Pulmonary-Renal Syndrome from Levamisole-Adulterated Cocaine-Induced Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: A Systematic Review

Levamisole is an anti-helminthic drug with immunomodulatory properties that is added to cocaine to increase its potency and weight. Levamisole-adulterated cocaine (LAC) may cause an antineutrophil cytoplasmic antibody (ANCA)-associated systemic small vessel vasculitis (AAV). We aimed to characterize the phenotype of persons developing pulmonary-renal syndrome (PRS) in LAC-induced AAV and summarize its treatment and outcomes. Pubmed and Web of Science were searched (until September 2022). Reports that described co-existing diffuse alveolar hemorrhage and glomerulonephritis in an adult (age ≥ 18) with confirmed or suspected LAC exposure were included. Reports, demographics, clinical and serologic features, treatment and outcome characteristics were extracted. Of the 280 records identified, eight met the inclusion criteria, including eight unique cases. Persons were aged 22–58 years, and 50% were women. Cutaneous involvement occurred in only half of the cases. Other associated vasculitis findings and serologies were heterogeneous. All patients received immunosuppression with steroids, with cyclophosphamide and rituximab commonly added. We concluded that PRS could occur from LAC-induced AAV. Distinguishing LAC-induced AAV from primary AAV is challenging as clinical and serologic presentations overlap. Asking about cocaine use is requisite in persons presenting with PRS to guide diagnosis and appropriately counsel on cocaine cessation in conjunction with immunosuppression as treatment

The Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study

ABSTRACT Amino acids are the building blocks of proteins, and sufficient protein intake is important for skeletal health. We utilized stored serum from the Cardiovascular Health Study in 1992–1993 to examine the relationship between levels of the essential amino acid tryptophan (trp) and its oxidized and nonoxidized metabolites to risk for incident hip fractures and mortality over 12 years of follow‐up. We included 131 persons who sustained a hip fracture during this time period and 131 without a hip fracture over these same 12 years of follow‐up; 58% female and 95% White. Weighted multivariable Cox hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher trp or its metabolites exposure. Relative risk regression was used to evaluate the cross‐sectional association of trp and its metabolites with frailty. Higher serum levels of trp were significantly associated with lower risk of incident hip fractures (HR = 0.75 per SD of trp (95% CI 0.57–0.99) but were not significantly associated with mortality or frailty status by Freid's frailty index. There were no statistically significant associations between any of the oxidized or nonoxidized products of trp with incident hip fractures (p ≥ 0.64), mortality (p ≥ 0.20), or cross‐sectional frailty status (p ≥ 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA

The maturation of auditory responses in infants and young children: a cross-sectional study from 6 to 59 months

Background: An understanding of the maturation of auditory cortex responses in typically developing infants and toddlers is needed to later identify auditory processing abnormalities in infants at risk for neurodevelopmental disorders. The availability of infant and young child magnetoencephalography (MEG) systems may now provide near optimal assessment of left and right hemisphere auditory neuromagnetic responses in young populations. To assess the performance of a novel whole-head infant MEG system, a cross-sectional study examined the maturation of left and right auditory cortex responses in children 6- to 50-months of age. Methods: Blocks of 1000Hz (1st and 3rd blocks) and 500Hz tones (2nd block) were presented while MEG data were recorded using an infant/young child biomagnetometer (Artemis 123). Data were obtained from 29 children (11 males; 6 months to 59 months). Latency measures were obtained for the first positive-to-negative evoked response waveform complex in each hemisphere. Latency and age associations as well as frequency and hemisphere latency differences were examined. For the 1000 Hz tone, measures of reliability were computed. Results: For the first response - a response with a ‘P2m’ topography - latencies decreased as a function of age. For the second response - a response with a ‘N2m’ topography - no N2m latency and age relationships were observed. A main effect of tone frequency showed earlier P2m responses for 1st 1000 Hz (150 ms) and 2nd 1000 Hz (148 ms) versus 500 Hz tones (162 ms). A significant main effect of hemisphere showed earlier N2m responses for 2nd 1000 Hz (226 ms) versus 1st 1000 Hz (241 ms) versus 500 Hz tones (265 ms). P2m and N2m interclass correlation coefficient latency findings were as follows: left P2m (0.72, p < 0.001), right P2m (0.84, p < 0.001), left N2m (0.77, p < 0.001), and right N2m (0.77, p < 0.01).Conclusions: Findings of strong age and latency associations, sensitivity to tone frequency, and good test-retest reliability support the viability of longitudinal infant MEG studies that include younger as well as older participants as well as studies examining auditory processing abnormalities in infants at risk for neurodevelopmental disorders

Regulation of Pyruvate Dehydrogenase Kinase 4 (PDK4) by CCAAT/Enhancer-binding Protein β (C/EBPβ)

The conversion of pyruvate to acetyl-CoA in mitochondria is catalyzed by the pyruvate dehydrogenase complex (PDC). Activity of PDC is inhibited by phosphorylation via the pyruvate dehydrogenase kinases (PDKs). Here, we examined the regulation of Pdk4 gene expression by the CCAAT/enhancer-binding protein β (C/EBPβ). C/EBPβ modulates the expression of multiple hepatic genes including those involved in metabolism, development, and inflammation. We found that C/EBPβ induced Pdk4 gene expression and decreased PDC activity. This transcriptional induction was mediated through two C/EBPβ binding sites in the Pdk4 promoter. C/EBPβ participates in the hormonal regulation of gluconeogenic genes. Previously, we reported that Pdk4 was induced by thyroid hormone (T3). Therefore, we investigated the role of C/EBPβ in the T3 regulation of Pdk4. T3 increased C/EBPβ abundance in primary rat hepatocytes. Knockdown of C/EBPβ with siRNA diminished the T3 induction of the Pdk4 and carnitine palmitoyltransferase (Cpt1a) genes. CPT1a is an initiating step in the mitochondrial oxidation of long chain fatty acids. Our results indicate that C/EBPβ stimulates Pdk4 expression and participates in the T3 induction of the Cpt1a and Pdk4 genes