Clinical Manifestations of Subjects With the Non-Specific Pulmonary Function Test Pattern.

Introduction: Non-specific pattern (NSP) is a subgroup of preserved ratio impaired spirometry (PRISm) that requires a normal total lung capacity measurement. NSP has been historically classified as being an obstructive lung disease pattern. There has been heightened interest and investigation into PRISm recently as it has been associated with an increased likelihood of developing chronic obstructive pulmonary disease (COPD). Given the inherent challenges of understanding the clinical significance of the NSP, the aim of this study was to further explore the clinical characteristics of patients with this pulmonary function test pattern. Material and methods: We identified 111 and 79 subjects using pre-bronchodilator (pre-BD) and post-bronchodilator (post-BD) values, respectively, that met criteria for NSP. The outpatient medical records were retrospectively reviewed for associated diagnoses that were then clustered into 'obstructive' or 'non-obstructive' groups based on the treating physician's primary pulmonary clinical diagnosis. Results: Within this NSP cohort, cough, wheezing and sputum production were documented more frequently in those with an obstructive lung disease diagnosis. Whether identified using pre-BD or post-BD spirometric values, those with NSP and a positive BD response were more likely to carry an obstructive lung disease diagnosis. Conclusion: Approximately one third of patients with NSP in this study were not given an obstructive lung disease diagnosis by their clinician, which supports the classification of NSP as not an exclusively obstructive lung disease pattern. However, the presence of supporting clinical symptoms, such as cough with sputum production and wheeze, and/or a positive BD response on PFT, support a diagnosis of obstruction in patients with NSP.

Introducción: El patrón inespecífico constituye un subgrupo de alteraciones de la espirometría con conservación de la relación (PRISm, siglas en inglés) que precisa de una medición de la capacidad pulmonar total normal; históricamente se ha clasificado como un patrón de neumopatía obstructiva. En épocas recientes se ha intensificado el interés en las PRISm y su investigación, ya que se ha asociado a un aumento de la probabilidad de aparición de una enfermedad pulmonar obstructiva crónica (EPOC). Dadas las dificultades inherentes que conlleva interpretar la importancia clínica del patrón inespecífico, el objetivo de este estudio consistió en explorar con más detalle las características clínicas de los pacientes con dicho patrón en las pruebas de la función pulmonar. Material y métodos: Se identificaron 111 y 79 sujetos empleando valores prebroncodilatador y posbroncodilatador, respectivamente, que cumplieron los criterios de patrón inespecífico. Se revisaron retrospectivamente las historias clínicas ambulatorias para detectar diagnósticos asociados que después se agregaron en grupos «obstructivos¼ o «no obstructivos¼ en función del diagnóstico clínico pulmonar primario del médico. Resultados: En esta cohorte de pacientes con patrones inespecíficos, se documentó una mayor incidencia de tos, sibilancias y producción de esputo entre los que tenían un diagnóstico de neumopatía obstructiva. Los pacientes con patrón inespecífico y una respuesta positiva al broncodilatador, que hubiesen sido identificados con valores pre o posbroncodilatador, tenían más probabilidades de haber recibido un diagnóstico de neumopatía obstructiva. Conclusión: Aproximadamente un tercio de los pacientes con patrón inespecífico de este estudio no habían recibido un diagnóstico de neumopatía obstructiva, dato que avala no clasificar los patrones inespecíficos exclusivamente en las neumopatías obstructivas. Sin embargo, la presencia de síntomas clínicos indicativos, como tos productiva y sibilancias, o una respuesta positiva al broncodilatador en las pruebas de la función pulmonar, sustenta un diagnóstico de obstrucción en los pacientes con patrón inespecífico.

A Novel Approach to Screening for Alpha-1 Antitrypsin Deficiency: Inpatient Testing at a Teaching Institution.

Chronic obstructive pulmonary disease (COPD) currently affects more than 16 million Americans and it is estimated that roughly 100,000 Americans have undiagnosed, severe alpha-1 antitrypsin deficiency (AATD) (Chest. 2005;128[3]:1179-1186) (Chest. 2002;122[5]:1818-1829). Patients with AATD have an accelerated rate of decline of lung function caused by proteolytic enzymes. The morbidity associated with this inherited disorder is preventable due to the availability of augmentation therapy. Appropriate inpatient screening of patients with COPD for AATD is lacking and most screening is exclusively limited to outpatient pulmonary clinics. Between May 2016 and February 2017, genetic screening was completed on 54 individuals who were admitted with either a former diagnosis of COPD or active COPD exacerbation to Arnot Ogden Medical Center (AOMC) in Elmira, New York. The incorporation of inpatient genetic screening by resident physicians for AATD in COPD patients led to a high rate of screened and newly diagnosed AATD carriers with a variety of AATD genotypes. It is recommended that there should be an expansion of screening for AATD in hospitalized patients with COPD, regardless of age or smoking history.

Ceftriaxone-Induced Hemolytic Anemia in a Jehovah's Witness.

BACKGROUND Drug-induced immune hemolytic anemia (DIIHA) is a rare condition that may result from the administration of an antibiotic, most notably the cephalosporin class, commonly used in both the adult and pediatric populations. A delay in recognition by a provider may lead to continuation of the offending agent and possibly result in fatal outcomes. CASE REPORT We report the case of a 65-year-old woman on ceftriaxone infusions after being diagnosed with acute mitral valve endocarditis 3 weeks prior, which presented with severe anemia and bilateral transient vision loss. Being a Jehovah's Witness, the patient refused blood product transfusions and was managed with alternative therapies. The etiology of the symptoms was suspected to be a hemolytic anemia directly related to her ceftriaxone infusions. CONCLUSIONS This report demonstrates the importance of close vigilance while prescribing drugs known to cause hemolytic anemia. Although rare, drug-induced immune hemolytic anemia caused by ceftriaxone may be a potentially fatal condition, but with early recognition and withdrawal of the offending agent, successful treatment may ensue. Serological tests should be utilized to obtain a definitive diagnosis.

Delayed Presentation of Acute Gluteal Compartment Syndrome.

BACKGROUND Acute gluteal compartment syndrome is a rare condition that usually results from prolonged immobilization following a traumatic event, conventionally involving the presence of compounding factors such as alcohol or opioid intoxication. If delay in medical treatment is prolonged, severe rhabdomyolysis may ensue, leading to acute renal failure and potentially death. CASE REPORT We report the case of a 23-year-old male with a recent history of incarceration and recreational drug use, who presented with reports of severe right-sided buttock pain and profound right-sided neurological loss following a questionable history involving prolonged immobilization after a fall from a standing position. The patient required an emergent gluteal fasciotomy immediately upon admission and required temporary hemodialysis. After an extended hospital stay, he ultimately recovered with only mild deficits in muscular strength in the right lower extremity. CONCLUSIONS This report demonstrates the importance of early recognition of gluteal compartment syndrome to prevent morbidity and mortality. Compartment syndrome presents in many unique ways, and healthcare practitioners must have a keen diagnostic sense to allow for early surgical intervention. Proper wick catheter measurements should be utilized more frequently, instead of relying on clinical symptomatology such as loss of peripheral pulses for diagnosis of compartment syndrome.

Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions.

Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H2O2 assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H2O2 levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival.

Preemptive donor apoptotic cell infusions induce IFN-γ-producing myeloid-derived suppressor cells for cardiac allograft protection.

We have previously shown that preemptive infusion of apoptotic donor splenocytes treated with the chemical cross-linker ethylcarbodiimide (ECDI-SPs) induces long-term allograft survival in full MHC-mismatched models of allogeneic islet and cardiac transplantation. The role of myeloid-derived suppressor cells (MDSCs) in the graft protection provided by ECDI-SPs is unclear. In this study, we demonstrate that infusions of ECDI-SPs increase two populations of CD11b(+) cells in the spleen that phenotypically resemble monocytic-like (CD11b(+)Ly6C(high)) and granulocytic-like (CD11b(+)Gr1(high)) MDSCs. Both populations suppress T cell proliferation in vitro and traffic to the cardiac allografts in vivo to mediate their protection via inhibition of local CD8 T cell accumulation and potentially also via induction and homing of regulatory T cells. Importantly, repeated treatments with ECDI-SPs induce the CD11b(+)Gr1(high) cells to produce a high level of IFN-γ and to exhibit an enhanced responsiveness to IFN-γ by expressing higher levels of downstream effector molecules ido and nos2. Consequently, neutralization of IFN-γ completely abolishes the suppressive capacity of this population. We conclude that donor ECDI-SPs induce the expansion of two populations of MDSCs important for allograft protection mediated in part by intrinsic IFN-γ-dependent mechanisms. This form of preemptive donor apoptotic cell infusions has significant potential for the therapeutic manipulation of MDSCs for transplant tolerance induction.

Transient B-cell depletion combined with apoptotic donor splenocytes induces xeno-specific T- and B-cell tolerance to islet xenografts.

Peritransplant infusion of apoptotic donor splenocytes cross-linked with ethylene carbodiimide (ECDI-SPs) has been demonstrated to effectively induce allogeneic donor-specific tolerance. The objective of the current study is to determine the effectiveness and additional requirements for tolerance induction for xenogeneic islet transplantation using donor ECDI-SPs. In a rat-to-mouse xenogeneic islet transplant model, we show that rat ECDI-SPs alone significantly prolonged islet xenograft survival but failed to induce tolerance. In contrast to allogeneic donor ECDI-SPs, xenogeneic donor ECDI-SPs induced production of xenodonor-specific antibodies partially responsible for the eventual islet xenograft rejection. Consequently, depletion of B cells prior to infusions of rat ECDI-SPs effectively prevented such antibody production and led to the indefinite survival of rat islet xenografts. In addition to controlling antibody responses, transient B-cell depletion combined with ECDI-SPs synergistically suppressed xenodonor-specific T-cell priming as well as memory T-cell generation. Reciprocally, after initial depletion, the recovered B cells in long-term tolerized mice exhibited xenodonor-specific hyporesponsiveness. We conclude that transient B-cell depletion combined with donor ECDI-SPs is a robust strategy for induction of xenodonor-specific T- and B-cell tolerance. This combinatorial therapy may be a promising strategy for tolerance induction for clinical xenogeneic islet transplantation.

Expression of cytosolic peroxiredoxins in Plasmodium berghei ookinetes is regulated by environmental factors in the mosquito bloodmeal.

The Plasmodium ookinete develops over several hours in the bloodmeal of its mosquito vector where it is exposed to exogenous stresses, including cytotoxic reactive oxygen species (ROS). How the parasite adapts to these challenging conditions is not well understood. We have systematically investigated the expression of three cytosolic antioxidant proteins, thioredoxin-1 (Trx-1), peroxiredoxin-1 (TPx-1), and 1-Cys peroxiredoxin (1-Cys Prx), in developing ookinetes of the rodent parasite Plasmodium berghei under various growth conditions. Transcriptional profiling showed that tpx-1 and 1-cys prx but not trx-1 are more strongly upregulated in ookinetes developing in the mosquito bloodmeal when compared to ookinetes growing under culture conditions. Confocal immunofluorescence imaging revealed comparable expression patterns on the corresponding proteins. 1-Cys Prx in particular exhibited strong expression in mosquito-derived ookinetes but was not detectable in cultured ookinetes. Furthermore, ookinetes growing in culture upregulated tpx-1 and 1-cys prx when challenged with exogenous ROS in a dose-dependent fashion. This suggests that environmental factors in the mosquito bloodmeal induce upregulation of cytosolic antioxidant proteins in Plasmodium ookinetes. We found that in a parasite line lacking TPx-1 (TPx-1KO), expression of 1-Cys Prx occurred significantly earlier in mosquito-derived TPx-1KO ookinetes when compared to wild type (WT) ookinetes. The protein was also readily detectable in cultured TPx-1KO ookinetes, indicating that 1-Cys Prx at least in part compensates for the loss of TPx-1 in vivo. We hypothesize that this dynamic expression of the cytosolic peroxiredoxins reflects the capacity of the developing Plasmodium ookinete to rapidly adapt to the changing conditions in the mosquito bloodmeal. This would significantly increase its chances of survival, maturation and subsequent escape. Our results also emphasize that environmental conditions must be taken into account when investigating Plasmodium-mosquito interactions.

Ethylenecarbodiimide-fixed donor splenocyte infusions differentially target direct and indirect pathways of allorecognition for induction of transplant tolerance.

Strategic exposure to donor Ags prior to transplantation can be an effective way for inducting donor-specific tolerance in allogeneic recipients. We have recently shown that pretransplant infusion of donor splenocytes treated with the chemical cross-linker ethylenecarbodiimide (ECDI-SPs) induces indefinite islet allograft survival in a full MHC-mismatched model without the need for any immunosuppression. Mechanisms of allograft protection by this strategy remain elusive. In this study, we show that the infused donor ECDI-SPs differentially target T cells with indirect versus direct allospecificities. To target indirect allospecific T cells, ECDI-SPs induce upregulation of negative, but not positive, costimulatory molecules on recipient splenic CD11c(+) dendritic cells phagocytosing the injected ECDI-SPs. Indirect allospecific T cells activated by such CD11c(+) dendritic cells undergo robust initial proliferation followed by rapid clonal depletion. The remaining T cells are sequestered in the spleen without homing to the graft site or the graft draining lymph node. In contrast, direct allospecific T cells interacting with intact donor ECDI-SPs not yet phagocytosed undergo limited proliferation and are subsequently anergized. Furthermore, CD4(+)CD25(+)Foxp3(+) T cells are induced in lymphoid organs and at the graft site by ECDI-SPs. We conclude that donor ECDI-SP infusions target host allogeneic responses via a multitude of mechanisms, including clonal depletion, anergy, and immunoregulation, which act in a synergistic fashion to induce robust transplant tolerance. This simple form of negative vaccination has significant potential for clinical translation in human transplantation.

Permanent protection of PLG scaffold transplanted allogeneic islet grafts in diabetic mice treated with ECDI-fixed donor splenocyte infusions.

Allogeneic islet cell transplantation is a promising treatment for human type 1 diabetes. Currently, human islets are transplanted via intra-portal infusions. While successful, it leads to significant early islet attrition from instant blood-mediated inflammatory reaction. An extra-hepatic site was established by transplanting islet-loaded microporous poly(lactide-co-glycolide) (PLG) scaffolds into the epididymal fat pad in syngeneic islet transplant models. This study examined this technology in allogeneic islet transplantation and determined whether transplant tolerance could be effectively induced to protect PLG scaffold transplanted allogeneic islets. The efficacy of an established tolerance induction strategy using donor splenocytes treated with ethylcarbodiimide(ECDI) was tested. ECDI-fixed donor splenocytes were infused 7 days before and 1 day after islet transplantation. Immediate normoglycemia was restored, and treated mice maintained indefinite normoglycemia whereas untreated mice rejected islet grafts within 20 days of transplantation. Interestingly, efficacy of tolerance induction was superior in PLG scaffold compared with intra-portal transplanted islets. Protection of PLG scaffold islet allografts was associated with several mechanisms of immune regulation. In summary, PLG scaffolds can serve as an alternative delivery system for islet transplantation that does not impair tolerance induction. This approach of combining tolerance induction with scaffold islet transplantation has potential therapeutic implications for human islet transplantation.