Joint replacement risk is markedly increased in alkaptonuria (AKU) in those with prior arthroplasty.

Background: Increased homogentisic acid (HGA) in alkaptonuria (AKU) causes severe arthritis. Nitisinone reduces the production of HGA, but whether it also decreases arthroplasty was examined in 237 AKU patients. Patients and methods: Patients attending the United Kingdom National Alkaptonuria Centre (NAC) and the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) study were studied. Assessments included questionnaires eliciting details of arthroplasty. Nitisinone was administered from baseline, 2 mg in the NAC and 10 mg in SONIA 2. In SONIA 2, subgroups consisted of those with baseline arthroplasty on and not on nitisinone (BR + N+, BR + N-), as well as those without baseline arthroplasty on and not on nitisinone (BR-N+, BR-N-). Results: In the SONIA2 subgroups, new joint replacement (JR) probabilities after baseline were significantly different (BR + N+, BR + N-, BR-N+, BR-N-) (χ2 = 23.3, p < 0.001); mean (SD) was 3.8 (0.1) years in BR-N-, 3.7 (0.1) years in BR-N+, 3.4 (0.3) years in BR + N-, and 3.0 (0.3) years in BR + N+. Further, the BR + N- showed more JR than the BR-N- subgroup (p < 0.01), while BR + N+ similarly showed more JR than the BR-N+ subgroup (p < 0.001).In the NAC, the BR- group had a mean age of 51.6 (7.0) years at baseline but 57.7 (8.7) years at final follow up during nitisinone therapy and showed only 7 incident JR. The BR+ group had an age at baseline of 57.4 (8.5) years and had undergone 94 JRs at baseline. Conclusion: The incidence of arthroplasty was earlier and more frequent after the first JR and was not affected by nitisinone.

Paranoia and Social Anxiety: Predicting Aggressive Behavior.

Aggression is a transdiagnostic behavior that is associated with poor clinical outcomes. As such, it is important to understand factors that contribute to various manifestations of aggressive behavior. Recent research has revealed a subtype of individuals with social anxiety disorder (SAD) who tend to display relatively high amounts of aggression and experience more severe social anxiety and dysfunction compared to individuals in the prototypical SAD group. The current study used a status threat manipulation along with behavioral indices of aggression to examine the impact of paranoia and social anxiety symptom severity on aggression in a sample of undergraduates with social anxiety (N = 220). Analyses indicated that paranoia uniquely predicted indirect aggression whereas an interaction between social status threat, paranoia, and social anxiety severity uniquely predicted direct aggression. These findings suggest that paranoia may be a particularly important contributor to aggression among individuals with social anxiety.

A maize semidwarf mutant reveals a GRAS transcription factor involved in brassinosteroid signaling.

Brassinosteroids (BR) and gibberellins (GA) regulate plant height and leaf angle in maize (Zea mays). Mutants with defects in BR or GA biosynthesis or signaling identify components of these pathways and enhance our knowledge about plant growth and development. In this study, we characterized three recessive mutant alleles of GRAS transcription factor 42 (gras42) in maize, a GRAS transcription factor gene orthologous to the DWARF AND LOW TILLERING (DLT) gene of rice (Oryza sativa). These maize mutants exhibited semi-dwarf stature, shorter and wider leaves, and more upright leaf angle. Transcriptome analysis revealed a role for GRAS42 as a determinant of BR signaling. Analysis of the expression consequences from loss of GRAS42 in the gras42-mu1021149 mutant indicated a weak loss of BR signaling in the mutant, consistent with its previously demonstrated role in BR signaling in rice. Loss of BR signaling was also evident by the enhancement of weak BR biosynthetic mutant alleles in double mutants of nana plant1-1 and gras42-mu1021149. The gras42-mu1021149 mutant had little effect on GA-regulated gene expression, suggesting that GRAS42 is not a regulator of core GA signaling genes in maize. Single cell expression data identified gras42 expressed among cells in the G2/M phase of the cell cycle consistent with its previously demonstrated role in cell cycle gene expression in Arabidopsis (Arabidopsis thaliana). Cis-acting natural variation controlling GRAS42 transcript accumulation was identified by expression genome-wide association study (eGWAS) in maize. Our results demonstrate a conserved role for GRAS42/SCARECROW-LIKE 28 (SCL28)/DLT in BR signaling, clarify the role of this gene in GA signaling, and suggest mechanisms of tillering and leaf angle control by BR.

Brassinosteroid biosynthesis and signaling: Conserved and diversified functions of core genes across multiple plant species.

Brassinosteroids (BRs) are important regulators that control myriad aspects of plant growth and development, including biotic and abiotic stress responses, such that modulating BR homeostasis and signaling presents abundant opportunities for plant breeding and crop improvement. Enzymes and other proteins involved in the biosynthesis and signaling of BRs are well understood from molecular genetics and phenotypic analysis in Arabidopsis thaliana; however, knowledge of molecular functions of these genes in other plant species, especially cereal crop plants, is minimal. In this manuscript, we comprehensively review functional studies of BR genes in Arabidopsis, maize, rice, Setaria, Brachypodium, and soybean to identify conserved and diversified functions across plant species and to highlight cases where additional research is in order. We performed phylogenetic analysis of gene families involved in the biosynthesis and signaling of BRs and re-analyzed publicly available transcriptomic data. Gene trees coupled with expression data provide a valuable guide to supplement future research on BRs in these important crop species, allowing researchers to identify genes to target through gene editing techniques to perform BR-related functional studies.

The Frequency of Anatomical Variants of the Bile Ducts: A Review Based on a Single Classification as Support for Cholangiographic Examinations.

Complications arising from hepatobiliary surgery can have adverse effects on both the quality of life and the survival of patients. Magnetic resonance cholangiography (MRC) techniques are highly effective at revealing anatomical variants of the bile ducts and thus play a vital role in minimizing the occurrence of complications. The aims of this review are threefold: to ascertain the classifications utilized for categorizing anatomical variants of the bile ducts, to present the reported results on the prevalence of these anatomical variants, and to explore the diagnostic modalities employed to visualize these anatomical variants and associated complications during surgical procedures. A review of the literature was carried out using the Cochrane Library database and the PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), and Google Scholar platforms. We conducted a comprehensive review of relevant studies to categorize the different anatomical variants according to the Huang classification. According to the Huang classification, our study showed type A1, 60.44%; type A2, 11.76%; type A3, 11.73%; type A4, 5.47%; type A5, 0.26%; and type B, which was identified in insignificant numbers (0.16%) or does not appear; additionally, variants that do not fit into the Huang classification have also been identified (10.18%). The Huang classification serves as an invaluable presurgical guide, aiding in the strategic planning of biliary interventions and effectively reducing the risk of iatrogenic complications, morbidity, mortality, and postoperative length of stay. MRC is still considered the noninvasive gold standard method for evaluating the bile ducts and their anatomical variations.

Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria.

Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] µmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] µmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.

Peritraumatic tonic immobility and posttraumatic symptoms among LGBTQ+ versus straight cisgender female sexual assault survivors.

OBJECTIVE: The current study examined group differences in peritraumatic tonic immobility (TI) and posttraumatic symptoms among lesbian, gay, bisexual, transgender, and queer (LGBTQ+) females and their straight, cisgender counterparts. METHOD: Adult female sexual assault (SA) survivors (N = 86; 41.9% LGBTQ+) completed a questionnaire battery assessing demographics, TI experience, posttraumatic stress disorder symptoms, dissociative symptoms, and posttraumatic cognitions. Chi-square analyses, analyses of variance, and hierarchical linear regressions were used to characterize the associations among these variables. RESULTS: Individuals identifying as LGBTQ+ endorsed higher rates and severity of TI as well as greater posttraumatic stress symptoms compared to their straight, cisgender counterparts. Both LGBTQ+ status and TI experience predicted greater posttraumatic stress symptoms. CONCLUSIONS: Findings suggest that LGBTQ+ individuals who endorse TI during SA experience greater posttraumatic symptoms than their non-LGBTQ+ and non-TI counterparts. These findings have important implications for future research and treatment of female SA survivors. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Interpretation bias modification for hostility to facilitate smoking cessation in a sample with elevated trait anger: A randomized trial.

Problematic anger is linked with multiple adverse smoking outcomes, including cigarette dependence, heavy smoking, and cessation failure. A smoking cessation intervention that directly targets anger and its maintenance factors may increase rates of smoking cessation. We examined the efficacy of an interpretation bias modification for hostility (IBM-H) to facilitate smoking cessation in smokers with elevated trait anger. Participants were 100 daily smokers (mean age = 38, 62% female, 55% white) with elevated anger were randomly assigned to eight computerized sessions of either IBM-H or a health and relaxation video control condition (HRVC). Participants in both conditions attempted to quit at mid-treatment. Measures of hostility, anger, and smoking were administered at pre-, mid-, post-treatment, as well as at up to three-month follow-up. Compared to HRVC, IBM-H led to greater reductions in hostile interpretation bias, both at posttreatment and follow-up. IBM-H also led to statistically significant reductions in hostility only at posttreatment, and trait anger only at three-month follow-up. Both conditions experienced reductions in smoking, although they did not differ in quit success. We discuss these findings in the context of literature on anger and smoking cessation and provide directions for future research.

Sampling pattern discrepancy in the application of compressed sensing hyperpolarized xenon-129 lung MRI.

Although hyperpolarized (HP) 129Xe ventilation MRI can be carried out within a breath hold, it is still challenging for many sick patients. Compressed sensing (CS) is a viable alternative to accelerate this approach. However, undersampled images with identical sampling ratios differ from one another. Twenty subjects (n = 10 healthy and n = 10 patients with asthma) were scanned using a GE MR750 3 T scanner, acquiring fully sampled 2D multi-slice HP 129Xe lung ventilation images (10 s breath hold, 128 × 80 (FE × PE-frequency encoding × phase encoding) and 16 slices). Using fully sampled data, 500 variable-density Cartesian random undersampling patterns were generated, each at eight different sampling ratios from 10% to 80%. The parallel imaging and compressed sensing (PICS) command from BART was employed to reconstruct undersampled data. The signal to noise ratio (SNR), structural similarity index measurement (SSIM) and sidelobe to peak ratio of each were subsequently compared. There was a high degree of variation in both SNR and SSIM results from each of the 500 masks of each sampling rate. As the undersampling increases, there is more variation in the quantifying metrics, for both healthy and asthmatic individuals. Our study shows that random undersampling poses a significant challenge when applied at sampling ratios less than 60%, despite fulfilling CS's incoherency criteria. Such low sampling ratios will result in a large variety of undersampling patterns. Therefore, skipped segments of k-space cannot be allowed to happen randomly at low sampling rates. By optimizing the sampling pattern, CS will reach its full potential and be able to be applied to a highly undersampled 129Xe lung dataset.

Different perceptual worlds: Parent and youth perspectives on parenting outcome trajectories from a Latino family-based program.

Discrepancies between parent and youth perceptions of their relationship are a common aspect of generational acculturation gaps influencing immigrant families. Programs designed to strengthen parenting practices among immigrant Latino families commonly address immigration stresses, including differences between parent and youth perceptions, but little is known about discrepancies in their appraisals of program effects on parenting behavior. A randomized trial was conducted examining effects on parent behavior of a program for immigrant families with youth aged 10-14, developed through community-based participatory research principles. Families (346 parents and youth) were recruited by organizations serving Latino families in a Midwestern metropolitan area and randomly assigned to the eight-session psychoeducation and skill-building program or a waitlist control. Parents and youth completed self-report measures at pre-intervention, post-intervention (4 months), and a 6-month follow-up regarding parents' expression of acceptance, efforts to solicit information about the child's experiences, and consistency of discipline, key foci of the program. Based on social cognition theory, the study focused on possible differences in parents' and youths' perceptions of change in parenting behavior. Parents in the treatment group reported pre-post improved acceptance, consistent discipline, and solicitation, whereas youth reported improvement only in parental solicitation, a pattern maintained at follow-up. In the control group, the only change was youth-reported reduction in parental acceptance. Parents' perceptions of improvement are encouraging, but overall lack of improvements from the youth perspective poses a potential problem for impact on parent-child relations. Interventions may need to target both parent and youth cognitions about behavior changes directly.

Suicidal ideation is associated with safety behavior usage among trauma-exposed individuals.

BACKGROUND: Long-standing theoretical perspectives on suicidal ideation (SI) have posited that SI arises, in part, as a way to obtain relief from intense emotional pain. Yet, little research has examined whether SI is linked with other relief-driven behaviors. The present study sought to provide preliminary support for the link between SI and relief-driven safety behavior usage, a commonly used strategy for managing distress among trauma-exposed individuals. METHODS: Trauma-exposed participants (n = 95) recruited for a larger study assessing mechanisms of posttraumatic stress disorder symptomology and completed a battery of self-report measures, including SI and their use of safety behaviors. Zero-inflated negative binomial regressions were utilized to examine the association of safety behavior usage with the presence/absence of SI (i.e., zero-inflation) and SI severity. RESULTS: In bivariate models, safety behaviors were associated with a greater likelihood of experiencing any SI and reporting more severe SI. When covariates were added to the model, safety behavior usage remained significantly and positively associated with SI severity. LIMITATIONS: The present study employed cross-sectional analyses of self-report data. Future research should use neurobehavioral tasks and intensive longitudinal data to test whether an underlying sensitivity to, or propensity to engage in, relief-driven behaviors contributes to SI. DISCUSSION: Among trauma-exposed individuals, those who more frequently engage in negatively reinforced safety behaviors also report more severe SI. These findings dovetail with theoretical foundations of suicide linking SI with relief-driven motivations and provide further support that a propensity to engage in relief-driven behaviors is associated with SI.

Decomposing the late positive potential to cannabis cues in regular cannabis users: A temporal-spatial principal component analysis.

Cannabis use disorder (CUD) is increasing in the United States, yet, specific neural mechanisms of CUD are not well understood. Disordered substance use is characterized by heightened drug cue incentive salience, which can be measured using the late positive potential (LPP), an event-related potential (ERP) evoked by motivationally significant stimuli. The drug cue LPP is typically quantified by averaging the slow wave's scalp-recorded amplitude across its entire time course, which may obscure distinct underlying factors with differential predictive validity; however, no study to date has examined this possibility. In a sample of 105 cannabis users, temporo-spatial Principal Component Analysis was used to decompose cannabis cue modulation of the LPP into its underlying factors. Acute stress was also inducted to allow for identification of specific cannabis LPP factors sensitive to stress. Factor associations with CUD severity were also explored. Eight factors showed significantly increased amplitudes to cannabis images relative to neutral images. These factors spanned early (~372 ms), middle (~824 ms), and late (>1000 ms) windows across frontal, central, and parietal-occipital sites. CUD phenotype individual differences were primarily associated with frontal, middle/late latency factor amplitudes. Acute stress effects were limited to one early central and one late frontal factor. Taken together, results suggest that the cannabis LPP can be decomposed into distinct, temporal-spatial factors with differential responsivity to acute stress and CUD phenotype variability. Future individual difference studies examining drug cue modulation of the LPP should consider (1) frontalcentral poolings in addition to conventional central-parietal sites, and (2) later LPP time windows.

Obsessive-compulsive symptoms, perceived burdensomeness, and thwarted belongingness: Associations and implications among US veterans.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is among the most debilitating psychiatric disorders worldwide, but has gone relatively unnoticed within the US veteran population. Simultaneously, suicide rates continue to remain high within this population despite the high volume of veterans who receive psychiatric care. With recent research demonstrating OCD's unique relationship with suicidality, it is imperative to explore this association and factors that may explain this association within veterans. METHODS: The present study investigated OCD symptoms and their relationship with two known risk factors of suicide, perceived burdensomeness (PB) and thwarted belongingness (TB), in two samples of veterans. RESULTS: In the first study (N = 100), OCD symptoms were found to be uniquely related to both PB and TB even after covarying for demographics, trauma exposure, and probable depression. In the second study (N = 99), these relationships were replicated longitudinally. OCD symptoms at baseline were found to be indirectly related to suicidal ideation severity at a 1-month follow-up via PB and TB at post-treatment. CONCLUSION: This study highlights the importance of assessing and addressing OCD symptoms within veterans due to the unique relationship these symptoms have with suicidal constructs. A deeper understanding of the impact of OCD within the veteran population will inform future prevention and intervention efforts.

Anxiety sensitivity reduction-smoking cessation intervention among individuals who engage in dual cigarette and cannabis use: A secondary analysis.

INTRODUCTION: Cannabis use among individuals who smoke is prevalent in the general population and related to adverse health effects, including higher levels of interoceptive perturbation (i.e., a disturbance in internal experiences). An important aspect of smoking cessation among individuals who co-use cannabis is to address behavioral associations between physiological sensations and habitual behaviors via integrated treatments focused on reducing reactivity to internal perturbations such as anxiety sensitivity (i.e., the belief that such symptoms produce personal harm). METHODS: The current study involved a secondary analysis of a randomized clinical trial (RCT) of an integrated anxiety sensitivity-smoking cessation intervention compared to standard smoking cessation. The current study sought to extend findings from the initial trial to examine if the integrated intervention produced better smoking cessation outcomes than standard care among individuals who engage in dual cigarette and cannabis use. Participants were 149 adults who engage in dual cigarette and cannabis use (41.6 % female; Mage = 30.89, SD = 13.1). RESULTS: Results indicated that the anxiety sensitivity intervention produced statistically significant differences in distal (long-term) smoking abstinence at 3-, 6-, and 12-month follow-up assessments but not proximal (short-term; quit-week to 2-weeks) smoking abstinence. CONCLUSIONS: Overall, the potential of an integrated anxiety sensitivity smoking cessation intervention to yield better long-term smoking abstinence rates than standard cessation treatment among individuals who engage in dual cigarette and cannabis use is clinically significant.

The interactive effects of AS and trauma exposure on suicide capability and suicide risk.

BACKGROUND: Trauma exposure has been linked with heightened suicide risk purportedly through habituation to threatening stimuli, thereby reducing fear of suicide. However, no research has examined variables that may influence this process. Anxiety sensitivity (AS) is one cognitive-affective factor that may strengthen the relationship between trauma exposure and reduced fear of suicide by amplifying traumatic reactivity. The present study evaluated this by examining the interaction of AS and trauma exposure type (e.g., direct vs. witnessed) predicting fear of suicide and self-reported suicide risk. METHODS: Participants (n = 124) were recruited for a long-term (∼3-4 years) follow-up after participation in a clinical trial targeting suicide risk factors and were asked to complete self-report measures of trauma history, AS, fear of suicide, and suicide risk. RESULTS: Significant interactions emerged such that a greater number of direct traumasexperienced predicted lower fear of suicide and greater suicide risk among those with greater AS. The interactive effect of witnessed traumas and AS predicting suicidality was insignificant. Results remained even after including relevant covariates. DISCUSSION: The current findings suggest that AS augments the effects of repeated trauma exposure on fear of suicide and suicide risk. It is plausible these painful and provocative events are more potent among those with high AS due to the amplification of traumatic affective responses, though future research examining the longitudinal relations is needed to confirm this process.

Potentially traumatic pandemic stressors and anxiety-related sleep disturbance among Latinx persons.

Latinx persons have endured elevated rates of traumatic stress related to the COVID-19 pandemic. The effect of potentially traumatic pandemic stressors on anxiety-related sleep disturbances, a factor implicated in trauma-related psychopathology, is largely unexamined in this population. The present study evaluated the additive effect of potentially traumatic pandemic stressors (e.g., hospitalization) on anxiety-related sleep disturbances. Further, given within-group disparities across Latinx communities with intersectional identities and COVID-19-related risk factors, comparisons of the likelihood of pandemic stressors, by subgroup (i.e., older persons, individuals with chronic illness, and Black Latinx persons), were evaluated. Participants were 292 (29.8% female, Mage = 35.03 years, SD = 8.72) Latinx adults who completed a questionnaire battery during a period of high contagion (June 2020-July 2021). There were statistically significant differences across groups such that participants who experienced any potentially traumatic pandemic stressors reported elevated scores on indices of anxiety, depressive symptoms, and anxiety-related sleep disturbances compared to those who had not experienced these stressors, ds = 0.54-93. Hierarchical regression analysis revealed that hospitalization was associated with anxiety-related sleep disturbances after controlling for age, sex, chronic illness history, other stressors, anxiety, depressive symptoms, and somatic symptom burden, ΔR2 = .01. Black Latinx identity and chronic illness were significantly associated with potentially traumatic pandemic-related stressors. This is the first empirical work to evaluate the role of potentially traumatic pandemic stressors on sleep disturbances among Latinx persons and indicates that hospitalization in a pandemic context has an incremental effect on sleep disturbances in this minoritized group.

Minority stress and mental health in lesbian, gay, bisexual, transgender, and queer survivors of sexual assault.

Extant research has shown that sexual violence disproportionately affects lesbian, gay, bisexual, transgender, and queer (LGBTQ+) individuals, conferring risk for the development of posttraumatic stress symptoms (PTSS) and related mental health conditions. However, little research has focused on specific vulnerabilities among LGBTQ+-identified sexual assault (SA) survivors (e.g., minority stress) and their associations with post-SA psychopathology. To address this gap, we examined associations between experiences of minority stress and post-SA psychopathology in a sample of LGBTQ+ individuals who experienced SA (N = 92) and completed a battery of self-report measures. Results revealed significant differences in internalized stigma, community connectedness, alcohol use, and cannabis use across sexual orientation and gender modality groups, ηp 2 = .08-11. Additionally, regression analyses indicated that experiences of violence and victimization were significantly associated with higher PTSS, ß = .31, p = .020; anxiety, ß = .39, p = .003; and alcohol use severity, ß = .31, p = .027, over and above other experiences of minority stress and psychopathology risk factors. Internalized stigma was significantly associated with cannabis use severity, ß =.34, p = .011. Finally, community connectedness was significantly associated with lower anxiety symptom severity, ß = -.42, p = .001. Although longitudinal work is needed, findings indicate that experiences of minority stress may serve as risk or maintenance factors for post-SA psychopathology. These results offer important considerations for future treatment approaches tailored to LGBTQ+ survivors of SA.

Hepatic Bile Formation: Developing a New Paradigm.

In 1959, Ivar Sperber contrasted bile formation with that of urine and proposed that water flow into the canalicular conduit is in response to an osmotic, not a hydrostatic, gradient. Early attempts to support the hypothesis using a bile acid, sodium taurocholate, and the hormone secretin to stimulate bile flow led to conflicting data and a moratorium on attempts to further develop the initial proposal. However, current data amplify the initial proposal and indicate both paracellular and transcellular water flow into hepatic ductules and the canalicular conduit in response to an osmotic gradient. Also, the need to further modify the initial proposal became apparent with the recognition that bile acid aggregates (micelles), which form in the canalicular conduit, generate lecithin-cholesterol vesicles that contain water unrelated to an osmotic gradient. As part of this development is the recent introduction of the fluorescent localization after photobleaching technique for direct determination of hepatic duct flow and clarification of the role of biomarkers such as mannitol and polyethylene glycol 900. With the new paradigm, these biomarkers may prove useful for quantifying paracellular and transcellular water flow, respectively. SIGNIFICANCE STATEMENT: It is essential to identify and characterize all the sites for water flow during hepatic bile formation to obtain more precision in evaluating the causes and possible therapeutic approaches to cholestatic syndromes. Updating the Sperber proposal provides a new paradigm that addresses the advances in knowledge that have occurred.