Sickle Cell Disease and Lead Poisoning in New York City, 2005-2019.

OBJECTIVES: Previous analyses of New York City (NYC) health department's lead registry indicated that, among children with lead poisoning, an increased prevalence of sickle cell disease (SCD) exists. However, SCD is not considered a risk factor for lead poisoning. We assessed the association between SCD and childhood lead poisoning to determine if specific lead poisoning prevention efforts are needed for children with SCD. METHODS: We analyzed NYC's lead registry data for children with venous blood lead levels (BLLs) ≥15 mcg/dL during 2005 to 2019. t tests and χ2 tests were performed to compare demographic characteristics, BLLs, and lead exposure risks in non-Hispanic Black children with and without SCD. A t test was used to compare observed SCD prevalence among Black children with BLLs ≥15 mcg/dL with an estimated 0.43% SCD prevalence among Black NYC children. RESULTS: Among 1728 Black children with BLLs ≥15 mcg/dL identified, 37 (2.14%) had SCD. When comparing children with and without SCD, both mean age at peak BLL (62.8 versus 42.7 months; P = .003) and peak BLL (42.59 versus 23.06 mcg/dL; P = .008) were higher for children with SCD. Among risk factors for lead exposure, children with SCD had higher prevalence of pica. Observed SCD prevalence was 1.71% higher than estimated SCD prevalence among Black NYC children (P < .001). CONCLUSIONS: We found a potential association between SCD and childhood lead poisoning. Pica emerged as a potentially important risk factor. Our findings might have implications for lead poisoning prevention guidelines for children with SCD.

Lead Poisoning in a Mother and Her Four Children Using a Traditional Eye Cosmetic - New York City, 2012-2023.

Even low levels of lead in children's blood are associated with developmental delays, difficulty learning, and behavioral issues. Adults are also vulnerable to the detrimental health effects of lead exposure. The New York City (NYC) Department of Health and Mental Hygiene receives blood lead test results for NYC residents and conducts investigations of lead poisoning cases. Blood lead testing of a child aged 4 years in 2012 led to the discovery of blood lead levels above the CDC blood lead reference value of 3.5 µg/dL in the child as well as four other family members over a period of 11 years, including the child's mother and three younger siblings born during 2012-2016. The only potential source of lead exposure identified for all cases was the use of surma, a traditional eye cosmetic, which was found to contain 390,000 ppm lead. The cases in this report highlight the challenges of risk communication when deeply ingrained cultural practices, such as the use of surma, persist despite health warnings. Moreover, they highlight the intergenerational nature of such practices and the need for comprehensive family follow-up once a member is identified as being at risk. These products continue to be available globally, even in places such as the United States where sales are prohibited. Multistakeholder efforts involving local and global engagement could promote reformulation of these products at the countries of origin to eliminate lead as an ingredient.

The C-terminal activating domain promotes Panx1 channel opening.

Pannexin 1 (Panx1) constitutes a large pore channel responsible for the release of ATP from apoptotic cells. Strong evidence indicates that caspase-mediated cleavage of the C-terminus promotes the opening of the Panx1 channel by unplugging the pore. However, this simple pore-plugging mechanism alone cannot account for the observation that a Panx1 construct ending before the caspase cleavage site remains closed. Here, we show that a helical region located immediately before the caspase cleavage site, referred to as the "C-terminal activating domain (CAD)," plays a pivotal role in facilitating Panx1 activation. Electrophysiology and mutagenesis studies uncovered that two conserved leucine residues within the CAD plays a pivotal role. Cryo-EM analysis of the construct ending before reaching the CAD demonstrated that the N-terminus extends into an intracellular pocket. In contrast, the construct including the CAD revealed that this domain occupies the intracellular pocket, causing the N-terminus to flip upward within the pore. Analysis of electrostatic free energy landscape in the closed conformation indicated that the intracellular side of the ion permeation pore may be occupied by anions like ATP, creating an electrostatic barrier for anions attempting to permeate the pore. When the N-terminus flips up, it diminishes the positively charged surface, thereby reducing the drive to accumulate anions inside the pore. This dynamic change in the electrostatic landscape likely contributes to the selection of permeant ions. Collectively, these experiments put forth a novel mechanism in which C-terminal cleavage liberates the CAD, causing the repositioning of the N-terminus to promote Panx1 channel opening.

ATP-release pannexin channels are gated by lysophospholipids.

Adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of heptameric large pore-forming channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Molecular docking, mutagenesis, and single-particle cryo-EM reconstructions suggest that lysophospholipids open pannexin channels by altering the conformation of the N-terminal domain. Our results provide a connection between lipid metabolism and ATP signaling, both of which play major roles in inflammation and neurotransmission. One-Sentence Summary: Untargeted metabolomics discovers a class of messenger lipids as endogenous activators of membrane channels important for inflammation and neurotransmission.

Xyloglucan Xylosyltransferase 1 Displays Promiscuity Toward Donor Substrates During in Vitro Reactions.

Glycosyltransferases (GTs) are a large family of enzymes that add sugars to a broad range of acceptor substrates, including polysaccharides, proteins and lipids, by utilizing a wide variety of donor substrates in the form of activated sugars. Individual GTs have generally been considered to exhibit a high level of substrate specificity, but this has not been thoroughly investigated across the extremely large set of GTs. Here we investigate xyloglucan xylosyltransferase 1 (XXT1), a GT involved in the synthesis of the plant cell wall polysaccharide, xyloglucan. Xyloglucan has a glucan backbone, with initial side chain substitutions exclusively composed of xylose from uridine diphosphate (UDP)-xylose. While this conserved substitution pattern suggests a high substrate specificity for XXT1, our in vitro kinetic studies elucidate a more complex set of behavior. Kinetic studies demonstrate comparable kcat values for reactions with UDP-xylose and UDP-glucose, while reactions with UDP-arabinose and UDP-galactose are over 10-fold slower. Using kcat/KM as a measure of efficiency, UDP-xylose is 8-fold more efficient as a substrate than the next best alternative, UDP-glucose. To the best of our knowledge, we are the first to demonstrate that not all plant XXTs are highly substrate specific and some do show significant promiscuity in their in vitro reactions. Kinetic parameters alone likely do not explain the high substrate selectivity in planta, suggesting that there are additional control mechanisms operating during polysaccharide biosynthesis. Improved understanding of substrate specificity of the GTs will aid in protein engineering, development of diagnostic tools, and understanding of biological systems.

Structure of xyloglucan xylosyltransferase 1 reveals simple steric rules that define biological patterns of xyloglucan polymers.

The plant cell wall is primarily a polysaccharide mesh of the most abundant biopolymers on earth. Although one of the richest sources of biorenewable materials, the biosynthesis of the plant polysaccharides is poorly understood. Structures of many essential plant glycosyltransferases are unknown and suitable substrates are often unavailable for in vitro analysis. The dearth of such information impedes the development of plants better suited for industrial applications. Presented here are structures of Arabidopsis xyloglucan xylosyltransferase 1 (XXT1) without ligands and in complexes with UDP and cellohexaose. XXT1 initiates side-chain extensions from a linear glucan polymer by transferring the xylosyl group from UDP-xylose during xyloglucan biosynthesis. XXT1, a homodimer and member of the GT-A fold family of glycosyltransferases, binds UDP analogously to other GT-A fold enzymes. Structures here and the properties of mutant XXT1s are consistent with a SNi-like catalytic mechanism. Distinct from other systems is the recognition of cellohexaose by way of an extended cleft. The XXT1 dimer alone cannot produce xylosylation patterns observed for native xyloglucans because of steric constraints imposed by the acceptor binding cleft. Homology modeling of XXT2 and XXT5, the other two xylosyltransferases involved in xyloglucan biosynthesis, reveals a structurally altered cleft in XXT5 that could accommodate a partially xylosylated glucan chain produced by XXT1 and/or XXT2. An assembly of the three XXTs can produce the xylosylation patterns of native xyloglucans, suggesting the involvement of an organized multienzyme complex in the xyloglucan biosynthesis.

Epidemiologic Characteristics of Children with Blood Lead Levels ≥45 µg/dL.

OBJECTIVES: To identify risk factors and describe outcomes for children newly identified with blood lead levels (BLLs) ≥45 µg/dL in New York City (NYC) during 2004-2010 to promote timely identification as well as inform clinical practice and public health policy. STUDY DESIGN: Inclusion criteria were residence in NYC and an elevated confirmatory venous test within 2 weeks of the initial BLL ≥45 µg/dL. Data collected during case coordination of these children were linked with blood testing data and home inspection reports. Children with BLLs ≥45 µg/dL also were compared with the general population of children younger than 18 years of age in NYC. RESULTS: A total of 145 children <18 years of age were newly identified with BLLs ≥45 µg/dL. The mean age was 3.83 years, and the median time for BLL to decline below 10 µg/dL was 3.26 years. Major reported risk factors were eating paint (36%), spending time outside the US (34%), having a developmental delay (27%), using imported products (26%), being foreign born (14%), being of Pakistani descent (12%), eating soil (5%), and having sickle cell disease (4%). Compared with the age-standardized NYC population, cases were more likely to be Asian or black and live in housing built before 1940. CONCLUSIONS: Although the incidence of lead poisoning has declined in the US, severe cases still occur. Physicians should be especially vigilant in certain at-risk populations including children who eat paint chips or soil, spend time outside the US (particularly in Pakistan), use imported products, or have developmental delays or sickle cell disease.

Examining pica in NYC pregnant women with elevated blood lead levels.

We sought to describe the impact of pica, the craving for and intentional ingestion of substances not defined as food, as a risk factor for lead poisoning in New York City (NYC) pregnant women. In order to describe pregnant women with elevated blood lead levels (BLLs) who report pica, NYC health department data from 491 cases of lead-poisoned pregnant women from January 2001 to June 2009 were reviewed. Descriptive frequencies were obtained for women reporting pica. Data were compared between women reporting and not reporting pica. In NYC, of the 43 (9%) lead-poisoned pregnant women reporting pica, 42 (97.7%) were immigrants and 28 (64.6%) had consumed soil. Compared to lead-poisoned pregnant women not reporting pica, women reporting pica had higher peak BLLs (29.5 vs. 23.8 µg/dL, P = 0.0001), were more likely to have had a BLL ≥ 45 µg/dL (OR = 3.3, 95% CI, 1.25, 8.68) and receive chelation (OR = 10.88, 95% CI, 1.49, 79.25), more likely to have emigrated from Mexico (OR = 3.05, 95% CI, 1.38­6.72), and less likely to have completed high school (OR = indeterminate; 0 vs. 34%; P = 0.003). Among NYC lead-poisoned pregnant women, pica was associated with higher peak BLLs. Providers in NYC, and possibly other urban settings, should be vigilant and question pregnant women, especially immigrants, about pica and strongly consider testing this at-risk population for lead poisoning.

Non-acquired immunodeficiency syndrome-defining malignancies in patients infected with human immunodeficiency virus.

CONTEXT: Non-acquired immunodeficiency syndrome (AIDS)-defining malignancies that occur in patients infected with human immunodeficiency virus (HIV) and the demographics and pathologic features associated with these malignancies have not been completely defined. OBJECTIVE: This study describes the age of onset of malignant disease in patients seropositive for HIV and in control patients presumed to be negative for HIV, but with the same primary site. We compare the demographics and histopathology for both groups. DESIGN: From 1993 to 1997, 57 cases involving HIV-positive patients with malignancies from 16 primary sites were recorded in the Cancer Registry files at Bellevue Hospital; 519 cases involving patients negative for HIV were recorded during this same period. We compared the age at diagnosis, sex, race, tumor histology, stage, and grade between these 2 groups. RESULTS: The average age of HIV-positive patients was 47.6 years, compared with 60.3 years in the control group (P <.001). When the 16 cancer sites were compared individually, HIV-positive patients were significantly younger at onset of lung (HIV-positive patients/control group) (19/245), skin (11/77), penile (3/5), laryngeal (3/18), tongue (5/16), and colorectal (2/38) carcinomas. Patients infected with HIV had a more frequent history of smoking (41/328; P =.04) and illicit drug use (30/49; P <.001). The HIV-positive patients also were found to have a lower clinical stage of disease, compared with controls, largely due to the higher prevalence of stage 0 tumors (13/46; P =.01). CONCLUSIONS: The finding of younger age at diagnosis in HIV-positive compared to presumed HIV-negative patients may be related in part to earlier detection, as well as preexisting immunosuppression. The specific sites for which a significant difference in age between the HIV-positive and control cases was observed may be related to the mechanisms of immunosurveillance in parts of the body that have ready access to the outside environment. Knowledge of younger age of onset for these malignancies should prompt closer physical examination of these sites by clinicians.