Research Articles (Immunology)

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The mechanism of action of oral corticosteroids in relation to short- and long-term-burst therapy
Cordier, Werner; Rossouw, Theresa M. (Allergy Society of South Africa, 2025-03)
Corticosteroids, potent anti-inflammatory agents, are broadly used in various inflammatory and immune-dependent pathologies, which include asthma. Through non-genomic and genomic mechanisms of action, corticosteroids reduce pro-inflammatory mediators while promoting anti-inflammatory molecule expression. Furthermore, in the context of asthma treatment, they also promote the expression of β2 adrenergic receptors which increase the therapeutic potential of β2-receptor agonists to promote bronchodilation. However, corticosteroids also precipitate a variety of adverse events which reduce the quality of life of patients and predispose them to further pathological alterations. Given the ubiquitous expression of the glucocorticoid receptor, alongside the non-genomic and genomic mechanisms of corticosteroids, a myriad interconnecting physiological processes are altered upon receptor modulation. Both long- and short-course treatment has been linked to immune suppression, metabolic and cardiovascular disease, cerebrovascular accidents, osteoporosis, ophthalmic disorders, pneumonia and mood disorders. Consequently, clinical decision-making should consider the potential risks involved in short- and long-term use of corticosteroids because pathophysiological changes may be precipitated in both.
Effect of adipose-derived mesenchymal stromal/stem cells on mouse mammary tumour growth and formation of lung metastases
Peta, Kimberly Thando; Durandt, Chrisna; Van Heerden, Marlene B.; Pepper, Michael Sean; Ambele, Melvin (Elsevier, 2025-12)
The role of mesenchymal stromal/stem cells (MSCs) in tumour development and progression remains a subject of debate. Previous studies have reported contradictory outcomes, possibly due to variations in experimental design and the use of xenograft models. Xenograft models limit interpretation and translation due to cross-species variability. To address these limitations, we employed an isogenic mouse model of spontaneous breast cancer (BC) to investigate the impact of murine MSCs on BC development and progression. Methods: MSCs isolated from FVB/N mouse adipose tissue (mASCs) were administered to female mice with palpable mammary tumours. Tumour volume and mass were assessed, and analysis of histopathological necrosis and gene expression was conducted on mammary (MT) and lung metastatic tumours (LT). Results: No change in MT mass and volume was observed between mASC-treated and control mice. However, mASC treatment led to increased necrosis in LT but not in MT. Immunohistochemistry revealed that mASC-treated mice had fewer CD163+ anti-inflammatory macrophages in the LT but not in the MT. Tgf-β3, vegfr1, and cd105 were observed and downregulated in both MT and LT in mASC-treated mice. The downregulation of cd36 and tgf-β3 contributes to pro-tumourigenic activities, whereas the downregulation of vegfr1 and cd105 is associated with an anti-tumour effect. In the mASC treatment group, all cytokines tested for, except IL-27, were elevated. Conclusion: This study suggests that mASCs are anti-tumourigenic in pulmonary metastatic BC. Our findings emphasize the importance of considering the tumour microenvironment and employing relevant animal models when investigating the impact of MSCs on tumour progression.
Sustained activation of myeloperoxidase is associated with oxidative stress and inflammation in people living with the human immunodeficiency virus at risk of cardiovascular disease
Mokoena, Haskly; Choshi, Joel; Hanser, Sidney; Mabhida, Sihle E.; Steel, Helen Carolyn; Mokgalaboni, Kabelo; Phoswa, Wendy N.; Maarman, Gerald; Nkambule, Bongani B.; Dludla, Phiwayinkosi V. (MDPI, 2025-11)
People living with the human immunodeficiency virus (PLWH) are continually subjected to challenges involving the development of non-acquired immunodeficiency syndrome (AIDS)-related comorbidities despite the effectiveness of highly active antiretroviral therapy (HAART). Exacerbated oxidative stress, which is intrinsically linked to chronic inflammation, is implicated in non-AIDS comorbidities, including the increased risk of cardiovascular disease (CVD) observed in PLWH. Here, we review evidence on the potential pathological implications of myeloperoxidase (MPO), a leukocyte-derived enzyme and a key mediator of oxidative stress and inflammation, in driving CVD-related complications in PLWH. A systematic review approach was taken to identify relevant clinical studies through searches of Cochrane Libraries, PubMed, Web of Science, ScienceDirect, and Google Scholar, up to the 30 June 2025. The summarized data appraised clinical studies (n = 14) on adults (n = 1445) with a mean age of 45 years reporting on the association between MPO and enhanced lipid peroxidation marked by elevated concentrations of oxidized low-density lipoprotein cholesterol (oxLDL-C) in PLWH. Such results were consistent with elevated inflammatory markers, including high sensitivity C-reactive protein (hsCRP), which was also linked with endothelial dysfunction. There is a lack of evidence linking the duration of HAART to MPO levels or an increased risk of CVD. However, there is room to explore whether enhanced levels of oxLDL-C, in association with sustained MPO activation, could drive CVD risk in PLWH. The present review provides essential information on the pathological relevance of MPO in endothelial dysfunction and CVD risk in PLWH.
Comprehensive chemoanatomical mapping, and the gonadal regulation, of seven kisspeptin neuronal populations in the mouse brain
Hernandez, Vito S.; Zetter, Mario A.; Hernandez-Perez, Oscar R.; Hernandez-Gonzalez, Rafael; Camacho-Arroyo, Ignacio; Millar, Robert P.; Eiden, Lee E.; Zhang, Limei (Wiley, 2025-05)
Kisspeptinergic signaling is well-established as crucial for the regulation of reproduction, but its potential broader role in brain function is less understood. This study investigates the distribution and chemotyping of kisspeptin-expressing neurons within the mouse brain. RNAscope single, dual, and multiplex in situ hybridization methods were used to assess kisspeptin mRNA (Kiss1) expression and its co-expression with other neuropeptides, excitatory and inhibitory neurotransmitter markers, and sex steroid receptors in wild-type intact and gonadectomized young adult mice. Seven distinct kisspeptin neuronal chemotypes were characterized, including two novel kisspeptin-expressing groups described for the first time, that is, the Kiss1 population in the ventral premammillary nucleus and the nucleus of the solitary tract. Kiss1 mRNA was also observed to localize in both somatic and dendritic compartments of hypothalamic neurons. High androgen receptor expression and changes in medial amygdala and septo-hypothalamic Kiss1 expression following GDX in males, but not in females, suggest a role for androgen receptors in regulating kisspeptin signaling. This study provides a detailed chemoanatomical map of kisspeptin-expressing neurons, highlighting their potential functional diversity. The discovery of a new kisspeptin-expressing group and gonadectomy-induced changes in Kiss1 expression patterns suggest broader roles for kisspeptin in brain functions beyond those of reproduction.
Synthesis and characterisation of DOTA-kisspeptin-10 as a potential gallium-68/lutetium-177 pan-tumour radiopharmaceutical
Kleynhans, Janke; Reeve, Robert; Driver, Cathryn Helena Stanford; Marjanovic-Painter, Biljana; Sathekge, Mike Machaba; Zeevaart, Jan Rijn; Ebenhan, Thomas; Millar, Robert P. (Wiley, 2025-03)
Kisspeptin (KISS1) and its cognate receptor (KISS1R) are implicated in the progression of various cancers. A gallium-68 labelled kisspeptin-10 (KP10), the minimal biologically active structure, has potential as a pan-tumour radiopharmaceutical for the detection of cancers. Furthermore, a lutetium-177 labelled KP10 could find therapeutic application in treating oncological diseases. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was attached to the NH2-terminus of KP10 as we posited from our previous publications that this modification would not impair biological activity. Here, we showed that the biological activity, as monitored by stimulation of inositol phosphate accumulation in HEK293 transfected with the KISS1R gene, was indeed similar for KP10 and DOTA-KP10. The optimisation of radiolabelling with gallium-68 and lutetium-177 is described. Stability in serum, plasma and whole blood was also investigated. Pharmacokinetics and biodistribution were established with micro-PET/CT (positron emission tomography/computerised tomography) and ex vivo measurements. Dynamic studies with micro-PET/CT demonstrated that background clearance for the radiopharmaceutical was rapid with a blood half-life of 18 ± 3 min. DOTA-KP10 demonstrated preserved functionality at KISS1R and good blood clearance. These results lay the foundation for the further development of DOTA-KP10 analogues that have high binding affinity along with proteolytic resistance.
Predicting cerebral palsy and 18-month neurodevelopmental outcome in infants with presumed hypoxic ischaemic encephalopathy : role of general movements assessment and early neurological examination
Kali, Gugulabatembunamahlubi T.J.; Du Preez, Jacomina C.F.; Van Zyl, Jeanetta I.; Burger, Marlette; Katsabola, Hillary; Pepper, Michael Sean (Frontiers Media, 2025-10-03)
INTRODUCTION : General movements assessment (GMA), including the Motor Optimality Score—Revised (MOS-R) and the Hammersmith Infant Neurological Examination (HINE), has been shown in different settings to predict cerebral palsy (CP) and delayed neurodevelopment with high accuracy. However, their combined predictive ability has not been fully evaluated in infants with presumed hypoxic–ischaemic encephalopathy (HIE). OBJECTIVE : This study aimed to assess the predictive ability of combined GMA, MOS-R, and HINE at 3 months in term or near-term infants diagnosed with presumed HIE, for neurodevelopmental outcome at 18 months. METHODS : A cohort of presumed HIE infants treated with therapeutic hypothermia (TH) underwent GMA, MOS-R, and HINE at 12–15 weeks, and neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at 9–12 and at 18–24 months of age. Combined early assessments were analysed for their predictive ability across different domains on the BSID-III. RESULTS : Twenty-four infants were included; 7 (29%) had both 12-month and 18-month BSID-III assessments, 12 (50%) were seen only at 12 months, and 5 (21%) only at 18 months. Two infants with absent fidgety movements (FMs) and poor motor repertoire were later diagnosed with CP or showed delays in two domains on the BSID-III assessment at 18 months. While most infants had some abnormality in the MOS-R categories, only absent FMs and abnormal finger variability showed some association with the 18-month BSID-III assessment on univariate analysis. Of the four infants classified as at risk for CP on the HINE at 3 months, two had some motor abnormalities at 18 months. Combining the GMA, MOS-R, and HINE had high sensitivity and negative predictive value (100%), but low specificity (0–17.6%) and positive predictive value (6.2%–25%) for the BSID-III outcome. CONCLUSION : Combining GMA, MOS-R, and HINE was highly sensitive in this cohort, but had low specificity. This may lead to overdiagnosis, but it may be a useful screening tool for identifying typically developing infants who do not need intensive follow-up.
Minimal impact of feed intolerance during therapeutic hypothermia for hypoxic ischaemic encephalopathy in a South African cohort with a standardised feeding regimen
Samaai, Ilhaam; Pepper, Michael Sean; Pillay, Shakti; Horn, Alan R. (Frontiers Media, 2025-07-30)
INTRODUCTION : Enteral feeding during therapeutic hypothermia (TH) for neonatal hypoxic ischaemic encephalopathy (HIE), is beneficial, but there is insufficient evidence to guide timing and feed advancement strategies. The aim of this study was to describe feed tolerance and outcomes after TH with a standardized progressive early enteral feeding regimen. METHODS : Data were retrospectively reviewed from neonates with HIE who were treated with TH for HIE in the Groote Schuur Hospital (GSH) Neonatal intensive care unit (NICU), between 1 July 2019 and 31 October 2022. Enteral feeds were commenced at age 12–24 h and incremented daily if tolerated, at 12 ml/kg/day for the first 3 days and 24 ml/kg thereafter. Nutritional, morbidity and mortality outcomes were compared between neonates with and without early feed intolerance (EFI) by the fourth day of life. RESULTS : Thirty three percent (16/48) developed EFI. However, by day six the median (IQR) enteral volumes were, 120 (110–120) and 90 (90–99), in neonates without and with feed intolerance respectively. There were no differences in resuscitation characteristics. Neonates with EFI, had higher HIE grades, more amplitude integrated electro-encephalograph (aEEG) suppression at 48 h (p = 0.002), later attainment of full nutritive sucking or cup feeds (p < 0.001) and longer hospital stays (p = 0.038). There were no differences in other morbidities. Mortality was 6% and necrotising enterocolitis did not occur in either group. CONCLUSIONS : Early feeding was generally well tolerated. Feed intolerance was more frequent in neonates with severe HIE, but most neonates achieved independence from IV fluids by day six.
Management of HER2-low metastatic breast cancer : a comprehensive statement by an expert group from the Middle East and Africa region
Dawood, Shaheenah S.; Mokhtar, Mohsen; Alwbari, Ahmed M.; Rapoport, Bernardo Leon; Esin, Ece; Jaafar, Hassan N.; Zekri, Jamal M.; Berrada, Narjiss; Özyılkan, Özgür; El-Saghir, Nagi S. (Shiraz University of Medical Sciences, 2025-10)
Approximately 50 to 67% of breast cancers (BCs), traditionally categorized as human epidermal growth factor receptor 2 (HER2)-negative, but demonstrating low HER2 expression, are now being defined as a new HER2-low subset or HER2-low category of BC. For metastatic BC (mBC), standard therapy options include targeted approaches, such as cyclin-dependent kinase 4/6 inhibitors, phosphoinositide 3-kinase inhibitors, poly (adenosine diphosphate-ribose) polymerase inhibitors, and anti-programmed death-ligand 1 agents, depending on tumor type and its molecular profile. Recent clinical trials reported significant clinical benefits from novel anti‑HER2 antibody‑drug conjugates, such as trastuzumab deruxtecan in HER2‑low mBC. Novel treatment options have increased the complexity of the clinical decision‑making process, particularly for treatment sequencing for each clinical setting. A regional expert committee meeting was held to discuss the challenges, overcome limitations, and present recommendations to enhance HER2 reporting as well as treatment of patients with HER2‑low mBC in the Middle East and Africa region.
Genetic variants associated with suspected neonatal hypoxic ischaemic Encephalopathy : a study in a South African context
Foden, Caroline J.; Durant, Kevin; Mellet, Juanita; Joubert, Fourie; Van Rensburg, Jeanne; Masemola, Mogomane Yvonne Khomotso; Velaphi, Sithembiso C.; Nakwa, Firdose L.; Horn, Alan R.; Pillay, Shakti; Kali, Gugu; Coetzee, Melantha; Ballot, Daynia E.; Kalua, Thumbiko; Babbo, Carina; Pepper, Michael Sean; NESHIE Working Group (MDPI, 2025-03)
Neonatal encephalopathy suspected to be due to hypoxic ischaemic encephalopathy (NESHIE) carries the risk of death or severe disability (cognitive defects and cerebral palsy). Previous genetic studies on NESHIE have predominantly focused on exomes or targeted genes. The objective of this study was to identify genetic variants associated with moderate–severe NESHIE through whole-genome, unbiased analysis. Variant filtering and prioritization were performed, followed by association testing both on a case–control basis and to compare the grades of severity and/or progression. Association testing on neonates with NESHIE (N = 172) and ancestry-matched controls (N = 288) produced 71 significant genetic variants (false discovery rate corrected p-value < 6.2 × 10−4), all located in non-coding regions and not previously implicated in NESHIE. Disease-associated variants in non-coding regions are considered to affect regulatory functions, possibly by modifying gene expression, promoters, enhancers, or DNA structure. The most significant variant was at position 6:162010973 in the Parkin RBR E3 ubiquitin protein ligase (PRKN) intron. Intronic variants were also identified in genes involved in inflammatory processes (SLCO3A1), DNA repair (ZGRF1), synaptogenesis (CNTN5), haematopoiesis (ASXL2), and the transcriptional response to hypoxia (PADI4). Ten variants were associated with a higher severity or lack of improvement in NESHIE, including one in ADAMTS3, which encodes a procollagen amino protease with a role in angiogenesis and lymphangiogenesis. This analysis represents one of the first efforts to analyze whole-genome data to investigate the genetic complexity of NESHIE in diverse ethnolinguistic groups of African origin and provides direction for further study.
Antiretroviral-induced toxicity in umbilical cord blood-derived haematopoietic stem/progenitor cells
Hendricks, Candice Laverne; Ellero, Andrea Antonio; Mellet, Juanita; Stivaktas, Voula; Pepper, Michael Sean (Wiley, 2025-04)
Improvements in administration and efficacy of antiretroviral therapy (ART) have reduced rates of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) to < 2%. However, in utero exposure to antiretrovirals (ARVs) leads to abnormalities in HIV-exposed uninfected (HEU) infants. We determined the effect of five ARVs on human umbilical cord blood (UCB)-derived haematopoietic stem/progenitor cells (HSPC) with the aim of exploring a potential causal relationship with haematological abnormalities. Efavirenz (EFV) was cytotoxic to HSPCs alone and in combination with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). Dolutegravir (DTG) had a biphasic effect on HSPC expansion. Immunophenotypic analysis showed increased erythroid and granulocyte precursors after 7-day culture with these drugs. Finally, using colony forming unit (CFU) assays, we observed impairment in the formation of CFU-GEMM and CFU/Burst forming unit (BFU) erythroid (E) in the presence of DTG, lamivudine (3TC) and TDF, both visually and immunophenotypically. We conclude that multiple potential HSPC toxicities exist with ARVs commonly used in pregnancy, prompting the need for further research to confirm the safety of these drugs in this vulnerable group.
Comparative effects of efavirenz and dolutegravir on metabolomic and inflammatory profiles, and platelet activation of people living with HIV
Roux, Crystal Gayle; Mason, Shayne; Du Toit, Louise; Nel, Jan-Gert; Rossouw, Theresa M.; Steel, Helen Carolyn (MDPI, 2024-09-14)
Antiretroviral therapy (ART) has reduced the mortality and morbidity associated with HIV. However, irrespective of treatment, people living with HIV remain at a higher risk of developing non-AIDS-associated diseases. In 2019, the World Health Organization recommended the transition from efavirenz (EFV)- to dolutegravir (DTG)-based ART. Data on the impact of this transition are still limited. The current study therefore investigated the metabolic profiles, cytokine inflammatory responses, and platelet activation before and after the treatment transition. Plasma samples from nine virally suppressed adults living with HIV and sixteen healthy, HIV-uninfected individuals residing in Gauteng, South Africa were compared. Metabolite and cytokine profiles, and markers associated with platelet activation, were investigated with untargeted proton magnetic resonance metabolomics, multiplex suspension bead array immunoassays, and sandwich enzyme-linked immunosorbent assays, respectively. In those individuals with normal C-reactive protein levels, the transition to a DTG-based ART regimen resulted in decreased concentrations of acetoacetic acid, creatinine, adenosine monophosphate, 1,7-dimethylxanthine, glycolic acid, 3-hydroxybutyric acid, urea, and lysine. Moreover, increased levels of formic acid, glucose, lactic acid, myo-inositol, valine, glycolic acid, and 3-hydroxybutyric acid were observed. Notably, levels of interleukin-6, platelet-derived growth factor-BB, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, soluble cluster of differentiation 40 ligand, as well as regulated on activation, normal T-cell expressed and secreted (RANTES) reached levels close to those observed in the healthy control participants. The elevated concentration of macrophage inflammatory protein-1 alpha was the only marker indicative of elevated levels of inflammation associated with DTG-based treatment. The transition from EFV- to DTG-based regimens therefore appears to be of potential benefit with metabolic and inflammatory markers, as well as those associated with cardiovascular disease and other chronic non-AIDS-related diseases, reaching levels similar to those observed in individuals not living with HIV.
Neonatal encephalopathy due to suspected hypoxic-ischaemic encephalopathy
Horn, Alan Richard; Pillay, Shakti; Velaphi, Sithembiso Christopher; Ballot, Daynia Elizabeth; Mellet, Juanita; Foden, Caroline J.; Van Rensburg, Jeanne; Babbo, Carina Corte-Real; Kali, Gugulabatembunahlubi Tenjiwe Jabulile; Coetzee, Melantha; Masemola, Mogomane Yvonne Khomotso; Nakwa, Firdose Lambey; Pepper, Michael Sean (Springer, 2025-09)
No abstract available.
Comparison of SARS-CoV-2 molecular results from the first two COVID-19 waves in Gauteng
Govender, Kreshalen; Mafuyeka, Rendani T.; Lukhwareni, Azwidowi; Meyer, Pieter Willem Adriaan (AOSIS, 2024-11-24)
BACKGROUND : Laboratory-based molecular assays return cycle threshold (Ct) values for each gene target. There is limited hyperlocal information describing the Ct, age and sex trends during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) waves in South Africa. OBJECTIVES : To analyse the demographic and Ct value trends of SARS-CoV-2 molecular assays from two South African hospitals. METHOD : The Seegene Allplex 2019-nCoV™ results from the first two waves (June–July 2020 and November 2020–January 2021) from two major hospitals in Gauteng, South Africa, were extracted from the laboratory information system. Demographic variables and Ct values were analysed. RESULTS : Overall, 2391 samples were analysed over two waves. In both waves, more women were tested than men; 68.4% versus 31.2% in the first wave and 59.8% versus 39.7% in the second wave. Differences in Ct values among the age groups were non-significant overall; however, most median Ct values in all age groups were < 30. Men had lower median Ct values in the first wave, but this trend reversed in the second wave (p < 0.001). The first wave had significantly lower mean and median Ct values per gene target (p < 0.001). CONCLUSION : Patients tested in the first wave had lower Ct values. All age groups in both waves demonstrated infectivity potential; the demographic analysis agreed with South Africa’s coronavirus disease 2019 (COVID-19) epidemiological trends in both waves. CONTRIBUTION : Granular insight into the basic demographic variables and Ct trends of SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) results within and between SARS-CoV-2 waves in South Africa.
HIV-exposed uninfected umbilical cord blood haematopoietic stem/progenitor cells differ immunophenotypically from those from HIV unexposed umbilical cord blood but have similar expansion and colony-forming properties in vitro
Hendricks, Candice Laverne; Mellet, Juanita; Stivaktas, Voula; Ambele, Melvin Anyasi; Pepper, Michael Sean (Springer, 2025-06)
No abstract available.
A new dawn : vitalising translational oncology research in Africa with the help of advanced cell culture models
Klima, Stefanie; Hurrell, Tracey; Goolam, Mubeen; Gouws, Chrisna; Engelbrecht, Anna-Mart; Kaur, Mandeep; Van den Bout, Iman (Elsevier, 2025-06)
The advent of in vitro models such as induced pluripotent stem cells (iPSC) and patient derived (disease) organoids is supporting the development of population and patient specific model systems reflecting human physiology and disease. However, there remains a significant underrepresentation of non-European, especially African model systems. The development of such models should be enthusiastically embraced by Sub-Saharan African countries (SSAC) and middle-income countries (LIMC) to direct their own research focused on the improvement of health of their own populations at a sustainable cost within their respective funding environments. Great care needs to be taken to develop national frameworks to direct, sustainably fund and support such efforts in a way that maximises the output of such models for the investment required. Here, we highlight how advanced culture models can play a role in vitalising local healthcare research by focusing on locally relevant health care questions using appropriate cell culture models. We also provide a potential national platform example that could maximise such output at the lowest cost. This framework presents an opportunity for SSAC and LMIC to base their healthcare research on locally relevant models to ensure that developed health care initiatives and interventions are best suited for the populations they serve and thus represent a reset in global health care research at large. HIGHLIGHTS • Advanced cell culture models herald a unique opportunity for African oncology research. • Rationalizing model development at a national level will achieve amplified advances. • A national framework to optimize African models is proposed.
Kisspeptin fiber and receptor distribution analysis suggests its potential role in central sensorial processing and behavioral state control
Zhang, Limei; Hernandez, Vito Salvador; Zetter, Mario Alberto; Hernandez-Perez, Oscar Rene; Hernandez-Gonzalez, Rafael; Camacho-Arroyo, Ignacio; Eiden, Lee E.; Millar, Robert P. (Wiley, 2025-05)
Kisspeptin (KP) signaling in the brain is defined by the anatomical distribution of KP-producing neurons, their fibers, receptors, and connectivity. Technological advances have prompted a re-evaluation of these chemoanatomical aspects, originally studied in the early years after the discovery of KP and its receptor Kiss1r. Previously, we characterized (Hernández et al. bioRxiv 2024) seven KP neuronal populations in the mouse brain at the mRNA level, including two novel populations, and examined their response to gonadectomy. In this study, we mapped KP fiber distribution in rats and mice using immunohistochemistry under intact as well as short- and long-term post-gonadectomy conditions. Kiss1r mRNA expression was examined via RNAscope, in relation to vesicular GABA transporter (Slc32a1) in whole mouse brain, and to KP and vesicular glutamate transporter 2 (Slc17a6), Kiss1, and Slc32a1 in hypothalamic RP3V and arcuate regions. We identified KP fibers in 118 brain regions, primarily in extra-hypothalamic areas associated with sensorial processing and behavioral state control. KP-immunoreactive fiber density and distribution were largely unchanged by gonadectomy. Kiss1r was expressed prominently in sensorial and state control regions such as the septal nuclei, the suprachiasmatic nucleus, locus coeruleus, hippocampal layers, thalamic nuclei, and cerebellar structures. Co-expression of Kiss1r and Kiss1 was observed in hypothalamic neurons, suggesting both autocrine and paracrine KP signaling mechanisms. These findings enhance our understanding of KP signaling beyond reproductive functions, particularly in sensorial processing and behavioral state regulation. This study opens new avenues for investigating KP's role in controlling complex physiological processes, including those unrelated to reproduction.
Genome sequencing projects reveal new insights into the mammalian Gonadotropin-releasing Hormone II system
Morgan, Kevin; Millar, Robert P. (Wiley, 2024-10)
The type II gonadotropin-releasing hormone (GnRH-II) was first discovered in chicken (Gallus gallus) brain and then shown to be present in many vertebrates. Indeed, its structure is conserved unchanged throughout vertebrate evolution from teleost fish through to mammals suggesting a crucial function. Yet the functional significance has been largely unexplored. Studies in comparative endocrinology show that the GnRH-II system is differentially functional in mammalian species. Intact GnRH-II neuropeptide and receptor genes (GnRH2 and GnRH receptor 2 GnRHR2) occur in marmoset monkeys (Callithrix jacchus), musk shrews (Suncus murinus) and pigs (Sus scrofa). However, one or other or both of these genes are inactivated in other species, where mutations or remnants affecting GnRH2 neuropeptide and/or type II GnRHR exons are retained in conserved genomic loci. New data from DNA sequencing projects facilitate extensive analysis of species-specific variation in these genes. Here, we describe GnRH2 and GnRHR2 genes spanning a collection of 21 taxonomic orders, encompassing around 140 species from Primates, Scandentia, Eulipotyphla, Rodentia, Lagomorpha, Artiodactyla, Carnivora, Perissodactyls, Pholidota, Chiroptera, Afrotheria, Xenarthra and Marsupialia. Intact coding exons for both GnRH2 and GnRHR2 occur in monkeys, tree shrews, shrews, moles, hedgehogs, several rodents (degu, kangaroo-rat, pocket mouse), pig, pecarry and warthog, camels and alpaca, bears, Weddell seal, hyena, elephant, aardvark and marsupials. Inactivating mutations affecting GnRH2 and GnRHR2, some located at conserved sites within exons, occur in species of primates, most rodents, lagomorphs, bovidae, cetaceans, felidae, canidae and other carnivora, pangolins, most bats, armadillo, brushtail and echidna. A functional GnRH-II system appears retained within several taxonomic families of mammals, but intact retention does not extend to whole taxonomic orders. Defining how endogenous GnRH-II neuropeptide operates in different mammals may afford functional insight into its actions in the brain, especially as, unlike the type I GnRH system, it is expressed in the mid brain and not the hypothalamus.
Outcomes of lumen apposing metal stent placement in patients with surgically altered anatomy : multicenter international experience
Mangiavillano, Benedetto; Ramai, Daryl; Kahaleh, Michel; Tyberg, Amy; Shahid, Haroon; Sarkar, Avik; Samanta, Jayanta; Dhar, Jahnvi; Bronswijk, Michiel; Van der Merwe, Schalk; Kouanda, Abdul; Ji, Hyun; Dai, Sun-Chuan; Deprez, Pierre; Vargas-Madrigal, Jorge; Vanella, Giuseppe; Leone, Roberto; Arcidiacono, Paolo Giorgio; Robles-Medranda, Carlos; Vasquez, Juan Alcivar; Arevalo-Mora, Martha; Fugazza, Alessandro; Ko, Christopher; Morris, John; Lisotti, Andrea; Fusaroli, Pietro; Dhaliwal, Amaninder; Mutignani, Massimiliano; Forti, Edoardo; Cottone, Irene; Larghi, Alberto; Rizzatti, Gianenrico; Galasso, Domenico; Barbera, Carmelo; Di Matteo, Francesco Maria; Stigliano, Serena; Binda, Cecilia; Fabbri, Carlo; Pham, Khanh Do-Cong; Di Mitri, Roberto; Amata, Michele; Crino, Stefano Francesco; Ofosu, Andrew; De Luca, Luca; Al- Lehibi, Abed; Auriemma, Francesco; Paduano, Danilo; Calabrese, Federica; Gentile, Carmine; Hassan, Cesare; Repici, Alessandro; Facciorusso, Antonio (Thieme Gruppe, 2024-10)
BACKGROUND AND STUDY AIMS : Although outcomes of lumen-apposing metal stents (LAMS) placement in native anatomy have been reported, data on LAMS placement in surgically altered anatomy (SAA) are sparse. We aimed to assess outcomes of LAMS placement in patients with SAA for different indications. PATIENTS AND METHODS : This was an international, multicenter, retrospective, observational study at 25 tertiary care centers through November 2023. Consecutive patients with SAA who underwent LAMS placement were included. The primary outcome was technical success defined as correct placement of LAMS. Secondary outcomes were clinical success and safety. RESULTS : Two hundred and seventy patients (125 males; average age 61 ± 15 years) underwent LAMS placement with SAA. Procedures included EUS-directed transgastric ERCP (EDGE) and EUS-directed transenteric ERCP (EDEE) (n = 82), EUS-guided entero-enterostomy (n = 81), EUS-guided biliary drainage (n = 57), EUS-guided drainage of peri-pancreatic fluid collections (n = 48), and EUS-guided pancreaticogastrostomy (n = 2). Most cases utilized AXIOS stents (n = 255) compared with SPAXUS stents (n = 15). Overall, technical success was 98%, clinical success was 97%, and the adverse event (AE) rate was 12%. Using AGREE classification, five events were rated as Grade II, 21 events as Grade IIIa, and six events as IIIb. No difference in AEs were noted among stent types ( P = 0.52). CONLUSIONS : This study shows that placement of LAMS is associated with high technical and clinical success rates in patients with SAA. However, the rate of AEs is noteworthy, and thus, these procedures should be performed by expert endoscopists at tertiary centers.
Characterization of portable ultra-low field MRI scanners for multi-center structural neuroimaging
Ljungberg, Emil; Padormo, Francesco; Poorman, Megan; Clemensson, Petter; Bourke, Niall; Evans, John C.; Gholam, James; Vavasour, Irene; Kollind, Shannon H.; Lafayette, Samson L.; Bennallick, Carly; Donald, Kirsten A.; Bradford, Layla E.; Lena, Beatrice; Vokhiwa, Maclean; Shama, Talat; Siew, Jasmine; Sekoli, Lydia; Van Rensburg, Jeanne; Pepper, Michael Sean; Khan, Amna; Madhwani, Akber; Banda, Frank A.; Mwila, Mwila L.; Cassidy, Adam R.; Moabi, Kebaiphe; Sephi, Dolly; Boakye, Richard A.; Ae-Ngibise, Kenneth A.; Asante, Kwaku P.; Hollander, William J.; Karaulanov, Todor; Williams, Steven C.R.; Deoni, Sean (Wiley, 2025-06)
The lower infrastructure requirements of portable ultra-low field MRI (ULF-MRI) systems have enabled their use in diverse settings such as intensive care units and remote medical facilities. The UNITY Project is an international neuroimaging network harnessing this technology, deploying portable ULF-MRI systems globally to expand access to MRI for studies into brain development. Given the wide range of environments where ULF-MRI systems may operate, there are external factors that might influence image quality. This work aims to introduce the quality control (QC) framework used by the UNITY Project to investigate how robust the systems are and how QC metrics compare between sites and over time. We present a QC framework using a commercially available phantom, scanned with 64 mT portable MRI systems at 17 sites across 12 countries on four continents. Using automated, open-source analysis tools, we quantify signal-to-noise, image contrast, and geometric distortions. Our results demonstrated that the image quality is robust to the varying operational environment, for example, electromagnetic noise interference and temperature. The Larmor frequency was significantly correlated to room temperature, as was image noise and contrast. Image distortions were less than 2.5 mm, with high robustness over time. Similar to studies at higher field, we found that changes in pulse sequence parameters from software updates had an impact on QC metrics. This study demonstrates that portable ULF-MRI systems can be deployed in a variety of environments for multi-center neuroimaging studies and produce robust results.
Nitric oxide mediated kisspeptin regulation of steroidogenesis and gametogenesis in the catfish, Clarias batrachus
Singh, Ankur; Lal, Bechan; Kumar, Pankaj; Parhar, Ishwar S.; Millar, Robert P. (Springer, 2024-08)
Nitric oxide (NO) is a gaseous molecule that regulates various reproductive functions. It is a well-recognized regulator of GnRH-FSH/LH-sex steroid secretion in vertebrates including fish. Kisspeptin is a recently discovered neuropeptide which also regulates GnRH secretion. Nitrergic and kisspeptin neurons are reported in close physical contact in the mammalian brain suggesting their interactive role in the release of GnRH. The existence of kisspeptin and NOS is also demonstrated in vertebrate gonads, but information on their reciprocal relation in gonads, if any, is obscure. Therefore, attempts were made to evaluate the functional reciprocal relation between nitric oxide and kisspeptin in the catfish gonads, if any, by administering the nitric oxide synthase (NOS) inhibitor, L-NAME {N(G)-nitro-l-arginine methyl ester}, which reduces NO production, and kisspeptin agonist (KP-10) and assessing their impacts on the expressions of kisspeptin1, different NOS isoforms, NO and steroid production in the gonadal tissue. The results revealed that L-NAME suppressed the expression of kiss1 in gonads of the catfish establishing the role of NO in kisspeptin expression. However, KP-10 increased the expression of all the isoforms of NOSs (iNOS, eNOS, nNOS) and concurrently NO and steroids in the ovary and testis. In vitro studies also indicate that kisspeptin stimulates the production of NO and estradiol and testosterone levels in the gonadal explants and medium. Thus, in vivo results clearly suggest a reciprocal interaction between kisspeptin and NO to regulate the gonadal activity of the catfish. The in vitro findings further substantiate our contention regarding the interactive role of kisspeptin and NO in gonadal steroidogenesis.

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