PCP Treatment Research Articles

Activation of Metabotropic Glutamate Receptor 3 Modulates Thalamo-accumbal Transmission and Rescues Schizophrenia-Like Physiological and Behavioral Deficits

BackgroundPolymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu3) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu3 can regulate brain circuits involved in schizophrenia pathophysiology are not clear. MethodsWe employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu3 activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits. A chemogenetic approach was used to evaluate the role of thalamo-accumbal transmission in PCP-induced sociability deficits. ResultsWe first established that PCP treatment augmented excitatory transmission onto dopamine D1 receptor–expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) and induced sociability deficits. Our studies revealed a selective increase in glutamatergic synaptic transmission from thalamic afferents to D1-MSNs in the NAc shell. Chemogenetic silencing of thalamo-accumbal inputs rescued PCP-induced sociability deficits. Pharmacological activation of mGlu3 normalized PCP-induced impairments in thalamo-accumbal transmission and sociability deficits. Mechanistic studies revealed that mGlu3 activation induced robust long-term depression at synapses from the thalamic projections onto D1-MSNs in the NAc shell. ConclusionsThese data demonstrate that activation of mGlu3 decreases thalamo-accumbal transmission and thereby rescues sociability deficits in mouse modeling schizophrenia-like symptoms. These findings provide novel insights into the NAc-specific mechanisms and suggest that agents modulating glutamatergic signaling in the NAc may provide a promising approach for treating negative symptoms in schizophrenia.

The Efficacy of Porcine Dermal Collagen to Treat Complex Anal Fistulae. Results of a Multicenter Cohort

Abstract Introduction The management of complex anal fistulae remains a topical surgical problem. The choice and success of surgical management are based on the balance between healing and continence. Although porcine dermal collagen (Permacol Collagen Paste [PCP]- Covidien plc, Gosport, Hampshire, UK) represents a new generation of non-solid biomaterials, its results in anal fistulae are mixed. Methods A multicenter observational retrospective analysis of consecutive patients with cryptoglandular anal fistula treated in four colorectal surgery units was performed between 2015 and 2020. Clinical cure of the fistula was the main outcome measure. Adverse events and alterations in anal continence were secondary outcomes. Results The study included 119 patients (87 males, 71.1%), with a mean age of 53 years (IR 44–65). Most patients had complex (80.6%) and recurrent (91.6%) fistulae. With the first PCP treatment, the overall cure rate was 41.2% (49 patients) and 45.4% with the second treatment (5 out of 17 patients). The mean follow-up period was 17 months (IR 5–25). Healing was not affected by the location and type of fistula, the existence or not of a cavity, the number of tracts, or the administration of prophylactic antibiotics. After the PCP treatment, no patient in the series had worsening of continence. Morbidity affected 22.7% of the patients (27), with postoperative abscesses being the most frequent adverse event. There were no statistical differences between the four hospitals studied. Conclusions Permacol collagen paste is a safe and easily reproducible therapy for complicated anal fistulae that has moderate efficacy. The overall success rate is slightly over 40%, with no detriment to fecal continence.

Two modified treatment methods for pretreated corn stalk and its composites with modified lignosulfonate

Effects of two different modified treatments were investigated relative to the chemical and mechanical properties of pretreated corn stalk particles and their composites prepared with a modified lignosulfonate (ML) binder. Corn stalk particles (CP) first were prepared by treating corn stalk particles with oxalic acid in ultrasonic conditions (pretreated corn stalk particles, PCP). These particles were then modified by treatment with either laccase-vanillin system with ultrasound (LU) or polyethylenimine-glutaraldehyde with ultrasound (PU), and the surface chemistries of the modified PCP and mechanical properties of LU-PCP/ML composites and PU-PCP/ML composites, such as modulus of rupture (MOR), modulus of elasticity (MOE), internal bonding strength (IB), 24-h thickness swelling (TS), and crystallinity were compared. Both modified treatments dramatically enhanced the mechanical properties of the composites. The MOR, MOE, and IB of the PU-PCP/ML composites were improved by up to 148%, 81%, and 62%, respectively, compared to LU-PCP/ML. Moreover, the 24-h TS of the LU-PCP/ML composites was reduced by 16%. These results show that the pretreatment method of CP and ultrasonic collaborative treatment of PCP can effectively improve the properties of its composites. Modified PCP with PU was more favorable for surface chemical and mechanical properties.

The Dual Benefit of Sulfasalazine on Pneumocystis Pneumonia-Related Immunopathogenesis and Antifungal Host Defense Does Not Require IL-4Rα-Dependent Macrophage Polarization.

Pneumocystis is a respiratory fungal pathogen that is among the most frequent causes of life-threatening pneumonia (PcP) in immunocompromised hosts. Alveolar macrophages play an important role in host defense against Pneumocystis, and several studies have suggested that M2 polarized macrophages have anti-Pneumocystis effector activity. Our prior work found that the immunomodulatory drug sulfasalazine (SSZ) provides a dual benefit during PcP-related immune reconstitution inflammatory syndrome (IRIS) by concurrently suppressing immunopathogenesis while also accelerating macrophage-mediated fungal clearance. The benefits of SSZ were associated with heightened Th2 cytokine production and M2 macrophage polarization. Therefore, to determine whether SSZ improves the outcome of PcP through a mechanism that requires Th2-dependent M2 polarization, RAG2-/- mice lacking interleukin 4 receptor alpha chain (IL-4Rα) on macrophage lineage cells were generated. As expected, SSZ treatment dramatically reduced the severity of PcP-related immunopathogenesis and accelerated fungal clearance in immune-reconstituted RAG2-/- mice. Similarly, SSZ treatment was also highly effective in immune-reconstituted RAG2/IL-4Rα-/- and RAG2/gamma interferon receptor (IFN-γR)-/- mice, demonstrating that neither IL-4Rα-dependent M2 nor IFN-γR-dependent M1 macrophage polarization programs were required for the beneficial effects of SSZ. Despite the fact that macrophages from RAG2/IL-4Rα-/- mice could not respond to the Th2 cytokines IL-4 and IL-13, M2-biased alveolar macrophages were identified in the lungs following SSZ treatment. These data demonstrate that not only does SSZ enhance phagocytosis and fungal clearance in the absence of macrophage IL-4Rα signaling, but also that SSZ promotes M2 macrophage polarization in an IL-4Rα-independent manner. These findings could have implications for the treatment of PcP and other diseases in which M2 polarization is beneficial.

Prognostic factors and clinical efficacy of second-line treatments of Pneumocystis jirovecii pneumonia for non-HIV patients after first-line treatment failure

BackgroundPneumocystis jirovecii pneumonia (PCP) is a life-threatening opportunistic infection. In non-HIV immunocompromised patients with PCP, a standard second-line treatment has not been established up to now.MethodsNon-HIV immunocompromised patients with confirmed PCP between April 2013 and December 2020 were included. Their PCP treatment history was tracked. Factors related to first-line trimethoprim/sulfamethoxazole (TMP/SMX) and second-line treatment failure were identified. Different second-line treatment strategies were compared.ResultsAmong the 220 patients, 127 (57.73%) did not respond to first-line TMP/SMX treatment. Risk factors related to treatment failure included symptom triad with breathlessness at rest, persistent fever and cough (85% in the treatment failure group versus 74% in the treatment success group, P = 0.034), treatment with invasive mechanical ventilation (67 vs. 19%, P < 0.001), coinfection with CMV (69 vs. 47%, P = 0.035), and bacteremia (59 vs. 10%, P < 0.001). A total of 49 patients received second-line treatment on the basis of TMP/SMX, and 28 (57.1%) of them responded to the treatment. No clinical parameter, including selection of different therapies, was found to be significantly associated with second-line treatment failure. Further, the prognosis of different second-line therapies showed no drug or drug combination strategy superior to others. The primaquine group had lower 90-day mortality rate (45.9%) but showed no statistically significant difference compared with the non-primaquine group (64.6%). The patients in the clindamycin plus primaquine group had the lowest in-hospital mortality rate (22.2%, P = 0.042) among different second-line therapies, although the in-hospital mortality of the primaquine group was not significantly different from that of the non-primaquine group. The differences in 28 day mortality and overall mortality rates were not statistically significant, too.ConclusionCMV infection and bacteremia were risk factors significantly associated with treatment failure of TMP/SMX. The response and survival rates of second-line treatment, including clindamycin, primaquine, and caspofungin, were poor, maybe clindamycin plus primaquine as second line treatment was better than other treatment strategies. These results suggest that clinicians should carefully evaluate whether the treatment of TMP/SMX has failed due to a coinfection rather than hastily changing to a second-line drug when the patient worsens.

Targeting α6GABAA receptors as a novel therapy for schizophrenia: A proof-of-concept preclinical study using various animal models.

GABAA receptors containing α6 subunits (α6GABAARs) in the cerebellum have -been implicated in schizophrenia. It was reported that the GABA synthesizing enzymes were downregulated whereas α6GABAARs were upregulated in postmortem cerebellar tissues of patients with schizophrenia and in a rat model induced by chronic phencyclidine (PCP). We have previously demonstrated that pyrazoloquinolinone Compound 6, an α6GABAAR-highly selective positive allosteric modulator (PAM), can rescue the disrupted prepulse inhibition (PPI) induced by methamphetamine (METH), an animal model mimicking the sensorimotor gating deficit based on the hyper-dopaminergic hypothesis of schizophrenia. Here, we demonstrate that not only Compound 6, but also its structural analogues, LAU463 and LAU159, with similarly high α6GABAAR selectivity and their respective deuterated derivatives (DK-I-56-1, DK-I-58-1 and DK-I-59-1) can rescue METH-induced PPI disruption. Besides, Compound 6 and DK-I-56-I can also rescue the PPI disruption induced by acute administration of PCP, an animal model based on the hypo-glutamatergic hypothesis of schizophrenia. Importantly, Compound 6 and DK-I-56-I, at doses not affecting spontaneous locomotor activity, can also rescue impairments of social interaction and novel object recognition in mice induced by chronic PCP treatments. At similar doses, Compound 6 did not induce sedation but significantly suppressed METH-induced hyperlocomotion. Thus, α6GABAAR-selective PAMs can rescue not only disrupted PPI but also hyperlocomotion, social withdrawal, and cognitive impairment, in both METH- and PCP-induced animal models mimicking schizophrenia, suggesting that they are a potential novel therapy for the three core symptoms, i.e. positive symptoms, negative symptoms, and cognitive impairment, of schizophrenia.

Allosteric Modulation of the Sigma-1 Receptor Elicits Antipsychotic-like Effects.

Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent sigma-1 receptor allosteric modulator, discovered in our laboratory. The present work investigates the potential therapeutic effects of SOMCL-668 on phencyclidine (PCP)-induced schizophrenia-related behavior in mice and further elucidates underlying mechanisms for its antipsychotic-like effects. SOMCL-668 not only attenuated acute PCP-induced hyperactivity and PPI disruption, but also ameliorated social deficits and cognitive impairment induced by chronic PCP treatment. Pretreatment with the selective sigma-1 receptor antagonist BD1047 blocked the effects of SOMCL-668, indicating sigma-1 receptor-mediated responses. This was confirmed using sigma-1 receptor knockout mice, in which SOMCL-668 failed to ameliorate PPI disruption and hyperactivity induced by acute PCP and social deficits and cognitive impairment induced by chronic PCP treatment. Additionally, in vitro SOMCL-668 exerted positive modulation of sigma-1 receptor agonist-induced intrinsic plasticity in brain slices recorded by patch-clamp. Furthermore, in vivo lower dose of SOMCL-668 exerted positive modulation of improvement in social deficits and cognitive impairment induced by the selective sigma-1 agonist PRE084. Also, SOMCL-668 reversed chronic PCP-induced down-regulation in expression of frontal cortical p-AKT/AKT, p-CREB/CREB and BDNF in wide-type but not sigma-1 knockout mice. Moreover, administration of the PI3K/AKT inhibitor LY294002 abolished amelioration by SOMCL-668 of chronic PCP-induced schizophrenia-related behaviors by inhibition of BDNF expression. The present data provide initial, proof-of-concept evidence that allosteric modulation of the sigma-1 receptor may be a novel approach for the treatment of psychotic illness.

Cytotoxic, genotoxic, and oxidative stress-related effects of lysergic acid diethylamide (LSD) and phencyclidine (PCP) in the human neuroblastoma SH-SY5Y cell line

Lysergic acid diethylamide (LSD) is a classic hallucinogen, widely abused for decades, while phencyclidine (PCP) has increased in popularity in recent years, especially among the adolescents. Very little is known about the general toxicity of these compounds, especially about their possible neurotoxic effects at the cell level. The aim of this study was to address these gaps by assessing the toxic effects of 24-hour exposure to LSD and PCP in the concentration range of 0.39–100 μmol/L in the human neuroblastoma SH-SY5Y cell line. After cell viability was established, cells treated with concentrations that reduced their viability up to 30 % were further subjected to the alkaline comet assay and biochemical assays that enable estimation of oxidative stress-related effects. Treatment with LSD at 6.25 μmol/L and with PCP at 3.13 μmol/L resulted with 88.06±2.05 and 84.17±3.19 % of viable cells, respectively, and led to a significant increase in primary DNA damage compared to negative control. LSD also caused a significant increase in malondialdehyde level, reactive oxygen species (ROS) production, and glutathione (GSH) level, PCP significantly increased ROS but lowered GSH compared to control. Treatment with LSD significantly increased the activities of all antioxidant enzymes, while PCP treatment significantly increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) but decreased catalase (CAT) activity compared to control. Our findings suggest that LSD has a greater DNA damaging potential and stronger oxidative activity than PCP in SH-SY5Y cells.

Neonatal NMDA blockade alters the LTP, LTD and cognitive functions in male and female Wistar rats

There is compelling evidence that neonatal blockade of NMDA receptors by phencyclidine (PCP) is associated with cognitive impairment in adulthood but little is known about the effects of early life PCP treatment on synaptic function later in life. Here, we sought to determine whether early life exposure to PCP alters the electrophysiologic function of hippocampal CA1 neurons in adult rats. To this end, male and female Wistar rats received either saline or PCP (10 mg/kg) on postnatal days (PND) 7, 9, and 11, and then underwent separate behavioral and electrophysiology tests in adulthood. Neonatal PCP treatment did not alter basic synaptic transmission and had only a modest effect on frequency following (FF) capacity but significantly decreased the paired-pulse facilitation (PPF) in the Schaffer collateral (SC)–CA1 pathway. We found that PCP treatment significantly attenuated the long-term potentiation (LTP) and long-term depression (LTD) in CA1 neurons accompanied by pronounced alteration in complex response profile in adult rats. The electrophysiology data were comparable in male and female rats and reliably associated with impaired spatial reference and working memories in these animals. Overall, this study suggests that blockade of NMDA receptors during early life deteriorates the short-term and long-term synaptic plasticity and complex response profile of CA1 neurons in adulthood.

EYES DO NOT SEE WHAT MIND DOESN'T SEEK: A PUZZLING CASE OF METHEMOGLOBINEMIA

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Methemoglobinemia must be considered in the differential diagnosis of hypoxia not improving with supplemental oxygen. CASE PRESENTATION: An 84-year-old male patient with a past medical history of Atrial fibrillation, scleritis, hypertension presented with complaints of fever, chills, shortness of breath for 5 days. Medication history included triamterene/hydrochlorothiazide, Amiodarone, warfarin, ezetimibe, prednisone, and methotrexate. On presentation, the patient was saturating 79% on ambient air and was put on Hiflo nasal oxygen, and saturation improved to 95% on Fi02 100% at 35 l/min. The lab was significant for WBC count of 12.1, procalcitonin 1.06, a chest x-ray revealed bilateral opacities left greater than right with air bronchograms. Chest CT done showed bilateral ground-glass opacities with interposed consolidation. Bronchoscopy was deferred due to the clinical condition of the patient The patient was started on cefepime, doxycycline, methylprednisone, primaquine, and clindamycin for empiric treatment of PCP pneumonia with superimposed bacterial pneumonia and was transferred to ICU for hypotension secondary to sepsis. Pt initially improved clinically and Hiflo was weaned to Fi02 of 50% and maintained saturation above 95%. Over the course of 3-4 days after downgrading to the medical floor, the patient's oxygen requirement uptrend, though a repeat CT scan of the chest showed radiological improvement. An ABG with co-oximetry done showed Po2 of 302 mmHg, saturation of 91 % on Fi02 of 100%, and Methemoglobin content of 7.8%. IV methylene blue infusion was given and the patient's respiratory status improved with the Fio2 requirement coming down. Repeat ABG with co-oximetry showed a methemoglobin level of 2.4%. Repeat labs did not show evidence of hemolysis and G6PD levels were normal. The patient's increased susceptibility to methemoglobinemia would have been due to drug interaction as he is on thiazide diuretic and was started on primaquine increasing the oxidative stress coupled with oxidative stress secondary to sepsis. Primaquine was discontinued and started on atovaquone for PCP treatment. The patient continued to improve clinically. DISCUSSION: Methemoglobinemia can occur after exposure to a number of medications, including primaquine, sulfonamides, nitrates, topical anesthetics. Methemoglobin is the oxidized form of Hb, Oxygen does not bind as easily to the heme subunit with the ferric form of iron. The remaining heme sites have increased affinity for oxygen, resulting in decreased ability to release oxygen to tissues, causing left-shift of the oxygen-hemoglobin dissociation curve leading to tissue hypoxia. A clue to diagnosis is the cyanosis-saturation gap. CONCLUSIONS: An obvious mismatch between the PaO2 (which is >>100 mm) versus the pulse oximetry ( typically ~80-90%), known as the PaO2-saturation gap, is a clue to the diagnosis of methemoglobinemia REFERENCE #1: Gibson QH. The reduction of methemoglobin in red blood cells and studies on the cause of idiopathic methemoglobinemia. Biochem J 1948;42: 13-23. REFERENCE #2: Ohashi K, Yukioka H, Hayashi M, Asada A. Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand 1998;42: 713-716. REFERENCE #3: Beutler E. Methemoglobinemia and other causes of cyanosis. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 5th ed. New York: McGraw-Hill; 1994: 654-662. DISCLOSURES: No relevant relationships by Santhosh Bayambe, source=Web Response No relevant relationships by Nadish Garg, source=Web Response No relevant relationships by Killol Patel, source=Web Response No relevant relationships by ARCHANA SREEKANTAN NAIR, source=Web Response

Sustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in mice.

Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown. The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction. Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis. The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP. Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.

Estimation of treatment and prognostic factors of pneumocystis pneumonia in patients with connective tissue diseases

ObjectivesTo investigate short-term prognosis and prognostic factors for connective tissue disease-associated pneumocystis pneumonia (CTD-PCP) using the Japanese nationwide diagnosis procedure combination (DPC) inpatient database.MethodsThe present retrospective cohort study from April...

Phencyclidine-induced cognitive impairments in repeated touchscreen visual reversal learning tests in rats

Reversal learning, a component of executive functioning, is commonly impaired among schizophrenia patients and is lacking effective treatment. N-methyl-ᴅ-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), impair reversal learning of rodents. Touchscreen-based pairwise visual discrimination and reversal test is a translational tool to assess reversal learning in rodents. However, to fully exploit this task in testing of novel compounds, it is necessary to perform several reversal learning experiments with trained animals. Firstly, we assessed whether PCP-induced deficits in visual reversal learning in rats would be detectable with a short (5 sessions) reversal learning phase, and whether the short reversal phases could be repeated with novel stimulus pairs. Secondly, we assessed whether the PCP-induced deficits in reversal learning could be seen upon repeated PCP challenges with the same animals. Finally, we tested the effect of a novel compound, a selective α2C adrenoceptor antagonist, ORM-13070, to reverse PCP-induced cognitive deficits in this model. A 4-day PCP treatment at a dose of 1.5 mg/kg/day impaired early reversal learning in male Lister Hooded rats without inducing non-specific behavioral effects. We repeated the reversal learning experiment four times using different stimulus pairs with the same animals, and the PCP-induced impairment was evident in every single experiment. The α2C adrenoceptor antagonist ameliorated the PCP-induced cognitive deficits. Our results suggest that repeated PCP challenges in the touchscreen set-up induce schizophrenia-like cognitive deficits in visual reversal learning, improve throughput of the test and provide a protocol for testing novel drugs.

Preventive role of regular low-intensity exercise during adolescence in schizophrenia model mice with abnormal behaviors

Schizophrenia is probably ascribed to perinatal neurodevelopmental deficits, and its onset might be affected by environmental factors. Hypofrontality with glutamatergic and dopaminergic neuronal dysfunction are known factors, but a way to mitigate abnormalities remains unfound. An early enriched environment such as a wheel running in rodents may contribute to the prevention, but its clinical applicability is very limited. From our studies, low-intensity exercise training (LET) based on physiological indices, such as lactate threshold, easily translates to humans and positively affects the brains. Hence, LET during adolescence may ameliorate abnormalities in neurodevelopment and prevent the development of schizophrenia. In the current study, LET prevented sensitization to phencyclidine (PCP) treatment, impairment of cognition, and affective behavioral abnormalities in an animal model of schizophrenia induced by prenatal PCP treatment. Further, LET increased dopamine turnover and attenuated the impairment of phosphorylation of ERK1/2 after exposure to a novel object in the prenatal PCP-treated mice. These results suggest that LET during adolescence completely improves schizophrenia-like abnormal behaviors associated with improved glutamate uptake and the dopamine-induced ERK1/2 signaling pathway in the PFC.

P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia.

Background: It has been consistently reported that the deficiency of the adenosine triphosphate (ATP) sensitive purinergic receptor P2X7 (P2X7R) ameliorates symptoms in animal models of brain diseases.Objective: This study aimed to investigate the role of P2X7R in rodent models of acute and subchronic schizophrenia based on phencyclidine (PCP) delivery in animals lacking or overexpressing P2X7R, and to identify the underlying mechanisms involved.Methods: The psychotomimetic effects of acute i.p. PCP administration in C57Bl/6J wild-type, P2X7R knockout (P2rx7−/−) and overexpressing (P2X7-EGFP) young adult mice were quantified. The medial prefrontal cortex (mPFC) of P2rx7−/− and heterozygous P2X7-EGFP acutely treated animals was characterized through immunohistochemical staining. The prefrontal cortices of young adult P2rx7−/− and P2rx7tg/+ mice were examined with tritiated dopamine release experiments and the functional properties of the mPFC pyramidal neurons in layer V from P2rx7−/− mice were assessed by patch-clamp recordings. P2rx7−/− animals were subjected to a 7 days subchronic systemic PCP treatment. The animals working memory performance and PFC cytokine levels were assessed.Results: Our data strengthen the hypothesis that P2X7R modulates schizophrenia-like positive and cognitive symptoms in NMDA receptor antagonist models in a receptor expression level-dependent manner. P2X7R expression leads to higher medial PFC susceptibility to PCP-induced circuit hyperactivity. The mPFC of P2X7R knockout animals displayed distinct alterations in the neuronal activation pattern, microglial organization, specifically around hyperactive neurons, and were associated with lower intrinsic excitability of mPFC neurons.Conclusions: P2X7R expression exacerbated PCP-related effects in C57Bl/6J mice. Our findings suggest a pleiotropic role of P2X7R in the mPFC, consistent with the observed behavioral phenotype, regulating basal dopamine concentration, layer-specific neuronal activation, intrinsic excitability of neurons in the mPFC, and the interaction of microglia with hyperactive neurons. Direct measurements of P2X7R activity concerning microglial ramifications and dynamics could help to further elucidate the molecular mechanisms involved.

MULTIPLE CHEST CT FINDINGS IN A POST-TRANSPLANT PATIENT

SESSION TITLE: Fellows Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pulmonary complications are common in hematopoietic stem cell transplantation recipients. Late complications occur more than 100 days after HSCT. During this time frame noninfectious causes are more common than infectious complications. CASE PRESENTATION: 57 y/o Panamanian female never-smoker with history of Common Variable Immune Deficiency, and recurrent non-Hodgkin lymphoma status post-chemotherapy and autologous stem cell transplant 2015 followed by allogeneic bone marrow transplant in 2017 presented with dyspnea and non-productive cough. She had presumed pneumonia two months prior but denied infectious or constitutional symptoms. Initial CT chest demonstrated diffuse bilateral GGOs and PFTs had a restrictive pattern with decreased DLCO. PET CT lacked findings suggesting recurrent lymphoma and connective tissue disease. Initial differential diagnosis included infection, organizing pneumonia, and eosinophilic lung disease. The patient underwent bronchoscopy with bronchoalveolar lavage (negative cultures and cytology). Prednisone therapy for presumed cryptogenic organizing pneumonia was initiated. Shortly after she developed worsening dyspnea, tachycardia and new exertional hypoxia and was found to have pneumomediastinum. Bronchoscopy was repeated and again cultures and cytology negative and TTE demonstrated only mild diastolic dysfunction. Without an alternative diagnosis treatment for PCP was provided for 21 days and 50 mg prednisone continued. At completion of treatment there was no improvement on her CT. A surgical lung biopsy was performed, and multidisciplinary radiologic-pathologic diagnosis of pleuroparenchymal fibroelastosis (PPFE) was rendered. DISCUSSION: Predominant findings such as the GGO and pneumomediastinum, can overshadow less conspicuous features such as PPFE which can be confounding. PPFE is a rare disorder usually occurring between age 40 to 70. Numerous potential risk factors for the development of PPFE have been described most common of which are bone marrow, hematopoietic stem cell and lung transplant along with CTD, familial, post infectious, and idiopathic. Clinical features include exertional dyspnea, insidious dry cough, and weight loss. Typically a restrictive ventilatory defect and reduced DLCO are noted. In 2012 Reddy and colleagues proposed diagnostic criteria integrating histopathologic and radiographic features included bilateral upper zone pleural thickening with associated subpleural fibrosis on CT and intraalveolar fibrosis and elastosis on histopathological exam. Pneumothorax and pneumomediastinum are frequent complications of PPFE. CONCLUSIONS: PPFE is a rare condition but should be considered in patients a history of transplant. Treatment remains a clinical challenge and lung transplant is an option. In our patient, possible contributing factors for the development of PPFE were recurrent pulmonary infection and late-onset complication following HSCT. Reference #1: Pena E, Souza CA, Escuissato DL, et al. Noninfectious pulmonary complications after hematopoietic stem cell transplantation: practical approach to imaging diagnosis. Radiographics 2014; 34: 663–683 Reference #2: Chua, F, Desai, SR, Nicholson, AG, et al. Pleuroparenchymal fibroelastosis: a review of clinical, radiological and pathological characteristics. Ann Am Thorac Soc 2019; 16: 1351–1359 Reference #3: Reddy TL, Tominaga M, Hansell DM, von der Thusen J Jr, Rassl D, Parfrey H, Guy S, Twentyman O, Rice A, Maher TM, et al. Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. Eur Respir J 2012;40:377–385 DISCLOSURES: No relevant relationships by Sally Delvecchio, source=Web Response No relevant relationships by Teri Franks, source=Web Response No relevant relationships by Jeffrey Galvin, source=Web Response No relevant relationships by Michael Luca, source=Web Response

PNEUMONIA IN AN IMMUNOCOMPROMISED PATIENT: DIAGNOSTIC AND THERAPEUTIC CHALLENGES

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pneumocystis jirovecii can cause life-threatening pneumonia in immunocompromised patients. A significant number of HIV-positive patients are still affected, including those not yet diagnosed with HIV and those not taking antiretroviral therapy or prophylaxis. Diagnosis and treatment often present challenges. CASE PRESENTATION: A 39 year-old man presented with several weeks of worsening shortness of breath and pleuritic chest pain. He was mildly tachypneic, and oxygen saturation decreased to 80% upon ambulation. He was found to be HIV positive with a CD4 count of 9. Serum beta-D-glucan and lactate dehydrogenase levels were elevated. PaO2 was 64 mmHg with an alveolar-arterial gradient of 35 mm Hg. Calcofluor white (CW) stain of induced sputum was negative. Chest radiography showed increased perihilar interstitial markings. Computed tomography showed septal thickening with scattered ground glass opacities. Bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL CW stain and Pneumocystis polymerase chain reaction (PCR) were positive. He was treated with trimethoprim-sulfamethoxazole (TMP-SMX) and steroids and developed hyperkalemia. He was switched to primaquine and clindamycin with a plan for 21 days of therapy. DISCUSSION: Traditional diagnostic testing for PCP relied on staining and visualization of organisms in BAL fluid. The sensitivity of non-immunofluorescent stains such as CW ranges from 31-97% depending on sample quality and stain interpretation. Many centers have started to utilize sputum staining for diagnosis of PCP, but as our case demonstrates, this is not adequate to rule out PCP in patients for whom there is high clinical suspicion. BAL fluid has greater sensitivity than sputum testing, and bronchoscopy after negative sputum testing yields the diagnosis in 51% of cases. PCR on BAL fluid is the best test for detection with 97-99% sensitivity. Unfortunately, no PCR-based diagnostic methods have been approved to date by the FDA. TMP-SMX remains the first line treatment for PCP. Its side effect profile includes hyperkalemia, hypersensitivity reactions, hepatitis, myelosuppression, and interstitial nephritis. Because toxicity necessitates a change in therapy in up to 17% of patients, it is crucial to be familiar with second line treatments such as pentamidine, atovaquone, and clindamycin-primaquine. Clindamycin-primaquine was chosen for our patient, as it has been shown to lead to higher clinical response and survival rates than pentamidine. Corticosteroids should be used as an adjunct therapy if PaO2 is under 70 mmHg on room air or the alveolar-arterial gradient is greater than 35, as this can improve outcomes in HIV-positive patients. CONCLUSIONS: Practitioners should not rely on negative sputum testing if clinical suspicion for PCP is high. Patients should be monitored for side effects of TMP-SMX and switched to an alternative regimen if necessary. Reference #1: Bateman ME, Oladele R, Kolls JK. Diagnosing Pneumocystis jirovecii Pneumonia: A Review of Current Methods and Novel Approaches. Medical Mycology. 2020. PMID: 32400869. Doi: 10.1093/mmy/myaa024. Reference #2: Cruciani M, Marcati P, Malena M, et al. Meta-analysis of diagnostic procedures for Pneumocystis carinii pneumonia in HIV-1 infected patients. European Respiratory Journal. 2002; 20: 982-989. Reference #3: Huang L, Hecht FM, Stansell JD, et al. Suspected pneumocystis carinii pneumonia with a negative induced sputum examination. Is early bronchoscopy useful? American Journal of Respiratory and Critical Care Medicine. 1995; 151: 1866-1871. DISCLOSURES: No relevant relationships by Marjorie Bateman, source=Web Response No relevant relationships by JENNIFER CHIURCO, source=Web Response

A CONFUSING CASE OF PNEUMONIA IN A PATIENT WITH HUMAN IMMUNODEFICIENCY VIRUS

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: The incidence of acquired immunodeficiency syndrome (AIDS) related opportunistic infections has declined dramatically following the introduction of potent antiretroviral therapy. However, pulmonary infections remain a significant cause of morbidity and mortality (1). The spectrum of pulmonary disease that can affect patients with human immunodeficiency virus (HIV) is wide and includes opportunistic infection with many bacterial, fungal, viral, and parasitic organisms (2). Herein, we present a rare case of pneumonia caused by four different pathogens: Strongyloides Stercoralis, Pneumocystis Jirovecii (PCP), Cytomegalovirus (CMV) and Pseudomonas Aeruginosa. CASE PRESENTATION: A 65-year-old female from Mexico with a past medical history of HIV presents to the emergency department with subacute dyspnea, mild hemoptysis, melena, and fatigue. She was non-compliant with her anti-retroviral therapy. Her CD4 count was <20 cells/uL with a HIV PCR of 1,690,000 copies/mL. CBC demonstrated normocytic anemia (hemoglobin: 6.0 g/dl); hemolysis was excluded. Her Pa02 was 60 mmHg on room air. A computed tomography (CT) scan of the chest with contrast (image) revealed diffuse bilateral ground-glass opacities with diffuse interlobular septal thickening. Severe enteritis and colitis were seen on the CT abdomen/pelvis with contrast. The patient was empirically started on levofloxacin, metronidazole, intravenous (IV) trimethoprim-sulfamethoxazole and prednisone. Sputum cultures were positive for pan sensitive Pseudomonas Aeruginosa. Bronchoalveolar lavage (BAL), upper and lower endoscopy were performed. Blood and BAL CMV PCR were positive. She was subsequently started on IV ganciclovir. BAL PCP PCR was high. Several days later, numerous Strongyloides Stercoralis larvae were seen in the BAL and on the duodenal biopsy. Daily ivermectin was initiated. The patient progressed to septic shock requiring IV norepinephrine and her oxygenation worsened. The patient refused escalation of care and decided to proceed with comfort measures. The patient passed away within a few hours. DISCUSSION: Prior to the era of potent antiretroviral therapy, parasitic pulmonary infections were more commonly seen than they are today (2). Immunocompromised patients are at high risk for systemic strongyloidiasis which presents as either disseminated strongyloidiasis or hyper infection syndrome (3). Aside from HIV, our patient was empirically started on prednisone for PCP treatment which might have contributed to worsening systemic strongyloidiasis and therefore worsening clinical status. For severe disease, patients should be started on daily ivermectin along with empiric antibiotic therapy with activity against gram-negative bacteria. CONCLUSIONS: We describe a rare case of HIV related pneumonia caused by four different pathogens. Reference #1: Boyton RJ. Infectious lung complications in patients with HIV/AIDS. Curr Opin Pulm Med. 2005 May;11(3):203-7. Reference #2: Skalski JH, Limper AH. Fungal, Viral, and Parasitic Pneumonias Associated with Human Immunodeficiency Virus. Semin Respir Crit Care Med. 2016;37(2):257. Reference #3: Celedon JC, Mathur-Wagh U, Fox J, Garcia R, Wiest PM. Systemic strongyloidiasis in patients infected with the human immunodeficiency virus. A report of 3 cases and review of the literature. Medicine (Baltimore). 1994;73(5):256 DISCLOSURES: No relevant relationships by Ahmad Al-Shyoukh, source=Web Response No relevant relationships by Laith Derbas, source=Web Response No relevant relationships by Ashraf Gohar, source=Web Response No relevant relationships by Raed Qarajeh, source=Web Response No relevant relationships by Moustafa Younis, source=Web Response

Implications of carbohydrate sources and rate of body weight gain on puberty in ewe lambs in tropical climate conditions.

The objectives were to evaluate the effects of two non-fibrous carbohydrate sources and the rate of body weight gain on puberty status in ewe lambs. Sixty ewe lambs (½ Dorper × ½ Santa Ines) with an initial body weight of 25.1 ± 4.1kg and 102.8 ± 1.5days old were distributed in a randomized complete block design with 10 blocks and 3 treatments. The trial lasted 119days, in which performance was evaluated on days 28, 56, 84, and 119, and puberty status was every week evaluated by progesterone concentration. The treatments were characterized by the inclusion of different carbohydrate sources in the diets in order for ewe lambs to reach different rates of body weight gain: CORN, total diet containing 46% of corn (% DM); PCP, total diet containing 46% of pelleted citrus pulp (% DM); and HAY, total diet containing 80% of coastcross hay (% DM). The CORN- and PCP-based diets were formulated for an average daily gain (ADG) of 0.200kg/day and a HAY-based diet for an ADG of 0.100kg/day. There was an interaction between treatments and experimental periods for dry matter intake (DMI) (P < 0.01), in which lambs in the CORN treatment presented DMI similar to PCP in the first and second periods, but lambs from the PCP treatment presented lower DMI than the CORN treatment in subsequent periods. In all periods, the body weight, average daily gain, and feed efficiency of CORN lambs were similar to PCP lambs, but higher than HAY lambs. The age at puberty was not affected by treatments; however, lambs fed with non-fibrous carbohydrate sources reached puberty heavier (P < 0.0001) than lambs from the HAY treatment. Despite the high increase in body weight for lambs fed with non-fibrous carbohydrate sources, it did not affect the age of puberty.

Serum-based diagnosis of Pneumocystis pneumonia by detection of Pneumocystis jirovecii DNA and 1,3-\u03b2-D-glucan in HIV-infected patients: a retrospective case control study

BackgroundPneumocystis jirovecii pneumonia (PCP) is one of the most common HIV-related opportunistic infections. The diagnosis of PCP is based on analyses from respiratory tract specimens which may require the invasive procedure of a diagnostic bronchoscopy. The objective of this study was to evaluate the diagnostic potential of Pneumocystis jirovecii PCR in serum combined with the 1,3-β-D-glucan (betaglucan) test for the diagnosis of PCP in HIV-infected patients.MethodsThis was a retrospective case-control study including serum samples from 26 HIV-infected patients with PCP collected within 5 days prior to the start of PCP treatment, 21 HIV-infected control subjects matched by blood CD4+ cell counts, and 18 blood donors. The serum samples were analyzed for Pneumocystis jirovecii PCR and betaglucan. The reference standard for PCP was based on previously described microbiological and clinical criteria.ResultsAll patients with PCP had detectabe Pneumocystis jirovecii DNA in serum yielding a sensitivity for the Pneumocystis jirovecii PCR assay in serum of 100%. All blood donors had negative Pneumocystis PCR in serum. The specificity when testing HIV-infected patients was 71%, but with a PCR Cycle threshold (Ct) value of 34 as cut-off the specificity was 90%. At a putative pretest probaility of 20%, the negative and positive predictive value for the Pneumocystis PCR assay in serum was 0.99 and 0.71, respectively. Betaglucan with cut-off level 200 pg/ml combined with a positive Pneumocystis jirovecii PCR result had sensitivity and specificity of 92 and 90%, respectively. The concentration of Pneumocystis jirovecii DNA in serum samples, expressed by the PCR Ct values, correlated inversely to the betaglucan levels in serum.ConclusionIn this case-control study including 70% of all HIV-infected patients with PCP treated at Sahlgrenska University Hospital during a time period of 13 years, Pneumocystis PCR analysis on serum samples had a very high sensitivity and negative predictive value for the diagnosis of PCP in HIV-infected patients. A serum-based diagnostic procedure either based on Pneumocystis jirovecii PCR alone or in combination with betaglucan analysis may thus be feasible and would facilitate the care of HIV-infected patients with suspected PCP.