The research team, led by G. Osthoff of the University of the Free State with collaborators from North-West University and the University of Pretoria, set out with three objectives: to describe quantified blood metabolites in healthy giraffes and southern white rhinoceroses, to test for sex-associated differences within each species, and to compare the two species using matrix-matched samples. The choice of animals was deliberate. Giraffes are foregut-fermenting ruminant browsers, while white rhinoceroses are hindgut-fermenting grazers, meaning their blood chemistry could plausibly differ because of species physiology, diet, and the microbial fermentation that occurs at opposite ends of the digestive tract.

The rhinoceros dataset was substantial: 45 apparently healthy, free-ranging white rhinoceroses, 31 females and 14 males, were sampled during routine management procedures on a single semi-extensive wildlife property in the Northern Cape Province over five days in May 2019. Each animal was immobilised with etorphine, hyaluronidase and azaperone, and blood was drawn from the posterior auricular vein into EDTA tubes, centrifuged within two hours, and stored at minus 80 degrees Celsius. The giraffe data came from 24 valid sampling occasions involving 19 animals at Rooipoort and Sandveld Nature Reserves, with serum collected in 2017 and EDTA plasma from six animals in 2018.

The analytical pipeline was exacting. Samples were filtered through 10 kDa membranes to remove proteins, mixed with a phosphate buffer in deuterium oxide containing an internal standard, and run on a Bruker Avance III HD 500 MHz spectrometer. Metabolites were annotated against pure-compound spectral libraries supplemented with two-dimensional J-resolved and COSY spectra, and identities were graded according to the Metabolomics Standards Initiative, with Level 1 assignments confirmed against reference standards. Concentrations were reported in micromoles per litre, and blank cells where no resonance was discernible were treated as non-detections rather than zeros, a distinction the authors stress is critical for honest interpretation.

The statistics were equally careful. Concentrations were log2-transformed and tested with Welch’s t-test, which does not assume equal variances, followed by Benjamini-Hochberg false-discovery correction across each family of metabolites. Effect sizes were expressed as ratios of geometric means with Hedges’ g confidence intervals, and robustness was probed with equal-variance t-tests, Mann-Whitney U tests, Monte Carlo permutation tests with 50,000 label permutations, and leave-one-out analyses that removed each animal in turn. Notably, the team explicitly declined to use PLS-DA, OPLS-DA, VIP-based feature selection or pathway enrichment as inferential evidence, positioning the study as a model of statistical restraint in a field often criticised for overinterpretation.

The first headline result concerned sex. In the design-compatible giraffe comparison, restricted to 2017 Rooipoort serum from 10 females and six males, no metabolite differed significantly even before correction for multiple testing; the smallest p value, for 3-hydroxyisobutyric acid, was just 0.070. The authors caution that this null result should not be read as proof that the sexes are metabolically equivalent, given the small sample and the absence of a predefined equivalence margin, but it aligns with growing evidence that sex effects are not universal across wildlife metabolomes.

The rhinoceros sex comparison told a more nuanced story. Nine metabolites met the primary false-discovery criterion, with females showing higher N-acetylglucosamine, creatinine, alanine, cholic acid, glycocholic acid, acetoacetic acid, isoleucine and valine, and lower allantoin than males. Yet only N-acetylglucosamine survived every sensitivity analysis, remaining significant under Welch, permutation and rank-based testing and in all 45 leave-one-out runs. Alanine and creatinine showed moderate support, while the remaining six findings were threshold-sensitive, hovering near the significance boundary. The result is a textbook demonstration of why multiplicity control and transparent robustness categories matter: without them, six fragile findings might have been reported alongside one genuinely solid one.

The interspecies comparison produced the study’s most dramatic pattern. Comparing EDTA plasma from six verified 2018 giraffes with all 45 rhinoceroses, 36 of 50 directly comparable metabolites differed significantly, and 28 formed a conservative core supported by every statistical test and every leave-one-giraffe-out analysis. Giraffe plasma contained markedly more pyruvic acid, glycine, allantoin and trimethylamine, and far less methanol, N-acetylglucosamine, acetic acid, 3-hydroxyisovaleric acid and methylamine. Most intriguingly, a coherent pattern emerged among branched-chain amino-acid-related compounds: giraffes showed lower leucine, 2-oxoisocaproic acid, 3-methyl-2-oxovaleric acid, 3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid, consistent with a genuine difference in circulating branched-chain amino-acid chemistry between the species. Lower acetate and propionate in giraffes is biologically compatible with the contrast between foregut and hindgut fermentation, though the study did not measure feed intake or fermentation products directly.

The authors are admirably candid about the limits of their data. Species was perfectly confounded with NMR acquisition batch, since giraffe spectra were acquired in 2018 and rhinoceros spectra in 2021 with no shared quality-control material, so not every difference can be attributed to biology. Collection year was completely confounded with serum versus plasma in the giraffe dataset, precluding any inferential temporal comparison. The six-animal giraffe plasma group, while shown by leave-one-out analysis not to be driven by a single outlier, is small, and the concentrations are offered as exploratory baseline data rather than formal veterinary reference intervals, which would require dedicated reference-interval methodology. Adjustment for sex did not materially change the conservative core, ruling out the different sex ratios as an explanation for the broad pattern.

Why does this matter beyond the curiosity factor? Blood metabolomics is increasingly used in conservation medicine to detect disease, nutritional stress and environmental exposure in endangered species, from iron storage disease in Sumatran rhinoceroses to mitochondrial dysfunction in black rhinoceroses. Reliable baseline data from healthy animals are the foundation on which such diagnostic applications must be built, and they are scarce for wildlife. This study provides carefully curated concentration data for two keystone African herbivores, along with a methodological template, predefined contrasts, multiplicity correction, permutation testing and leave-one-out stability checks, that future wildlife metabolomics studies would do well to follow. The authors call for prospective work sampling both species with the same specimen matrix, balanced sexes, contemporaneous acquisition and shared quality controls. Until then, the branched-chain amino-acid signature separating the world’s tallest ruminant from its second-largest land mammal stands as an intriguing candidate for targeted investigation into how gut architecture writes itself into the blood.

Subject of Research: Comparative 1H-NMR blood metabolite profiling of giraffes and white rhinoceroses

Article Title: Comparative 1H-NMR profiling of plasma and serum metabolites in giraffes and white rhinoceroses

Article References: Osthoff, G., Mason, S., Schmidt, L., Tordiffe, A., & Deacon, F. (2026). Comparative 1H-NMR profiling of plasma and serum metabolites in giraffes and white rhinoceroses. Metabolomics, 22(5), Article 159. https://doi.org/10.1007/s11306-026-02535-0

Image Credits: AI Generated

DOI: 10.1007/s11306-026-02535-0

Keywords: metabolomics, giraffe, white rhinoceros, NMR spectroscopy, blood plasma, serum, branched-chain amino acids, wildlife physiology, conservation medicine, foregut fermentation, hindgut fermentation, South Africa

PEDF is a 50-kilodalton glycoprotein that was first identified in the conditioned media of cultured human retinal pigment epithelial cells in the early 1990s, where it displayed potent neuronal differentiative activity. Subsequent work revealed that it belongs to the serpin family of proteins, although it lacks the protease-inhibiting function that characterizes most serpins. Instead, PEDF has earned a reputation as one of the most powerful endogenous inhibitors of angiogenesis known to biology, exceeding even the effects of thrombospondin-1 in some assay systems. Beyond its vascular effects, PEDF participates in metabolism, acting as an adipokine released from adipose tissue and influencing insulin sensitivity, which is one reason researchers suspected it might connect psoriasis with the metabolic syndrome.

The rationale for the Egyptian study rested on two converging lines of evidence. First, psoriasis is fundamentally a disease of disordered angiogenesis: the dermal papillae of psoriatic plaques are packed with dilated, tortuous capillaries, and vascular endothelial growth factor and other pro-angiogenic mediators are abundantly expressed in lesional skin. Second, earlier reports had suggested that circulating PEDF concentrations were elevated in psoriasis patients, raising the possibility that the protein could serve as a biomarker linking the skin disease to cardiovascular and metabolic comorbidity. However, few studies had simultaneously examined serum levels and tissue expression, and none had rigorously tested whether PEDF tracks with clinical severity or metabolic status in the same cohort.

To address these gaps, the team, led by dermatologist Amr Abdelhamed, enrolled 26 patients with psoriasis vulgaris and 26 age- and sex-matched healthy controls. Each patient underwent a detailed clinical assessment, including calculation of the Psoriasis Area and Severity Index, the standard composite measure that grades erythema, induration, and desquamation across body regions. The investigators also screened participants for metabolic syndrome using established diagnostic criteria encompassing waist circumference, triglycerides, high-density lipoprotein cholesterol, blood pressure, and fasting glucose. Blood samples were drawn for serum PEDF quantification by enzyme-linked immunosorbent assay, while punch biopsies were taken from both lesional plaque skin and peri-lesional, normally appearing skin for immunohistochemical staining of PEDF expression.

The serum results defied expectations. Median serum PEDF concentration in the psoriasis group was 21.5 nanograms per milliliter, with a range spanning 13 to 162, compared with 22.2 nanograms per milliliter, ranging from 7 to 193, in the controls. The difference was statistically non-significant, with a p-value of 0.261, meaning that circulating PEDF offered no meaningful discrimination between patients and healthy individuals in this cohort. This finding stands in tension with earlier studies that reported elevated serum PEDF in psoriasis, and it underscores how cohort characteristics, assay methodology, and sample size can shape biomarker conclusions in dermatology research.

The tissue data told a far more striking story. Immunohistochemical analysis revealed a median PEDF expression score of 1.4, on a scale ranging from 0.5 to 2.2, in lesional psoriatic skin. That figure was dramatically lower than the median of 5, ranging from 2 to 5.5, observed in the peri-lesional skin of the same patients, and lower still than the median of 5.8, ranging from 5.7 to 7.3, in the skin of healthy controls. Both comparisons yielded p-values below 0.001, indicating differences that are extremely unlikely to have arisen by chance. In other words, the very skin that bears the hallmark of psoriasis is markedly depleted of one of the body’s chief anti-angiogenic defenses, while the skin immediately adjacent to the plaques retains near-normal expression.

This spatial gradient carries important mechanistic implications. Angiogenesis in psoriasis is thought to be fueled by an imbalance between pro-angiogenic drivers, such as vascular endothelial growth factor, interleukin-8, and angiopoietins released by keratinocytes and inflammatory cells, and anti-angiogenic brakes like PEDF and thrombospondin-1. The new data suggest that the loss of the PEDF brake is a local phenomenon confined to diseased tissue rather than a systemic shift detectable in the blood. That localization is consistent with the histopathology of psoriatic plaques, where elongated and dilated capillaries in the papillary dermis supply nutrients to the hyperproliferative epidermis above. It also aligns with experimental work showing that topical application of PEDF-derived anti-angiogenic peptides can ameliorate psoriasis-like skin changes in animal models.

Perhaps the most clinically consequential negative finding concerned the metabolic syndrome. Psoriasis patients are known to carry an elevated burden of obesity, dyslipidemia, hypertension, and insulin resistance, and PEDF has been implicated in insulin resistance in obesity, with adipose-derived PEDF rising as fat mass expands. Yet in this study, neither serum nor tissue PEDF levels correlated with the presence or absence of metabolic syndrome, nor with the PASI score, with all corresponding p-values exceeding 0.05. The authors also explored univariate correlations between PEDF levels and various histopathological features, reported in supplementary tables, without uncovering significant associations. The disconnect suggests that PEDF is unlikely to serve as a convenient blood-based biomarker tying psoriasis severity to cardiometabolic risk, at least in populations resembling this one.

Several caveats temper the conclusions. The sample size of 26 patients per group was modest, calculated with power analysis software but still vulnerable to type II error, particularly for correlation analyses that require larger cohorts to detect weak associations. The cross-sectional design captures a single time point, so it cannot establish whether reduced tissue PEDF is a cause or a consequence of plaque formation. Serum PEDF concentrations also varied enormously within both groups, spanning nearly an order of magnitude, which may reflect confounders such as body composition, age, and comorbid disease that a larger study could adjust for more thoroughly. Longitudinal follow-up of patients during effective therapy would help determine whether PEDF expression rebounds as plaques resolve.

Even so, the study sharpens the picture of psoriasis as a disease in which the local vascular microenvironment is decisively tilted toward vessel growth. The near absence of PEDF in lesional skin, contrasted with its preservation in neighboring tissue, provides a measurable target for therapeutic intervention and reinforces the rationale for anti-angiogenic strategies in dermatology. It also serves as a cautionary tale about biomarker research: a molecule can be abundant in the circulation yet irrelevant to the diseased tissue, and only paired serum-and-tissue studies can reveal that distinction. As researchers continue to map the angiogenic circuitry of psoriasis, PEDF now stands as a locally silenced guardian whose restoration might one day complement existing anti-inflammatory treatments.

Subject of Research: Serum and tissue levels of the anti-angiogenic protein PEDF in patients with psoriasis vulgaris

Article Title: Evaluation of serum and tissue levels of pigment epithelium-derived factor (PEDF) in patients with psoriasis vulgaris

Article References: Evaluation of serum and tissue levels of pigment epithelium-derived factor (PEDF) in patients with psoriasis vulgaris. (n.d.). https://doi.org/10.1007/s00403-026-04887-y

Image Credits: AI Generated

DOI: 10.1007/s00403-026-04887-y

Keywords: psoriasis vulgaris, PEDF, angiogenesis, metabolic syndrome, PASI score, serum biomarkers, immunohistochemistry, lesional skin, dermatology research, Archives of Dermatological Research, Evaluation, serum

Inflammatory bowel disease, which encompasses Crohn’s disease and ulcerative colitis, is a chronic immune-mediated condition of the digestive tract that produces abdominal pain, diarrhea, bleeding, and profound impairment of quality of life. Its relationship with psychiatric illness runs deep: anxiety is markedly overrepresented among people with IBD, and the two conditions appear to feed each other through inflammatory, neural, and behavioral pathways. Yet in patients whose primary clinical picture is dominated by anxiety, the gastrointestinal symptoms of IBD can be dismissed as somatic expressions of psychological distress, delaying diagnosis and treatment. The researchers behind the new study set out to determine whether a simple laboratory value already collected in virtually every hospitalized patient could help close that diagnostic gap.

Serum osmolality reflects the balance of sodium, glucose, urea nitrogen, and other osmotically active solutes in the blood, and it is a fundamental indicator of hydration status and metabolic homeostasis. It has previously been linked to a range of chronic inflammatory and immune-mediated disorders, but evidence connecting it specifically to inflammatory bowel disease in anxious populations was scarce. To address this, the team turned to the Medical Information Mart for Intensive Care IV database, known as MIMIC-IV, a large, de-identified repository of clinical data from patients admitted to Boston-area hospitals. They identified 9,511 inpatients with anxiety who had been admitted to general wards, of whom 211 carried a diagnosis of inflammatory bowel disease and 9,300 did not.

The analytical strategy was unusually thorough for a cross-sectional study. The researchers began with univariate screening and variance inflation factor tests to eliminate redundant variables and assess multicollinearity. To correct for baseline differences between patients with and without IBD, they applied stabilized inverse probability of treatment weighting, a technique that reweights the comparison groups so that confounders such as age, comorbidities, and medication use are statistically balanced. They then modeled the association between serum osmolality and IBD using both conventional multivariable logistic regression and Firth penalized logistic regression, the latter being a method designed to produce stable estimates when outcomes are rare—an important consideration given that only about 2 percent of the cohort had IBD.

The headline finding was striking. After full adjustment, patients with high serum osmolality, defined as a value at or above 296.71 milliosmoles per kilogram, had roughly fourteen times the odds of having inflammatory bowel disease compared with those below that threshold, with an odds ratio of 14.36 and a 95 percent confidence interval of 9.77 to 21.12, a result that remained highly significant. Restricted cubic spline analysis, which allows the data to reveal the shape of a relationship rather than forcing it into a straight line, showed a significant nonlinear dose-response pattern, with the association between osmolality and IBD varying across the physiological range rather than rising uniformly.

To test how well serum osmolality alone could discriminate between patients with and without IBD, the team employed nested 10-fold cross-validation, a rigorous machine learning practice in which the data are repeatedly split into training and testing sets to guard against over-optimistic performance estimates. The resulting area under the receiver operating characteristic curve was 0.695, indicating moderate discriminative ability. In parallel, the researchers trained an XGBoost gradient-boosting model and interrogated it with SHapley Additive exPlanations, a game-theoretic framework that quantifies each feature’s contribution to individual predictions. In that analysis, serum osmolality ranked as the second most important predictor of IBD, surpassed only by platelet count—a biologically plausible companion finding, since platelets participate directly in the inflammatory cascade driving bowel disease.

Robustness checks reinforced the result. The association held when the researchers reran the models without weighting, when they applied inverse probability of selection weighting, and when they used a narrower definition of anxiety to classify the cohort. An E-value estimation, which quantifies how strong an unmeasured confounder would need to be to explain away the observed association, suggested considerable resilience. Subgroup analyses across demographic and clinical strata showed consistent associations, indicating that the relationship between osmolality and IBD was not confined to a particular age group, sex, or clinical profile within the anxious inpatient population.

The biological story behind the statistics remains speculative but coherent. Inflammatory bowel disease involves barrier dysfunction, fluid shifts, diarrhea-driven dehydration, and systemic inflammation, all of which can perturb serum osmolality. Elevated osmolality may reflect subclinical dehydration from chronic intestinal fluid loss, or it may track with the inflammatory and neuroendocrine stress responses that characterize both IBD and anxiety. Conversely, some investigators have proposed that hyperosmolar states can themselves promote inflammatory signaling, suggesting a possible bidirectional loop. The authors are careful to note that the cross-sectional design of the study makes causal inference impossible: high osmolality could be a consequence of IBD, a contributor to it, or a shared downstream marker of another process entirely.

Those caveats matter, and the study’s limitations deserve emphasis. The cohort consisted exclusively of hospitalized patients with anxiety drawn from a single academic medical center database, so the findings may not generalize to outpatients, community populations, or people without psychiatric comorbidity. Serum osmolality is influenced by hydration, renal function, medications, and acute illness, factors that weighting and adjustment can only partially neutralize. The authors explicitly state that serum osmolality should be viewed as a potential adjunctive quantitative marker rather than a stand-alone diagnostic test, pending validation in prospective studies that follow patients over time and can establish whether osmolality changes precede the onset or flares of bowel disease.

Even with those limitations, the implications are appealing in their simplicity. Serum osmolality is already measured or easily calculated in nearly every hospitalized patient, requires no specialized equipment, and adds essentially no cost to routine care. If prospective research confirms the association, a value above the threshold identified in this study could serve as a flag prompting clinicians caring for anxious patients to look more closely for gastrointestinal inflammation—ordering fecal inflammatory markers, referral to gastroenterology, or endoscopic evaluation—rather than attributing symptoms solely to anxiety. In a field where diagnostic delay measurably worsens outcomes, an inexpensive number already sitting in the electronic health record could prove a surprisingly powerful clue, and the study’s blend of classical epidemiology with modern machine learning offers a template for how overlooked routine biomarkers might be systematically rediscovered.

Subject of Research: Association between serum osmolality and inflammatory bowel disease in patients with anxiety using the MIMIC-IV database

Article Title: Serum osmolality as a potential marker of inflammatory bowel disease in patients with anxiety: a cross-sectional analysis based on the MIMIC-IV database

Article References: Wu, S., Chen, L., Shen, Y., & Qi, Y. (2026). Serum osmolality as a potential marker of inflammatory bowel disease in patients with anxiety: a cross-sectional analysis based on the MIMIC-IV database. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08611-y

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08611-y

Keywords: serum osmolality, inflammatory bowel disease, anxiety, MIMIC-IV, biomarker, cross-sectional study, machine learning, XGBoost, SHAP, logistic regression, BMC Psychiatry, Serum