Testicular macrophages are recruited during a narrow fetal time window and promote organ-specific developmental functions.

A growing body of evidence demonstrates that fetal-derived tissue-resident macrophages have developmental functions. It has been proposed that macrophages promote testicular functions, but which macrophage populations are involved is unclear. Previous studies showed that macrophages play critical roles in fetal testis morphogenesis and described two adult testicular macrophage populations, interstitial and peritubular. There has been debate regarding the hematopoietic origins of testicular macrophages and whether distinct macrophage populations promote specific testicular functions. Here our hematopoietic lineage-tracing studies in mice show that yolk-sac-derived macrophages comprise the earliest testicular macrophages, while fetal hematopoietic stem cells (HSCs) generate monocytes that colonize the gonad during a narrow time window in a Sertoli-cell-dependent manner and differentiate into adult testicular macrophages. Finally, we show that yolk-sac-derived versus HSC-derived macrophages have distinct functions during testis morphogenesis, while interstitial macrophages specifically promote adult Leydig cell steroidogenesis. Our findings provide insight into testicular macrophage origins and their tissue-specific roles.

Cdc42 activity in Sertoli cells is essential for maintenance of spermatogenesis.

Sertoli cells are highly polarized testicular supporting cells that simultaneously nurture multiple stages of germ cells during spermatogenesis. Proper localization of polarity protein complexes within Sertoli cells, including those responsible for blood-testis barrier formation, is vital for spermatogenesis. However, the mechanisms and developmental timing that underlie Sertoli cell polarity are poorly understood. We investigate this aspect of testicular function by conditionally deleting Cdc42, encoding a Rho GTPase involved in regulating cell polarity, specifically in Sertoli cells. Sertoli Cdc42 deletion leads to increased apoptosis and disrupted polarity of juvenile and adult testes but does not affect fetal and postnatal testicular development. The onset of the first wave of spermatogenesis occurs normally, but it fails to progress past round spermatid stages, and by young adulthood, conditional knockout males exhibit a complete loss of spermatogenic cells. These findings demonstrate that Cdc42 is essential for Sertoli cell polarity and for maintaining steady-state sperm production.

Event-related potentials in insomnia reflect altered perception of sleep.

STUDY OBJECTIVES: Insomnia is defined by the subjective complaint of poor sleep as well as daytime impairments. Since polysomnography (PSG) typically shows only modest sleep impairment, some still unidentified property of sleep, not mirrored in PSG, may be modified in insomnia.One possible mechanistic hypothesis is that insomnia patients may be more sensitive to inevitably occurring internal or external stimuli during the night, causing brief sleep disruptions then perceived as wake time. METHODS: Auditory event-related potentials (ERP) to low intensity (50 dB SPL) synthesized guitar tones played continuously throughout two nights of polysomnographically registered sleep were obtained in fifty patients with insomnia disorder (ID, without comorbidities) and 50 age- and sex-matched good sleeper controls (GSC) for each sleep stage and NREM/REM cycle. Phasic and tonic REM were treated as separate stages. Latencies and amplitudes of components P1, N1 and P2 were measured and analyzed by multivariate repeated-measures ANCOVA including effects of group, night, cycle, and age. RESULTS: ID showed reduced P2 amplitudes relative to GSC specifically in phasic REM sleep. The same reduction also correlated with the amount of sleep misperception across groups. Independent component analysis showed a frontal negativity to contribute most to this group difference. CONCLUSIONS: The present finding can be interpreted as increased mismatch negativity (MMN) in ID, reflecting automated detection of change in the auditory system and a concomitant orienting response. Specifically phasic REM sleep appears to be vulnerable to sensory afferences in ID patients, possibly contributing to the perception of being awake. CLINICAL TRIAL INFORMATION: Short name "PERSLEEP 2," URL https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008965, Registration DRKS00008965.

Loss of Mafb and Maf distorts myeloid cell ratios and disrupts fetal mouse testis vascularization and organogenesis†.

Testis differentiation is initiated when Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but cell types within the interstitial compartment, such as immune and endothelial cells, are also critical for organ formation. Our previous work implicated macrophages in fetal testis morphogenesis, but little is known about genes underlying immune cell development during organogenesis. Here, we examine the role of the immune-associated genes Mafb and Maf in mouse fetal gonad development, and we demonstrate that deletion of these genes leads to aberrant hematopoiesis manifested by supernumerary gonadal monocytes. Mafb; Maf double knockout embryos underwent initial gonadal sex determination normally, but exhibited testicular hypervascularization, testis cord formation defects, Leydig cell deficit, and a reduced number of germ cells. In general, Mafb and Maf alone were dispensable for gonad development; however, when both genes were deleted, we observed significant defects in testicular morphogenesis, indicating that Mafb and Maf work redundantly during testis differentiation. These results demonstrate previously unappreciated roles for Mafb and Maf in immune and vascular development and highlight the importance of interstitial cells in gonadal differentiation.

Distinct Roles for Rac1 in Sertoli Cell Function during Testicular Development and Spermatogenesis.

Sertoli cells are supporting cells of the testicular seminiferous tubules, which provide a nurturing environment for spermatogenesis. Adult Sertoli cells are polarized so that they can simultaneously support earlier-stage spermatogenic cells (e.g., spermatogonia) basally and later-stage cells (e.g., spermatids) apically. To test the consequences of disrupting cell polarity in Sertoli cells, we perform a Sertoli-specific conditional deletion of Rac1, which encodes a Rho GTPase required for apicobasal cell polarity. Rac1 conditional knockout adults exhibit spermatogenic arrest at the round spermatid stage, with severe disruption of Sertoli cell polarity, and show increased germline and Sertoli cell apoptosis. Thus, Sertoli Rac1 function is critical for the progression of spermatogenesis but, surprisingly, is dispensable for fetal testicular development, adult maintenance of undifferentiated spermatogonia, and meiotic entry. Our data indicate that Sertoli Rac1 function is required only for certain aspects of spermatogenesis and reveal that there are distinct requirements for cell polarity during cellular differentiation.

Variability in expression of the human MDR1 drug efflux transporter and genetic variation of the ABCB1 gene: implications for drug-resistant epilepsy.

Among individuals diagnosed with epilepsy, as many as one in three develop resistance to antiepileptic drugs (AEDs) thus rendering their seizures refractory to treatment. Despite current antiepileptic drugs (AEDs) having a variety of modes of action, seizures in drug-resistant individuals often persist even after treatment with two or more drugs. The underlying cause of this broad resistance is currently under debate, but two dominant theories have emerged and have been widely studied. Here we discuss current literature investigating the "transporter theory", the idea that individuals present with drug resistance due to genetic variability in the ABCB1 gene encoding the efflux transporter multidrug resistance protein 1 (MDR1). Results of in vitro and in vivo studies suggest that variability in the expression of the MDR1 transporter may be closely tied to drug resistance. While there is much support for this hypothesis from molecular and mechanistic studies, population-based studies of ABCB1 polymorphisms are divergent in their conclusions, and there is need for additional investigations.

Model Studies on the Antioxidative Effect of Polyphenols in Thermally Treated D-Glucose/L-Alanine Solutions with Added Metal Ions.

The influence of different polyphenolic compounds (PPs) on the Maillard reaction in a d-glucose/l-alanine model system with or without metal ions was studied under various reaction conditions. At temperatures up to 100 °C the PPs showed pro-oxidative effects due to their reducing effects on metal ions. This can be explained by a combined redox cycling mechanism of metals and PPs that promotes oxidation in the Maillard reaction. The antioxidative capacities of the PPs were measured with three different assays and correlated directly with their pro-oxidative effects on d-glucosone formation. The degree of the pro-oxidative effect depended not only on the PPs' reducing potential and their antioxidative ability but also on their concentration, the temperature, and the pH value of the model system. At low pH values and temperatures, the PPs were more stable and therefore showed an increased pro-oxidative tendency. In contrast, some of the used PPs were almost completely degraded at temperatures of 130 °C, and the formed polymers were able to complex metal ions. In the absence of these catalyzing ions, the oxidation ratio of d-glucose to d-glucosone was decreased.

Patients with diabetic retinopathy have high retinal venous pressure.

BACKGROUND: The introduction of ophthalmodynamometric measurement of retinal venous pressure (RVP) now permits the quantification, or at least an approximation, of the real pressure in the retinal veins. METHODS: We measured the RVP of healthy control subjects, patients with diabetes without diabetic retinopathy (nonDR) and patients with diabetes and diabetic retinopathy (DR). RESULTS: The mean ± SD RVP for the control, nonDR and DR groups were 23.4 ± 7.33, 22.5 ± 5.78 and 37.7 ± 10.1 mmHg, respectively. In the diabetes patients with DR, the RVP was markedly and significantly increased, and this result was significantly age dependent. RVP was not increased in the group of diabetes patients without DR. In our tested population, diabetes had a minor influence on intraocular pressure. CONCLUSION: Regardless of the cause, a marked increase in RVP in diabetes patients with DR is clinically relevant, as it reduces perfusion pressure and increases transmural pressure. The reduced perfusion pressure contributes to hypoxia, and the increased transmural pressure can facilitate retinal edema. Diabetes is an increasing burden, and DR is one of its most severe complications. Strategies to recognize the risk for DR and to develop personalized prevention and therapy therefore have major implications. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01771835.