Micrococcin cysteine-to-thiazole conversion through transient interactions between the scaffolding protein TclI and the modification enzymes TclJ and TclN.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a broad group of compounds mediating microbial competition in nature. Azole/azoline heterocycle formation in the peptide backbone is a key step in the biosynthesis of many RiPPs. Heterocycle formation in RiPP precursors is often carried out by a scaffold protein, an ATP-dependent cyclodehydratase, and an FMN-dependent dehydrogenase. It has generally been assumed that the orchestration of these modifications is carried out by a stable complex including the scaffold, cyclodehydratase, and dehydrogenase. The antimicrobial RiPP micrococcin begins as a precursor peptide (TclE) with a 35-amino acid N-terminal leader and a 14-amino acid C-terminal core containing six Cys residues that are converted to thiazoles. The putative scaffold protein (TclI) presumably presents the TclE substrate to a cyclodehydratase (TclJ) and a dehydrogenase (TclN) to accomplish the two-step installation of the six thiazoles. In this study, we identify a minimal TclE leader region required for thiazole formation, demonstrate complex formation between TclI, TclJ, and TclN, and further define regions of these proteins required for complex formation. Our results point to a mechanism of thiazole installation in which TclI associates with the two enzymes in a mutually exclusive fashion, such that each enzyme competes for access to the peptide substrate in a dynamic equilibrium, thus ensuring complete modification of each Cys residue in the TclE core. IMPORTANCE: Thiopeptides are a family of antimicrobial peptides characterized for having sulfur-containing heterocycles and for being highly post-translationally modified. Numerous thiopeptides have been identified; almost all of which inhibit protein synthesis in gram-positive bacteria. These intrinsic antimicrobial properties make thiopeptides promising candidates for the development of new antibiotics. The thiopeptide micrococcin is synthesized by the ribosome and undergoes several post-translational modifications to acquire its bioactivity. In this study, we identify key interactions within the enzymatic complex that carries out cysteine to thiazole conversion in the biosynthesis of micrococcin.

Three genes controlling streptomycin susceptibility in Agrobacterium fabrum.

Streptomycin (Sm) is a commonly used antibiotic for its efficacy against diverse bacteria. The plant pathogen Agrobacterium fabrum is a model for studying pathogenesis and interkingdom gene transfer. Streptomycin-resistant variants of A. fabrum are commonly employed in genetic analyses, yet mechanisms of resistance and susceptibility to streptomycin in this organism have not previously been investigated. We observe that resistance to a high concentration of streptomycin arises at high frequency in A. fabrum, and we attribute this trait to the presence of a chromosomal gene (strB) encoding a putative aminoglycoside phosphotransferase. We show how strB, along with rpsL (encoding ribosomal protein S12) and rsmG (encoding a 16S rRNA methyltransferase), modulates streptomycin sensitivity in A. fabrum. IMPORTANCE The plant pathogen Agrobacterium fabrum is a widely used model bacterium for studying biofilms, bacterial motility, pathogenesis, and gene transfer from bacteria to plants. Streptomycin (Sm) is an aminoglycoside antibiotic known for its broad efficacy against gram-negative bacteria. A. fabrum exhibits endogenous resistance to somewhat high levels of streptomycin, but the mechanism underlying this resistance has not been elucidated. Here, we demonstrate that this resistance is caused by a chromosomally encoded streptomycin-inactivating enzyme, StrB, that has not been previously characterized in A. fabrum. Furthermore, we show how the genes rsmG, rpsL, and strB jointly modulate streptomycin susceptibility in A. fabrum.

HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal.

Stalled replication forks are a critical problem for the cell because they can lead to complex genome rearrangements that underlie cell death and disease. Processes such as DNA damage tolerance and replication fork reversal protect stalled forks from these events. A central mediator of these DNA damage responses in humans is the Rad5-related DNA translocase, HLTF. Here, we present biochemical and structural evidence that the HIRAN domain, an ancient and conserved domain found in HLTF and other DNA processing proteins, is a modified oligonucleotide/oligosaccharide (OB) fold that binds to 3' ssDNA ends. We demonstrate that the HIRAN domain promotes HLTF-dependent fork reversal in vitro through its interaction with 3' ssDNA ends found at forks. Finally, we show that HLTF restrains replication fork progression in cells in a HIRAN-dependent manner. These findings establish a mechanism of HLTF-mediated fork reversal and provide insight into the requirement for distinct fork remodeling activities in the cell.

Clinical Features of Late-onset Semantic Dementia.

BACKGROUND: Semantic dementia (SD) is characterized by progressive semantic anomia extending to a multimodal loss of semantic knowledge. Although often considered an early-onset dementia, SD also occurs in later life, when it may be misdiagnosed as Alzheimer disease (AD). OBJECTIVE: To evaluate late-onset SD in comparison to early-onset SD and to AD. METHODS: We identified 74 individuals with SD and then compared those with late-onset SD (≥65 years of age) to those with early-onset SD (<65) on demographic and clinical features. We also compared a subgroup of 23 of the late-onset SD individuals with an equal number of individuals with clinically probable AD. RESULTS: Twenty-six (35.1%) of the SD individuals were late onset, and 48 (64.9%) were early onset. There were no differences between the two groups on clinical measures, although greater asymmetry of temporal involvement trended to significance in the late-onset SD group. Compared to the 23 AD individuals, the subgroup of 23 late-onset SD individuals had worse performance on confrontational naming, irregular word reading, and face recognition; however, this subgroup displayed better verbal delayed recall and constructions. The late-onset SD individuals also experienced early personality changes at a time when most individuals with AD had not yet developed behavioral changes. CONCLUSIONS: Approximately one-third of SD individuals may be late onset, and the differentiation of late-onset SD from AD can lead to better disease management, education, and prognosis. SD may be distinguished by screening for disproportionate changes in reading, face recognition, and personality.

Multiple calcifying hyperplastic dental follicles: a major diagnostic consideration in multiple pericoronal lesions - report of two cases.

BACKGROUND: Pericoronal radiolucent lesions are a common radiographic finding, but it is rare that they occur in multiple forms. Multiple calcifying hyperplastic dental follicles (MCHDF) are entities with few cases described to date; nevertheless, they appear to have a very particular phenotypic pattern. CASES PRESENTATION: Case 1: A 10-year-old male was evaluated radiographically, revealing four impacted canines, each accompanied by unilocular pericoronal radiolucency. Case 2: A 16-year-old male was planning orthodontic treatment; following his radiological evaluation all third molars were found to be accompanied with pericoronal radiolucencies. Enucleation, and third molar removal along with the pericoronal tissue were the respective treatments. Microscopically, in both cases, the specimens shown odontogenic epithelium, and type I and II calcifications in the hyperplastic follicles, all these characteristics were consistent with MCHDF. CONCLUSION: Although MCHDF are a rare entity, they must be considered in the differential diagnosis of multiple pericoronal lesions. Under the light of the current evidence, the histological findings may be relatively heterogeneous, but their integration with both the clinical data, which are apparently particular, and with the radiographic characteristics, can lead to a definitive diagnosis.

The HIRAN domain of helicase-like transcription factor positions the DNA translocase motor to drive efficient DNA fork regression.

Helicase-like transcription factor (HLTF) is a central mediator of the DNA damage response and maintains genome stability by regressing stalled replication forks. The N-terminal HIRAN domain binds specifically to the 3'-end of single-stranded DNA (ssDNA), and disrupting this function interferes with fork regression in vitro as well as replication fork progression in cells under replication stress. Here, we investigated the mechanism by which the HIRAN-ssDNA interaction facilitates fork remodeling. Our results indicated that HIRAN capture of a denatured nascent leading 3'-end directs specific binding of HLTF to forks. DNase footprinting revealed that HLTF binds to the parental duplex ahead of the fork and at the leading edge behind the fork. Moreover, we found that the HIRAN domain is important for initiating regression of forks when both nascent strands are at the junction, but is dispensable when forks contain ssDNA regions on either template strand. We also found that HLTF catalyzes fork restoration from a partially regressed structure in a HIRAN-dependent manner. Thus, HIRAN serves as a substrate-recognition domain to properly orient the ATPase motor domain at stalled and regressed forks and initiates fork remodeling by guiding formation of a four-way junction. We discuss how these activities compare with those of two related fork remodelers, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) and zinc finger RANBP2 type-containing 3 (ZRANB3) to provide insight into their nonredundant roles in DNA damage tolerance.

Bilingualism Delays Expression of Alzheimer's Clinical Syndrome.

OBJECTIVE: To evaluate the effects of bilingualism on the emergence of Alzheimer's clinical syndrome. BACKGROUND: Studies have proposed an increase in cognitive and neural reserve from the management and control of two languages, with a consequent delayed expression of dementia. METHODS: In a clinic with a large immigrant population, we identified 253 patients with probable Alzheimer's disease (AD) with intermediate or high evidence of AD pathophysiological process. These patients were reviewed for demographic variables, native language (L1) other than English, ages of onset and presentation, Mini-Mental State Examination (MMSE), digit spans, word fluencies, naming, and memory. RESULTS: Among these patients, 74 (29.2%) were bilinguals with various L1s (Farsi, Spanish, Chinese, Tagalog, Arabic, others). When compared to the 179 monolingual AD patients, those who were bilingual had significant delays in ages of onset and presentation of approximately 4 years (p = 0.003). These delays persisted despite bilinguals having worse MMSE scores on presentation. There were no significant group differences on other variables except for worse naming in English among bilinguals versus monolinguals. Caregiver/informants reported that 66 (89.2%) of the 74 bilingual AD patients had gradually regressed to the predominant use of their L1. CONCLUSIONS: In line with published reports worldwide, we found that bilingualism delays the expression of Alzheimer's clinical syndrome. We also found frequent reversion to the first learned language. These findings suggest that, among bilinguals, the availability of an L1 "back-up" either facilitates compensation or masks emergence of the early symptoms of dementia.

Repetitive Behaviors in Frontotemporal Dementia: Compulsions or Impulsions?

OBJECTIVE: The presence of repetitive behaviors is one of the core criteria for behavioral variant frontotemporal dementia (bvFTD). Patients with bvFTD often have perseverative, stereotyped, or compulsive-ritualistic behavior as an early aspect of their disorder. It is unclear whether such behaviors are related to compulsions, as in obsessive-compulsive disorder (OCD), or are part of the impulse disorder spectrum. METHODS: The authors investigated early (within 3 years) repetitive behaviors among 93 well-characterized patients who met International Consensus Criteria for clinically probable bvFTD and compared the results with the literature on OCD. The most common repetitive behaviors among 59 (63.4%) bvFTD patients were stereotypies of speech (35.5%), simple repetitive movements (15.2%-18.6%), hoarding and collecting (16.9%), and excessive or unnecessary trips to the bathroom (13.5%). RESULTS: Only hoarding and collecting was significantly common in both bvFTD and OCD; otherwise, the bvFTD patients had very low frequencies of the common OCD behaviors of checking, cleaning, counting, and ordering. The repetitive behaviors in bvFTD were not associated with verbalized anxiety, obsessional ideation, or reports of relief after completing the act. In contrast, these behaviors were often triggered by environmental stimuli and could be temporarily prevented from completion without undue distress. Finally, among the bvFTD patients, the repetitive behaviors were always associated with impulsive or disinhibited behaviors, such as inappropriate verbal or physical behavior. CONCLUSIONS: These findings suggest that the repetitive behaviors in bvFTD are repetitive impulsions, possibly from specific involvement of frontostriatal-anterior temporal pathology.

Viscoelastic Properties of Extracellular Polymeric Substances Can Strongly Affect Their Washing Efficiency from Reverse Osmosis Membranes.

The role of the viscoelastic properties of biofouling layers in their removal from the membrane was studied. Model fouling layers of extracellular polymeric substances (EPS) originated from microbial biofilms of Pseudomonas aeruginosa PAO1 differentially expressing the Psl polysaccharide were used for controlled washing experiments of fouled RO membranes. In parallel, adsorption experiments and viscoelastic modeling of the EPS layers were conducted in a quartz crystal microbalance with dissipation (QCM-D). During the washing stage, as shear rate was elevated, significant differences in permeate flux recovery between the three different EPS layers were observed. According to the amount of organic carbon remained on the membrane after washing, the magnitude of Psl production provides elevated resistance of the EPS layer to shear stress. The highest flux recovery during the washing stage was observed for the EPS with no Psl. Psl was shown to elevate the layer's shear modulus and shear viscosity but had no effect on the EPS adhesion to the polyamide surface. We conclude that EPS retain on the membrane as a result of the layer viscoelastic properties. These results highlight an important relation between washing efficiency of fouling layers from membranes and their viscoelastic properties, in addition to their adhesion properties.

Functional synthetic Antennapedia genes and the dual roles of YPWM motif and linker size in transcriptional activation and repression.

Segmental identity along the anteroposterior axis of bilateral animals is specified by Hox genes. These genes encode transcription factors, harboring the conserved homeodomain and, generally, a YPWM motif, which binds Hox cofactors and increases Hox transcriptional specificity in vivo. Here we derive synthetic Drosophila Antennapedia genes, consisting only of the YPWM motif and homeodomain, and investigate their functional role throughout development. Synthetic peptides and full-length Antennapedia proteins cause head-to-thorax transformations in the embryo, as well as antenna-to-tarsus and eye-to-wing transformations in the adult, thus converting the entire head to a mesothorax. This conversion is achieved by repression of genes required for head and antennal development and ectopic activation of genes promoting thoracic and tarsal fates, respectively. Synthetic Antennapedia peptides bind DNA specifically and interact with Extradenticle and Bric-à-brac interacting protein 2 cofactors in vitro and ex vivo. Substitution of the YPWM motif by alanines abolishes Antennapedia homeotic function, whereas substitution of YPWM by the WRPW repressor motif, which binds the transcriptional corepressor Groucho, allows all proteins to act as repressors only. Finally, naturally occurring variations in the size of the linker between the homeodomain and YPWM motif enhance Antennapedia repressive or activating efficiency, emphasizing the importance of linker size, rather than sequence, for specificity. Our results clearly show that synthetic Antennapedia genes are functional in vivo and therefore provide powerful tools for synthetic biology. Moreover, the YPWM motif is necessary--whereas the entire N terminus of the protein is dispensable--for Antennapedia homeotic function, indicating its dual role in transcriptional activation and repression by recruiting either coactivators or corepressors.

Prohibitins, Phb1 and Phb2, function as Atg8 receptors to support yeast mitophagy and also play a negative regulatory role in Atg32 processing.

The prohibitins Phb1 and Phb2 assemble at the mitochondrial inner membrane to form a multi-dimeric complex. These scaffold proteins are highly conserved in eukaryotic cells, from yeast to mammals, and have been implicated in a variety of mitochondrial functions including aging, proliferation, and degenerative and metabolic diseases. In mammals, PHB2 regulates PINK1-PRKN mediated mitophagy by interacting with lipidated MAP1LC3B/LC3B. Despite their high conservation, prohibitins have not been linked to mitophagy in budding yeasts. In this study, we demonstrate that both Phb1 and Phb2 are required to sustain mitophagy in Saccharomyces cerevisiae. Prohibitin-dependent mitophagy requires formation of the Phb1-Phb2 complex and a conserved AIM/LIR-like motif identified in both yeast prohibitins. Furthermore, both Phb1 and Phb2 interact and exhibit mitochondrial colocalization with Atg8. Interestingly, we detected a basal C terminus processing of the mitophagy receptor Atg32 that depends on the presence of the i-AAA Yme1. In the absence of prohibitins this processing is highly enhanced but reverted by the inactivation of the rhomboid protease Pcp1. Together our results revealed a novel role of yeast prohibitins in mitophagy through its interaction with Atg8 and regulating an Atg32 proteolytic event. Abbreviation: AIM/LIR: Atg8-family interacting motif/LC3-interacting region; ANOVA: analysis of variance; ATG/Atg: autophagy related; C terminus/C-terminal: carboxyl terminus/carboxyl-terminal; GFP: green fluorescent protein; HA: human influenza hemagglutinin; Idh1: isocitrate dehydrogenase 1; MAP1C3B/LC3B: microtubule associated protein 1 light chain 3 beta; mCh: mCherry; MIM: mitochondrial inner membrane; MOM: mitochondrial outer membrane; N starvation: nitrogen starvation; N terminus: amino terminus; PARL: presenilin associated rhomboid like; Pcp1: processing of cytochrome c peroxidase 1; PCR: polymerase chain reaction; PGAM5: PGAM family member 5 mitochondrial serine/threonine protein phosphatase; PHBs/Phb: prohibitins; PINK1: PTEN induced kinase 1; PMSF: phenylmethylsulfonyl fluoride; PRKN: parkin RBR E3 ubiquitin protein ligase; SD: synthetic defined medium; SDS: sodium dodecyl sulfate; SMD-N: synthetic defined medium lacking nitrogen; WB: western blot; WT: wild type; Yme1: yeast mitochondrial escape 1; YPD: yeast extract-peptone-dextrose medium; YPLac: yeast extract-peptone-lactate medium.

Effect of treated domestic wastewater on soil physicochemical and microbiological properties.

A main concern with reuse of treated domestic wastewater (DWW) in irrigation is its possible effect on the soil. Few studies have focused on DWW treated in on-site settings, which generally use low-tech systems that can be constructed and serviced locally. One such system is the recirculating vertical flow constructed wetland (RVFCW). The aim of this study was to assess short- to midterm effects of irrigation with DWW treated in the RVFCW. Four groups of plastic barrels, filled with a sandy loam soil, were irrigated for 36 mo with fresh water (FW), FW with added fertilizer, raw DWW, or DWW treated in the RVFCW followed by ultraviolet disinfection. Principal component analysis revealed that the soil irrigated with treated DWW had physicochemical properties similar to those irrigated with FW amended with fertilizer. Levels of surfactants in soil irrigated with treated DWW were identical to those expected from standard irrigation practices, abating concerns for possible changes in soil hydraulic properties. was not detected in the soil irrigated with treated DWW, demonstrating the importance of disinfection of treated effluents before reuse in irrigation. Furthermore, irrigation with treated DWW did not alter the bacterial community structure according to terminal restriction fragment analysis. This 3-yr study suggests that the practice of irrigation with RVFCW effluents is safe. Continuation of the experiment is required to determine whether longer-term irrigation might show a different pattern.

Jargonaphasia in logopenic variant primary progressive aphasia.

BACKGROUND: Logopenic variant primary progressive aphasia (lvPPA), which is most commonly an early onset variant of Alzheimer's disease (AD), is a progressive impairment in word retrieval and language expression. Clinicians often misdiagnose these patients when they present with severely unintelligible speech consistent with jargonaphasia. METHODS: We reviewed all patients presenting to a behavioral neurology program over a 23-year period who met criteria for lvPPA after completion of an evaluation extending to positron emission tomography (PET) of the brain. Among these lvPPA patients, we additionally identified and characterized those whose presentation involved incomprehensible yet fluent verbal output. RESULTS: Out of 95 patients with lvPPA, 9 (9.47%) had jargonaphasia on presentation. These patients differed from the remaining 86 patients in lacking awareness or concern for their impaired communication, having worse mental status scale scores, greater auditory comprehension difficulty, and more bilateral temporo-parietal hypometabolism. In addition, 44.4% of those with jargonaphasia, compared to 14% of those without, were bi/multilingual. CONCLUSION: Nearly 1 in 10 patients with lvPPA present with severely unintelligible speech. These patients have disease extending to bilateral temporoparietal areas affecting language comprehension and disease awareness. Jargonaphasia can be a confusing presentation of AD and must be differentiated from other progressive aphasias, Wernicke's aphasia, and the word salad of "schizoaphasia".

Micrococcin cysteine-to-thiazole conversion through transient interactions between a scaffolding protein and two modification enzymes.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a broad group of compounds mediating microbial competition in nature. Azole/azoline heterocycle formation in the peptide backbone is a key step in the biosynthesis of many RiPPs. Heterocycle formation in RiPP precursors is often carried out by a scaffold protein, an ATP-dependent cyclodehydratase, and an FMN-dependent dehydrogenase. It has generally been assumed that the orchestration of these modifications is carried out by a stable complex including the scaffold, cyclodehydratase and dehydrogenase. The antimicrobial RiPP micrococcin begins as a precursor peptide (TclE) with a 35-amino acid N-terminal leader and a 14-amino acid C-terminal core containing six Cys residues that are converted to thiazoles. The putative scaffold protein (TclI) presumably presents the TclE substrate to a cyclodehydratase (TclJ) and a dehydrogenase (TclN) to accomplish the two-step installation of the six thiazoles. In this study, we identify a minimal TclE leader region required for thiazole formation, we demonstrate complex formation between TclI, TclJ and TclN, and further define regions of these proteins required for complex formation. Our results point to a mechanism of thiazole installation in which TclI associates with the two enzymes in a mutually exclusive fashion, such that each enzyme competes for access to the peptide substrate in a dynamic equilibrium, thus ensuring complete modification of each Cys residue in the TclE core.

A large-scale genetic screen identifies genes essential for motility in Agrobacterium fabrum.

The genetic and molecular basis of flagellar motility has been investigated for several decades, with innovative research strategies propelling advances at a steady pace. Furthermore, as the phenomenon is examined in diverse bacteria, new taxon-specific regulatory and structural features are being elucidated. Motility is also a straightforward bacterial phenotype that can allow undergraduate researchers to explore the palette of molecular genetic tools available to microbiologists. This study, driven primarily by undergraduate researchers, evaluated hundreds of flagellar motility mutants in the Gram-negative plant-associated bacterium Agrobacterium fabrum. The nearly saturating screen implicates a total of 37 genes in flagellar biosynthesis, including genes of previously unknown function.

Engineering efficient termination of bacteriophage T7 RNA polymerase transcription.

The bacteriophage T7 expression system is one of the most prominent transcription systems used in biotechnology and molecular-level research. However, T7 RNA polymerase is prone to read-through transcription due to its high processivity. As a consequence, enforcing efficient transcriptional termination is difficult. The termination hairpin found natively in the T7 genome is adapted to be inefficient, exhibiting 62% termination efficiency in vivo and even lower efficiency in vitro. In this study, we engineered a series of sequences that outperform the efficiency of the native terminator hairpin. By embedding a previously discovered 8-nucleotide T7 polymerase pause sequence within a synthetic hairpin sequence, we observed in vivo termination efficiency of 91%; by joining 2 short sequences into a tandem 2-hairpin structure, termination efficiency was increased to 98% in vivo and 91% in vitro. This study also tests the ability of these engineered sequences to terminate transcription of the Escherichia coli RNA polymerase. Two out of 3 of the most successful T7 polymerase terminators also facilitated termination of the bacterial polymerase with around 99% efficiency.

Toxicological effect and enzymatic disorder of non-studied emerging contaminants in Artemia salina model.

Emerging contaminants such as sunscreens, hair dyes and flame retardants have been found at important concentrations in surface water (river, lake, ocean), but their negative impact on different aquatic species is not fully known. This study evaluated the effect of benzophenone (BZ), 2,5-diaminotoluene sulfate (PTD), p-phenylenediamine (PPD) and tetrabromobisphenol A (TBPA) on survival (LC50) and the impact of sublethal concentrations (LC25) on the activity of enzymes linked to stress oxidative process in brine shrimp under two temperature conditions (22 °C and 28 °C) for 24 h and 48 h of exposure time. LC50 values obtained for each chemical substance and the activity of GST, AChE and LDH were significantly affected by the temperature conditions and exposure time. In contrast, GPx was only altered by the tested compound. TBBPA (LC50 from 17.05 up to 28.55 µg/L) and BZ (LC50 from 14.86 up to 24.49 mg/L) resulted in the most toxic substances for A. salina. The impact of dyes, such as PTD and PPD, on aquatic organisms is limited. These are the first results that show that not only dyes, but their respective by-products induce harmful effects in brine shrimp (LC50 for PTD and PPD were 23.6-396.3 and 52.0-164.9 mg/L respectively). Although this study model was very useful to evaluate the ecotoxicity of the different ECs, additional research is needed to increase available information related to the effects of dyes and other non-studied micropollutants on aquatic systems in general.

Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome.

Importance: People with Down syndrome have a high risk of developing Alzheimer disease dementia. However, penetrance and age at onset are considered variable, and the association of this disease with life expectancy remains unclear because of underreporting in death certificates. Objective: To assess whether the variability in symptom onset of Alzheimer disease in Down syndrome is similar to autosomal dominant Alzheimer disease and to assess its association with mortality. Design, Setting, and Participants: This study combines a meta-analysis with the assessment of mortality data from US death certificates (n = 77 347 case records with a International Classification of Diseases code for Down syndrome between 1968 to 2019; 37 900 [49%] female) and from a longitudinal cohort study (n = 889 individuals; 46% female; 3.2 [2.1] years of follow-up) from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI). Main Outcomes and Measures: A meta-analysis was conducted to investigate the age at onset, age at death, and duration of Alzheimer disease dementia in Down syndrome. PubMed/Medline, Embase, Web of Science, and CINAHL were searched for research reports, and OpenGray was used for gray literature. Studies with data about the age at onset or diagnosis, age at death, and disease duration were included. Pooled estimates with corresponding 95% CIs were calculated using random-effects meta-analysis. The variability in disease onset was compared with that of autosomal dominant Alzheimer disease. Based on these estimates, a hypothetical distribution of age at death was constructed, assuming fully penetrant Alzheimer disease. These results were compared with real-world mortality data. Results: In this meta-analysis, the estimate of age at onset was 53.8 years (95% CI, 53.1-54.5 years; n = 2695); the estimate of age at death, 58.4 years (95% CI, 57.2-59.7 years; n = 324); and the estimate of disease duration, 4.6 years (95% CI, 3.7-5.5 years; n = 226). Coefficients of variation and 95% prediction intervals of age at onset were comparable with those reported in autosomal dominant Alzheimer disease. US mortality data revealed an increase in life expectancy in Down syndrome (median [IQR], 1 [0.3-16] years in 1968 to 57 [49-61] years in 2019), but with clear ceiling effects in the highest percentiles of age at death in the last decades (90th percentile: 1990, age 63 years; 2019, age 65 years). The mortality data matched the limits projected by a distribution assuming fully penetrant Alzheimer disease in up to 80% of deaths (corresponding to the highest percentiles). This contrasts with dementia mentioned in 30% of death certificates but is in agreement with the mortality data in DABNI (78.9%). Important racial disparities persisted in 2019, being more pronounced in the lower percentiles (10th percentile: Black individuals, 1 year; White individuals, 30 years) than in the higher percentiles (90th percentile: Black individuals, 64 years; White individuals, 66 years). Conclusions and Relevance: These findings suggest that the mortality data and the consistent age at onset were compatible with fully penetrant Alzheimer disease. Lifespan in persons with Down syndrome will not increase until disease-modifying treatments for Alzheimer disease are available.

Neurological Manifestations in Pediatric Patients Hospitalized for COVID-19: Experiences of the National Medical Center "20 de Noviembre" in Mexico City.

COVID-19 has affected millions of children and, while it was previously considered as a respiratory disease, neurologic involvement has also been documented. The objective of this study was to identify the neurological manifestations (NMs) and the outcomes of children with COVID-19 who attended the National Medical Center "20 de Noviembre". METHODS: A retrospective cohort study of children hospitalized for COVID-19 from April 2020 to March 2021 was conducted. Clinical-demographic data were registered. Neurologic manifestations were defined as any clinical neurological expression of the central and/or peripheral nervous system that occurred during admission or hospitalization. RESULTS: In total, 46 children with a confirmed COVID-19 result, 26 (56.5%) boys and 20 (43.5%) girls with a median age of 8.9 ± 4.6 years, constituted the study population. Half of the children showed some NMs, and this group of patients concomitantly showed acute lymphoblastic leukemia (ALL, 56%), obesity (17.3%), or acute myeloblastic leukemia (AML, 4.3%). The most frequently described NMs were headache (13, 56%), encephalopathy (10, 43.47%), and epilepsy (4, 17.39%). The mortality rate in children with NMs was 21.7% and they had a higher mortality rate when compared to those without NM p ≤ 0.025. CONCLUSIONS: NMs occurred predominantly in male children aged 6 to 12 years; ALL was the most frequent comorbidity. Headache prevailed and hypoxemia, hypocalcemia, elevated ferritin, and C-reactive protein were associated with NM. Finally, NMs were a risk factor for mortality.

Neurological Involvement in Pediatric Patients with Acute Leukemia: A Retrospective Cohort.

Acute leukemia (AL) is an important cause of morbidity and mortality in children, and neurological manifestations (NM) are frequent. The objective of this study was to analyze neurological manifestations in children with acute leukemia from cases attended in the last five years at the Centro Médico Nacional "20 de Noviembre". METHODS: Conducting a retrospective and analytical study from 1 January 2015 to 31 December 2020 in children with AL classified according to sex, age range and AL type. Participants were grouped according the presence of NM. RESULTS: We analyzed 607 patients: 54.85% boys and 44.14% girls, with a mean age of 7.27 ± 4.54 years. When comparing groups, the NM group was significantly older (p = 0.01), and the highest prevalence was between 6 and 12 years old. ALL was predominant over the other lineages (p ≤ 0.01). The most frequent NM was CNS infiltration, seizures, headache and neuropathy. Death outcomes occurred in 18.7% of children with AML, 11.8% with ALL and 50% with MPAL (p ≤ 0.002). The NM group was associated with higher mortality during a follow-up time of 77.9 ± 49 months (44.4% vs. 8.9% deaths, NM vs. non-NM, respectively; OR = 3.3; 95% CI 2.4 to 4.6; p ≤ 0.0001). CONCLUSIONS: ALL was the most prevalent leukemia type. CNS infiltration, seizures, headache, neuropathy and PRES were the most frequent symptoms in the NM group. NM was associated with a higher mortality rate.