltration or degranulation. Comparison of urticarial dermographism with delayed pressure urticaria showed marked differences in the patterns of infiltration. Delayed pressure urticaria, with eosinophil and neutrophil degranulation, was strikingly similar to the IgE-mediated late phase reaction. In contrast, eosinophil and neutrophil involvement in urticarial dermographism was minimal. Considering the extent of eosinophil granule protein deposition and the biological activities of the eosinophil granule proteins, the findings in delayed pressure urticaria point to an important pathophysiological role of eosinophils in the disease.