Environmental priming influences allergen-specific nasal reactivity

Background Preceding mucosal response to one allergen leads to the priming of the nasal mucosal response to another allergen. This study aimed t o determine whether environmental allergens, especially ubiquitous animal dander, can induce nasal priming.
Methods We investigated 26 grass-pollen-allergic subjects with additional sensitization to other aeroallergens. We performed continuous allergen challenge for 2 h with 1500 Dactylis glomerata pollen/m³ in the Vienna challenge chamber. The nasal flow at 150 Pa was examined, and subjective scores were obtained every 15 min. Statistical analysis was calculated from the area under curve of nasal flow reduction by Student's f-test and the Mann-Whitney U-test. Alpha was 0.05.
Results In subjects with positive cat-dander RAST (class of ≥ 3), besides grass-pollen allergy, the specific nasal allergic reaction to Dactylis challenge was significantly pronounced (P <0.01). and an earlier onset of reaction was evident. TTie same results were obtained with additional sensitization to dog dander (P<0.05). Concomitant sensitization to mugwort also led to escalating symptoms (P<0.05).
Conclusions These results indicate that a specific nasal allergic reaction is augmented by environmental priming caused by ubiquitous animal dander and possibly is influenced by the daily use of spices.     

Morphological evidence of reduced bone resorption in the osteosclerotic (oc) mouse

Osteopetrosis, a metabolic bone disease characterized by a generalized sclerosis of the skeleton, is inherited as an autosomal recessive in a number of mammalian species. The pathogenesis of congenital osteopetrosis is mediated by a reduction in bone resorption as a result of decreased osteoclast function. This hypothesis is based on both functional and structural evidence of reduced bone resorption in all mutations examined to date. The present study examined the histology of cartilage and bone, the ultrastructure of osteoclasts, and the morphology of mineralized bone surfaces in a lethal osteopetrotic mutation, the osteosclerotic (oc) mouse. Histologically, epiphyseal cartilage growth plates, especially the hypertrophic zone, are markedly thickened in oc mice and metaphyses contain excessive osteoid, features characteristic of rickets. Transmission electron microscopy revealed that less than one-quarter of osteoclasts in oc mice demonstrated evidence of ruffled border formation compared with three-quarters of the osteoclasts in normal littermates. In mutants, ruffled borders were less elaborate and cytoplasmic processes penetrated into bone surfaces, suggesting that bone may be removed by mechanical rather than by enzymatic means. There was little morphological evidence of cartilage degradation and broad laminae limitantes persisted in mutants. Mineralized surfaces that undergo resorption in normal mice showed no evidence of bone resorption by scanning EM in mutants. The presence of a rachitic condition, the observations of reduced bone resorption, and the possible contribution of undermineralized matrices to decreased bone resorption are charcteristics of the osteosclerotic mutation which suggest that it is a unqiue csteopetrotic mutant in which to study both the development and regulation of skeletal metabolism.     

Osteopetrosis in the toothless (tl) rat: Presence of osteoclasts but failure to respond to parathyroid extract or to be cured by infusion of spleen or bone marrow cells from normal littermates

Osteoclasts have been observed for the first time in toothless (tl ) rats, a mutation which inherits osteopetrosis as an autosomal recessive. The ability of tl rats to raise the serum calcium concentration after injection of parathyroid extract was severely limited when compared with normal littermates. In addition, osteopetrosis in tl rats is not cured by radiation and infusion of normal spleen or bone marrow cells from normal littermates, a method known to cure osteopetrosis in mutants of this and other species. This indirect evidence for a reduction in bone resorption as a cause of osteopetrosis in this mutation and the failure of transplanted cells to cure the disease are discussed in relation to the development and function of osteoclasts.     

Congenitally osteosclerotic (os/os) rabbits are not cured by bone marrow transplantation from normal littermates

The osteopetrotic (os) rabbit is a lethal mutation of autosomal recessive inheritance characterized by hypocalcemia, hypophosphatemia, fibrosis of marrow spaces, and ultrastructural abnormalities in both osteoclasts and osteoblasts. Procedures involving the transplantation of cells from normal hemopoietic tissues, which are sources of osteoclast precursors, are known to cure osteopetrosis in several mutations including some children. We tested the ability of transplanted bone marrow and/or spleen from normal littermates to reverse the skeletal sclerosis in os rabbits. Treatment of 15 neonatal mutants consisted of immunosuppression by whole-body irradiation followed by transplantation of normal bone marrow and/or spleen cell suspensions. This treatment failed to prolong life span or to cure osteopetrosis judged radiographically and histologically for up to 3 weeks posttreatment, the longest time of survival. These data indicate that transplantation of stem cells from multiple hemopoietic tissues, procedures known to cure osteopetrosis in other mutations, is not effective in the os rabbit. These results support the hypothesis that the skeletal microenvironment is not capable of supporting the development and function of normal osteoclasts in this mutation.     

Gunshot wounds. Incidence, cost, and concepts of prevention

The United States has the highest incidence of firearm-related deaths among the Western industrialized nations. Firearms are the second leading cause of injury death. In 1982, the National Center for Health Statistics showed that firearms killed more than 33,000 individuals: 1,756 unintentionally, 16,573 by suicide, 13,841 by homicide, 376 by legal action, and 540 of undetermined intent. In terms of the total number of years of life lost, trauma in general contributed more years than heart disease and cancer combined for the year 1975. The southern regions of the United States tend to have higher firearm-related death rates than other regions of the country. Data collected within Arkansas are consistent with this trend. Handguns are the most frequently used firearms in fatal injuries. Unfortunately, data on nonfatal injuries are lacking. The emotional and economic costs of firearm-related death and injury are staggering. The estimated daily cost of hospitalization is $2100, and the average length of hospitalization is 10 days. The emotional impact of a gun-related injury or death will be felt immediately by 950,000 people per year. The economic loss resulting from "premature" deaths due to firearms is estimated to be nearly $4 billion annually. Unfortunately, the firearm is so ingrained in the American experience that one must conclude gunshot injuries and fatalities are simply part of the cost of living in America today.     

Patterns of contrast enhancement of benign and malignant hepatic neoplasms during bolus dynamic and delayed CT

Bolus dynamic and delayed computed tomographic (CT) scans of the liver were evaluated in 43 patients with 54 hepatic hemangiomas and 111 patients with primary or secondary malignant hepatic neoplasms. Twelve patterns of contrast enhancement were recognized during the bolus dynamic phase and delayed scanning. A "typical" CT pattern for hemangiomas (present in 29 of 54 hemangiomas [53.7%]) was established: (a) diminished attenuation prior to intravenous contrast medium administration (excluding lesions arising in a liver with diffuse fatty infiltration), (b) peripheral contrast enhancement during the bolus dynamic phase, and (c) complete isodense fill-in on delayed scan images. Using these criteria, we distinguished hemangiomas from malignant neoplasms in most patients. Only one of 63 (1.6%) malignant neoplasms manifested these typical CT criteria of hemangioma. There is an 86% chance that a lesion with the typical CT appearance of hemangioma is actually a hemangioma, even when found in a patient with a known nonhepatic primary neoplasm.     

Induction of plasma membrane alterations in AKR-2B mouse embryo fibroblasts by endogenous growth factors from malignant human cells

AKR-2B mouse fibroblasts were treated with 50 micrograms/ml of crude transforming growth factor (TGF) of human origin. Cell surface proteins of treated cells were radioiodinated and compared to untreated cells at various times after the addition of TGF. Treated cells showed a severalfold increase (approximately 6-fold) in cell surface 125I incorporation relative to normal cells at 24 h. Electrophoretic comparison of treated and untreated cells showed large increases in the labelling of cell surface proteins of mol. wt. 50,000-90,000 from TGF-exposed cells between 10 and 24 h post treatment. By 48 h post treatment, the electrophoretic profiles of TGF-exposed cells had returned to a pattern similar to that of untreated cells. However, even after a 48 h exposure to TGF, the cells retained a transformed morphology indicating that the electrophoretic alterations were not simply due to the morphological transformation induced by TGF. The electrophoretic pattern of TGF-treated cells at 24 h post treatment was similar to that of AKR-2B cells permanently transformed by treatment with methylcholanthrene, but was clearly distinct from that induced by treatment of normal AKR-2B cells with epidermal growth factor (EGF). EGF induced an increase in a protein of mol. wt. 60,000 in the electrophoretic profiles taken 24 h post treatment. As with TGF, the appearance of electrophoretic profiles of EGF-treated cells returned to "normal" by 48 h. Again, these alterations did not appear to be dependent upon morphological changes since EGF-treated cells showed a morphological transformation similar to that of cells treated with TGF, and this was maintained throughout the 48 h experimental period.     

Elevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation

PurposeWe aimed to assess the prognostic value of Neutrophil to Lymphocyte Ratio (NLR) on long-term outcomes and graft dysfunction after lung transplantation.MethodsWe retrospectively reviewed all patients receiving a lung transplant at our institution from 2011 to 2014. The primary exposure was elevated NLR at the time of transplant, defined by NLR>4. The primary outcomes were graft failure and three-year all-cause mortality. Multivariate logistic regression and Kaplan-Meier survival analysis were used to analyze outcomes.Results95 patients were included. 40 patients (42%) had an elevated NLR. Elevated NLR was associated with graft failure (OR: 4.7 [1.2–18.8], p = 0.02), and three-year mortality (OR: 5.4 [1.3–23.2], p = 0.03) on multivariate logistic regression. Patients with elevated NLR demonstrated significantly lower survival on Kaplan-Meier analysis (50% versus 74%, p = 0.02). The c-statistic for our multivariate model was 0.91.ConclusionElevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation.     

The effect of respiratory activity,non-invasive respiratory support and facemasks on aerosol generation and its relevance to COVID-19

Respirable aerosols (< 5 µm in diameter) present a high risk of SARS-CoV-2 transmission. Guidelines recommend using aerosol precautions during aerosol-generating procedures, and droplet (> 5 µm) precautions at other times. However, emerging evidence indicates respiratory activities may be a more important source of aerosols than clinical procedures such as tracheal intubation. We aimed to measure the size, total number and volume of all human aerosols exhaled during respiratory activities and therapies. We used a novel chamber with an optical particle counter sampling at 100 l.min^-1 to count and size-fractionate close to all exhaled particles (0.5–25 µm). We compared emissions from ten healthy subjects during six respiratory activities (quiet breathing; talking; shouting; forced expiratory manoeuvres; exercise; and coughing) with three respiratory therapies (high-flow nasal oxygen and single or dual circuit non-invasive positive pressure ventilation). Activities were repeated while wearing facemasks. When compared with quiet breathing, exertional respiratory activities increased particle counts 34.6-fold during talking and 370.8-fold during coughing (p < 0.001). High-flow nasal oxygen 60 at l.min^-1 increased particle counts 2.3-fold (p = 0.031) during quiet breathing. Single and dual circuit non-invasive respiratory therapy at 25/10 cm.H₂O with quiet breathing increased counts by 2.6-fold and 7.8-fold, respectively (both p < 0.001). During exertional activities, respiratory therapies and facemasks reduced emissions compared with activities alone. Respiratory activities (including exertional breathing and coughing) which mimic respiratory patterns during illness generate substantially more aerosols than non-invasive respiratory therapies, which conversely can reduce total emissions. We argue the risk of aerosol exposure is underappreciated and warrants widespread, targeted interventions.     

Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal

CRADLE was a 36-month multicenter study in pediatric (≥1 to <18 years) kidney transplant recipients randomized at 4 to 6 weeks posttransplant to receive everolimus + reduced-exposure tacrolimus (EVR + rTAC; n = 52) with corticosteroid withdrawal at 6-month posttransplant or continue mycophenolate mofetil + standard-exposure TAC (MMF + sTAC; n = 54) with corticosteroids. The incidence of composite efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 36 was 9.8% vs 9.6% (difference: 0.2%; 80% confidence interval: −7.3 to 7.7) for EVR + rTAC and MMF + sTAC, respectively, which was driven by BPARs. Graft loss was low (2.1% vs 3.8%) with no deaths. Mean estimated glomerular filtration rate at month 36 was comparable between groups (68.1 vs 67.3 mL/min/1.73 m²). Mean changes (z-score) in height (0.72 vs 0.39; P = .158) and weight (0.61 vs 0.82; P = .453) from randomization to month 36 were comparable, whereas growth in prepubertal patients on EVR + rTAC was better (P = .050) vs MMF + sTAC. The overall incidence of adverse events (AEs) and serious AEs was comparable between groups. Rejection was the leading AE for study drug discontinuation in the EVR + rTAC group. In conclusion, though AE-related study drug discontinuation was higher, an EVR + rTAC regimen represents an alternative treatment option that enables withdrawal of steroids as well as reduction of CNIs for pediatric kidney transplant recipients. ClinicalTrials.gov: NCT01544491.