Novel psychoactive substances remain the popular recreational drugs of use over the years. They continue to bypass government restrictions due to their synthesis and modifications. Recent additions ...to the lists are the 4‐F‐PCP and 4‐Keto‐PCP, analogs of the drug phencyclidine (PCP) known to induce adverse effects and abuse potential. However, studies on the abuse potential of 4‐F‐PCP and 4‐Keto‐PCP remain scarce. The rewarding and reinforcing effects of the drugs were assessed using conditioned place preference (CPP), self‐administration, and locomotor sensitization tests. Dopamine (DA) receptor antagonists (SCH23390 and haloperidol) were administered during CPP to evaluate the involvement of the mesolimbic dopaminergic system. DA‐related protein expression in the nucleus accumbens (NAcc) and ventral tegmental area (VTA) was measured. Additionally, phosphorylated cyclic‐adenosine monophosphate‐activated protein (AMP) response element‐binding (p‐CREB) protein, deltaFosB (∆FosB), and brain‐derived neurotrophic factor (BDNF) protein levels in the NAcc were measured to assess the addiction neural plasticity effect of the drugs. Both 4‐F‐PCP and 4‐Keto‐PCP‐induced CPP and self‐administration; however, only 4‐F‐PCP elicited locomotor sensitization. Treatment with DA receptor antagonists (SH23390 and haloperidol) inhibited the 4‐F‐ and 4‐Keto‐induced CPP. Both substances altered the levels of DA receptor D1 (DRD1), thyroxine hydroxylase (TH), DA receptor D2 (DRD2), p‐CREB, ∆FosB, and BDNF. The results suggest that 4‐F‐PCP and 4‐Keto‐PCP may induce abuse potential in rodents via alterations in dopaminergic system accompanied by addiction neural plasticity.
Pre‐treatment with SCH23390 (DRD1 antagonist) and haloperidol (DRD2 antagonist) showed that 4‐F‐PCP and 4‐Keto‐PCP may alter the dopaminergic system as seen in drugs with abused potential properties.
Pneumocystis
pneumonia (PCP) is an opportunistic infection that commonly occurs in immunocompromised individuals. A definite diagnosis of PCP can be made only when the organism is identified in a ...respiratory specimen. It remains unclear whether qPCR can differentiate patients with PCP from those with
Pneumocystis jirovecii
colonization. In this study, we retrospectively collected data from HIV and non-HIV patients during 2013–2019. A diagnosis of definite, probable PCP, or PCP excluded was made based on clinical criteria, radiological reports, and three standard laboratory staining methods with blinding to qPCR data. Data from qPCR that was performed to determine the fungal burden (DNA copies/μl) in the BAL specimens of 69 HIV and 286 non-HIV patients were then obtained and reviewed. Receiver Operating Characteristic (ROC) curve analysis was performed to determine the upper and lower cut-off values for PCP diagnosis in HIV and non-HIV groups. In the non-HIV group, the lower cut-off value of 1,480 DNA copies/μl yielded a sensitivity of 100% (95% confidence interval CI, 91.0–100), specificity of 72.9% (95% CI, 64.0–80.7), a positive predictive value (PPV) of 54.9% (95% CI, 47.6–62.1), and a negative predictive value (NPV) of 100% with Youden index of 0.73 for PCP diagnosis. In this group, the upper cut-off value of 9,655 DNA copies/μl showed the sensitivity of 100% (95% CI, 91.0–100) and specificity of 95.8% (95% CI, 90.4–98.6) with PPV of 88.6% (95% CI, 76.8–94.8) and a NPV of 100% with Youden index of 0.96 for PCP diagnosis. Regarding the HIV group, the lower cut-off value of 1,480 DNA copies/μl showed the sensitivity of 100% (95% CI, 92.5–100%) and specificity of 91.7% (95% CI, 61.5–99.8) with PPV of 97.9% (95% CI, 87.8–99.7) and a NPV of 100% with Youden index of 0.92 for PCP diagnosis. The sensitivity and specificity of the upper cut-off value of 12,718 DNA copies/μl in this group were 97.9% (95%CI, 88.7–100) and 100% (95%CI, 73.5–100), respectively. The values above the upper cut-off point had a PPV of 100% (95% CI, N/A) and a NPV of 92.3% (95% CI, 63.3–98.8) with Youden index of 0.98 for PCP diagnosis in the HIV group.
In their last review, the IUIS reported 40 inborn errors of immunity (IEI) leading to combined immunodeficiency (CID). Yet, the genetic cause of CID in a sizeable percentage of patients remains ...unknown. We describe seven patients with CID from four continents with similar clinical presentations characterized by severe viral and recurrent respiratory infections, notably by Pneumocystis jirovecii. Two of the patients also suffered from mycobacterial disease. All these seven patients carry the heterozygous mutation T95R in the DNA binding domain of the interferon regulatory factor 4 (IRF4). Leveraging state-of-the-art transcriptomic, molecular, computational, and gene editing technologies, we discovered that IRF4-T95R does not fit into any single category of the Muller morphs but in three of them simultaneously. In fact, we showed that IRF4-T95R causes a unique combination of (i) gain-of-function by binding DNA with higher affinity than IRF4-WT; (ii) loss-of-function since IRF4-T95R fails to induce canonical IRF4 regulated genes, and; (iii) neomorphic functions by inducing the transcription of genes that IRF4-WT does not. These alterations in the transcriptional programming caused by the mutation lead to cellular and humoral immunological abnormalities. Patients’ B cells displayed impaired maturation, defective plasma cell differentiation, and isotype switching, all which resulted in agammaglobulinemia. Their T cells, despite proliferating normally, showed a decreased production of pro-inflammatory cytokines and a reduced capacity to differentiate into TH17 and TFH. Two different knock-in mouse models recapitulated the patients’ phenotypes. Overall, our data show that autosomal dominant IRF4-T95R is a new genetic cause of CID and defines a novel multimorphic molecular mechanism of a disease characterized by gain, loss, and new functions of IRF4.
Major depressive disorder is a leading cause of disability in more than 280 million people worldwide. Monoamine-based antidepressants are currently used to treat depression, but delays in treatment ...effects and lack of responses are major reasons for the need to develop faster and more efficient antidepressants. Studies show that ketamine (KET), a PCP analog, produces antidepressant effects within a few hours of administration that lasts up to a week. However, the use of KET has raised concerns about side effects, as well as the risk of abuse. 4 -F-PCP analog is a novel PCP analog that is also an NMDA receptor antagonist, structurally similar to KET, and might potentially elicit similar antidepressant effects, however, there has been no study on this subject yet. Herein, we investigate whether 4-F-PCP displays antidepressant effects and explored their potential therapeutic mechanisms. 4-F-PCP at 3 and 10 mg/kg doses showed antidepressant-like effects and repeated treatments maintained its effects. Furthermore, treatment with 4-F-PCP rescued the decreased expression of proteins most likely involved in depression and synaptic plasticity. Changes in the excitatory amino acid transporters (EAAT2, EAAT3, EAAT4) were also seen following drug treatment. Lastly, we assessed the possible side effects of 4-F-PCP after long-term treatment (up to 21 days). Results show that 4-F-PCP at 3 mg/kg dose did not alter the cognitive function of mice. Overall, current findings provide significant implications for future research not only with PCP analogs but also on the next generation of different types of antidepressants.
A high-valent, rhenium(V) oxo complex (PCP)ReOCl2 (1, where PCP = bis(2,6-di-tert-butylphosphinomethyl)phenyl), undergoes a deprotonation and "dearomatization" upon treatment with LiN(SiMe3)2 to ...furnish (P*CP)ReOCl (2a) in which Re is bound to a new dianionic P*CP ligand. 2a was studied spectroscopically, structurally, and computationally and was determined to have non-negligible Re=C multiple bond character, leading to its formulation as a novel pseudo-carbenoid species. Reaction of 2a or its iodo analog (P*CP)ReOI (2b) with CO2 provided access to (PCP)ReOX(CO2) (X = Cl or I, 3a/b), the product of 1,3-cycloaddition and C-C bond formation.
Ataxia-pancytopenia syndrome (ATXPC), a rare autosomal dominant disorder caused by pathogenic variants in the SAMD9L gene, is characterized by variable onset and severity of cerebellar ataxia, ...hematologic cytopenias, and immunodeficiency of myeloid, B-, and NK-cells. ATXPC has been associated with viral and bacterial infections, but no cases of opportunistic PJP have been reported.
At 6 weeks of age, the patient was admitted to the hospital for acute hypoxemic respiratory failure due to rhino/enterovirus bronchiolitis, requiring supplemental oxygen. The increased oxygen requirement later led to intubation. A chest x-ray showed diffuse bilateral opacities concerning for pediatric acute respiratory distress syndrome (PARDS). Bronchoalveolar lavage and silver stain revealed organisms morphologically suggestive of Pneumocystis jirovecii pneumonia (PJP), which was confirmed with a positive serum beta-glucan. Based on the diagnosis of PJP, the patient was started on steroids and Bactrim. Immunology was consulted for further evaluation for possible underlying immunodeficiency. The patient had a normal newborn screening. HIV PCR was negative. Repeated TRECs, CD3+, CD8+, CD19+, and immunoglobulin levels (IgG, IgE) were within normal limits, but modest reduction of CD45 RA/RO ratio and IgA were observed. Additionally, natural killer cell function was low. T-cell proliferation to mitogens were normal, but significantly decreased to candida and tetanus antigens. A significant reduction in the expression of HLA-ABC and HLA-DR was observed in the lymphocytes and monocytes of the patient compared to the control. Interestingly, HLA-DR expression on monocytes was particularly affected. A next-generation sequencing of primary immunodeficiency genes identified likely pathogenic, maternally inherited variants: a heterozygous SAMD9L variant (ataxia-pancytopenia syndrome) and NLRP12 variant (familial cold autoinflammatory syndrome 2).
ATXPC has been associated with variable cellular immunodeficiencies. While prior studies have reported recurrent bacterial and viral infections in ATXPC patients, this case is the first to document a PJP opportunistic infection in an infant. It is possible that the NLRP12 variant found in this patient could have also contributed to this clinical presentation. Early diagnosis of ATXPC through clinical recognition and genetic testing may improve prognosis.
Reconstitution of the 16
kDa N-terminal domain of the peridinin–chlorophyll–protein, N-PCP, with mixtures of chlorophyll
a (Chl
a) and Chl
b, resulted in 32
kDa complexes containing two pigment ...clusters, each bound to one N-PCP. Besides homo-chlorophyllous complexes, hetero-chlorophyllous ones were obtained that contain Chl
a in one pigment cluster, and Chl
b in the other. Binding of Chl
b is stronger than that of the native pigment, Chl
a. Energy transfer from Chl
b to Chl
a is efficient, but there are only weak interactions between the two pigments. Individual homo- and hetero-chlorophyllous complexes were investigated by single molecule spectroscopy using excitation into the peridinin absorption band and scanning of the Chl fluorescence, the latter show frequently well resolved emissions of the two pigments.
En 1992, fue detenida la cúpula del Partido Comunista del Perú-Sendero Luminoso (PCP-SL). Un año después, el líder de la organización subversiva anunciaba la renuncia a la violencia y mandaba ...delegados a las cárceles para convencer a sus principales cuadros de aceptar la decisión tomada. A partir de entonces, la dirección del PCP-SL en la cárcel articuló un nuevo discurso con la finalidad de fomentar una memoria que dé a conocer su versión de los hechos y que impulse su participación en la política legal. A lo largo del presente artículo demostraremos que la retórica de una parte de los exmiembros del PCP-SL se amolda a los lineamientos de la IV Etapa (de lucha política sin armas), y se propulsa a partir de la categoría de víctima, lo que evidencia el cambio en la autodefinición del subversivo, que pasa de ser un «militante» a ser una «víctima» a la cual se le vulneran sus derechos humanos. Con este objetivo, nos valdremos del análisis del discurso y del método cualitativo para interpretar las entrevistas semiestructuradas realizadas a cuatro ex-presos del PCP-SL, así como los testimonios recogidos por la Comisión de la Verdad y la Reconciliación en las cárceles.
Late-onset pneumocystis pneumonia (PCP) occurs beyond the first year after transplantation. PCP is associated with significant graft loss. Cytomegalovirus infection (CMV) and rejection are ...independent predictors of PCP. Targeted PCP prophylaxis after CMV infection or rejection may reduce the risk.
Abstract
Background
Pneumocystis pneumonia (PCP) is associated with morbidity and mortality in solid organ transplant (SOT) recipients. In this case-control study, we determined the association between posttransplant PCP and 3 variables: cytomegalovirus (CMV) infection, allograft rejection, and prophylaxis.
Methods
Eight transplant centers participated. For each case (SOT recipient with PCP), 3–5 controls (SOT recipients without PCP) were included. Controls were matched to the cases based on transplant center, type of allograft, and date of transplantation (±6 months).
Results
We enrolled 53 cases and 209 controls. Transplant types included kidney (n = 198), heart (n = 30), liver (n = 15), kidney-pancreas (n = 14), and lung (n = 5). PCP occurred beyond 12 months after transplantation in 43 (81.1%) cases. Thirty-four cases (64.1%) required admission to the intensive care unit, and 28 (52.8%) had mechanical ventilation. Allograft failure occurred in 20 (37.7%) cases, and 14 (26.9%) died. No patient developed PCP prophylaxis breakthrough. The proportion of female sex (P = .009), kidney dysfunction (P = .001), cardiac diseases (P = .005), diabetes mellitus (P = .03), allograft rejection (P = .001), CMV infection (P = .001), and severe lymphopenia (P = .001) were significantly higher in cases. In the logistic regression model, CMV infection (adjusted odds ratio aOR, 4.6 95% confidence interval {CI}, 2.0–10.5) and allograft rejection (aOR, 3.0 95% CI, 1.5–6.1) significantly increased the likelihood of PCP.
Conclusions
PCP was mostly a late-onset disease occurring after complete course of prophylaxis, particularly among patients with CMV infection or allograft rejection. PCP is associated with significant allograft loss. Extended prophylaxis targeting recipients with allograft rejection or CMV infection may reduce the risk of PCP.
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