Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. ...Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact.
We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the "episignature" associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression.
We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches.
Salmonella enterica serovar Typhimurium (S. Typhimurium) es una bacteria Gram negativo y un patógeno gastrointestinal de importancia mundial, ya que es uno de los principales agentes causantes de ...intoxicación alimentaria y de enfermedades invasivas no tifoideas, principalmente en niños. S. Typhimurium presenta varios factores de virulencia, algunos de ellos le permiten colonizar la barrera epitelial y sobrevivir en el espacio intracelular de células fagocíticas, tales como macrófagos y células dendríticas. Una de las células inmunes más importantes en el control del crecimiento y la diseminación de las bacterias son los neutrófilos, los cuales presentan diferentes mecanismos antimicrobianos tales como la fagocitosis, producción de especies reactivas de oxígeno (ROS), degranulación de componentes citotóxicos, y la liberación trampas extracelulares derivadas de neutrófilos (NETs). Además de este rol inflamatorio, se les ha atribuido un rol modulador debido a la producción de interleuquina 10 (IL-10). Sin embargo, no se conoce bien cuál es el rol que cumplen estas células en una infección causada por esta bacteria y si alguno de sus factores de virulencia modula la respuesta de estas células y le permiten a la bacteria sobrevivir en el espacio intracelular y/o secretar IL-10, con el fin de favorecer la diseminación. En este contexto, el presente trabajo evaluó el rol de los neutrófilos frente a una infección causada por S. Typhimurium. Para esto, se purificaron neutrófilos (Ly6G+) derivados de médula ósea de ratón y se evaluó la respuesta efectora midiendo la producción de ROS, la liberación de NETs y la supervivencia bacteriana durante el proceso de infección de los neutrófilos. Como respuesta antiinflamatoria se cuantificó la liberación de IL-10 en el sobrenadante de las células infectadas a diferentes tiempos. Nuestros resultados sugieren que: 1. S. Typhimurium infecta y sobrevive en el espacio intracelular de los neutrófilos a las 24h post infección. 2. La infección causada por S. Typhimurium induce la liberación de NETs 3h post infección. 3. La infección causada por S. Typhimurium induce la producción de IL-10 a las 24h post infección. 4. La respuesta inmune de los neutrófilos frente a una infección causada por S. Typhimurium depende del sexo del animal. En resumen, nuestros resultados sugieren que S. Typhimurium induce una respuesta antimicrobiana considerando la liberación de NETs y la inducción de ROS intracelular. Sin embargo, es posible que la bacteria module la respuesta inmune de estas células debido a la producción temprana de IL-10, así como las diferencias observadas en la internalización de la bacteria, lo cual podría depender de los genes codificados en la Isla de patogenicidad 1 de S. Typhimurium (SPI-1).
An important virulence trait of Salmonella enterica serovar Typhimurium (S. Typhimurium) is the ability to avoid the host immune response, generating systemic and persistent infections. Host cells ...play a crucial role in bacterial clearance by expressing the enzyme heme oxygenase 1 (Hmox1), which catalyzes the degradation of heme groups into Fesup.2+, biliverdin, and carbon monoxide (CO). The role of Hmox1 activity during S. Typhimurium infection is not clear and previous studies have shown contradictory results. We evaluated the effect of pharmacologic modulation of Hmox1 in a mouse model of acute and persistent S. Typhimurium infection by administering the Hmox1 activity inductor cobalt protoporphyrin-IX (CoPP) or inhibitor tin protoporphyrin-IX (SnPP) before infection. To evaluate the molecular mechanism involved, we measured the colocalization of S. Typhimurium and autophagosome and lysosomal markers in macrophages. Administering CoPP reduced the bacterial burden in organs of mice 5 days post-infection, while SnPP-treated mice showed bacterial loads similar to vehicle-treated mice. Furthermore, CoPP reduced bacterial loads when administered after infection in macrophages in vitro and in a persistent infection model of S. Typhimurium in vivo, while tin protoporphyrin-IX (SnPP) treatment resulted in a bacterial burden similar to vehicle-treated controls. However, we did not observe significant differences in co-localization of green fluorescent protein (GFP)-labeled S. Typhimurium with the autophagic vesicles marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the lysosomal marker lysosomal-associated membrane protein 1 (LAMP-1) in macrophages treated with CoPP. Our results suggest that CoPP can enhance antimicrobial activity in response to Salmonella infection, reducing bacterial dissemination and persistence in mice, in a CO and autophagy- independent manner.
The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in ...the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster.
During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT.
Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4+ T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4+ T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found.
Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4+T cell response may confer protection against the Omicron variant.
The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • Interleukin 10 production by innate immune cells is highly regulated by transcription factors and epigenetic and post-transcriptional regulatory mechanisms, ensuring a balanced ...production during a bacterial infection. • During infections with extracellular or highly inflammatory bacterial pathogens, IL-10 production facilitates host survival and the absence of this cytokine increase host death rate. • During infections with intracellular or low inflammatory bacterial pathogens, IL-10 production facilitates bacterial dissemination through the bloodstream, increasing host death rate. • Predicting the effect of the presence/absence of IL-10 during bacterial infections could facilitate the treatment of both local and invasive infections and could lead to the development of new drugs and therapies to treat these infections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Composite lymphoma (CL) is composed of 2 or more morphologically and immunophenotypically distinct lymphomas in a single anatomical site. Here we report a unique CL of the upper respiratory ...tract in an elderly male patient. Morphologically, the lymphoma was composed of 2 distinct and well-demarcated areas consisting of monotonous small to medium-sized lymphocytes and sheets of mature-appearing plasma cells. Immunophenotyping by both flow cytometry and immunohistochemistry revealed that the small to medium-sized lymphocytes were composed of 2 distinct subpopulations sharing a CD5+ /CD19+ /CD20+ /CD22+ /CD23− /FMC-7(+)/cyclin D1(+) immunophenotype but with different immunoglobulin (Ig) light and heavy chain expression, consistent with 2 immunophenotypically distinct mantle cell lymphomas (MCLs); the plasma cells were composed of CD38(bright +)/CD138+ /IgG κ -restricted plasma cells, consistent with a plasmacytoma. Fluorescence in situ hybridization showed the t(11;14) translocation present in the lymphocyte region but absent in the plasma cell area. Ig heavy chain gene rearrangement studies on manually dissected populations showed 2 distinct patterns for the MCL and plasmacytoma. To our knowledge, this is the first report of a 3-way CL consisting of 2 immunophenotypically distinct MCLs and a plasmacytoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
After pediatric cardiosurgical interventions, postoperative delirium can occur, which can be associated with undesirable consequences during and after the hospital stay. It is therefore important to ...avoid any factors causing delirium as far as possible. Electroencephalogram (EEG) monitoring can be used during anesthesia to individually adjust dosages of hypnotically acting drugs. It is necessary to gain knowledge about the relationship between intraoperative EEG and postoperative delirium in children.
In a dataset comprising 89 children (53 male, 36 female; median age: 0.99 (interquartile range: 0.51, 4.89) years) undergoing cardiac surgery involving use of a heart-lung machine, relationships between depth of anesthesia as measured by EEG (EEG index: Narcotrend Index (NI)), sevoflurane dosage, and body temperature were analyzed. A Cornell Assessment of Pediatric Delirium (CAP-D) score ≥ 9 indicated delirium.
The EEG could be used in patients of all age groups for patient monitoring during anesthesia. In the context of induced hypothermia, EEG monitoring supported individually adjusted sevoflurane dosing. The NI was significantly correlated with the body temperature; decreasing temperature was accompanied by a decreasing NI. A CAP-D score ≥ 9 was documented in 61 patients (68.5%); 28 patients (31.5%) had a CAP-D < 9. Delirious patients with an intubation time ≤ 24 h showed a moderate negative correlation between minimum NI (NI
) and CAP-D (rho = -0.41, 95% CI: -0.70 - -0.01, p = 0.046), i.e., CAP-D decreased with increasing NI
. In the analysis of all patients' data, NI
and CAP-D showed a weak negative correlation (rho = -0.21, 95% CI: -0.40 - 0.01, p = 0.064). On average, the youngest patients had the highest CAP-D scores (p = 0.002). Patients with burst suppression / suppression EEG had a longer median intubation time in the intensive care unit than patients without such EEG (p = 0.023). There was no relationship between minimum temperature and CAP-D score.
The EEG can be used to individually adjust sevoflurane dosing during hypothermia. Of the patients extubated within 24 h and classified as delirious, patients with deeper levels of anesthesia had more severe delirium symptoms than patients with lighter levels of anesthesia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose The purpose of this study is to compare the access afforded by the Le Fort I osteotomy with the more traditional sublabial and endonasal approaches to the pituitary fossa. Patients and ...Methods Five fresh cadaveric heads were obtained for this study. Endonasal, sublabial, and Le Fort I osteotomy approaches to the pituitary fossa were performed on each specimen. Retractors were placed in the surgical field to simulate the intraoperative speculum position for each approach. Fluoroscopic images were obtained in 2 views. For each specimen, all images for a given approach were digitally superimposed to compare the magnitude of exposure obtained by each approach. Angular measurements were then compared among the 3 approaches. Results In the axial plane the degree of lateral exposure with the Le Fort I approach ranged from 15° to 35°, with a mean of 22.6°. By comparison, minimal or no lateral movement of the speculum was possible with the sublabial and endonasal approaches. In the sagittal plane the degree of vertical exposure with the Le Fort I approach ranged from 13° to 22°, with a mean of 17°. The sublabial approach provided 6° to 17° of vertical exposure, with a mean of 11.4°. Minimal or no vertical movement of the speculum was possible with the endonasal approach. Conclusions The Le Fort I osteotomy is a valuable midline approach for pituitary lesions that require broad exposure. Access in both the axial and sagittal planes is greater than with traditional trans-septal approaches.
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GEOZS, NUK, OILJ, SBCE, UL
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