Search

Background: Perinatal inflammation increases the risk for bronchopulmonary dysplasia in preterm neonates, but the underlying pathophysiological mechanisms remain largely unknown. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising cell-based therapy to prevent and/or treat the negative pulmonary consequences of perinatal inflammation in the preterm neonate. Therefore, the pathophysiology underlying adverse preterm lung outcomes following perinatal inflammation and pulmonary benefits of MAPC treatment at the interface of prenatal inflammatory and postnatal ventilation exposures were elucidated. Methods: Instrumented ovine fetuses were exposed to intra-amniotic lipopolysaccharide (LPS 5 mg) at 125 days gestation to induce adverse systemic and peripheral organ outcomes. MAPC (10 × 106 cells) or saline were administered intravenously two days post LPS exposure. Fetuses were delivered preterm five days post MAPC treatment and either killed humanely immediately or mechanically ventilated for 72 h. Results: Antenatal LPS exposure resulted in inflammation and decreased alveolar maturation in the preterm lung. Additionally, LPS-exposed ventilated lambs showed continued pulmonary inflammation and cell junction loss accompanied by pulmonary edema, ultimately resulting in higher oxygen demand. MAPC therapy modulated lung inflammation, prevented loss of epithelial and endothelial barriers and improved lung maturation in utero. These MAPC-driven improvements remained evident postnatally, and prevented concomitant pulmonary edema and functional loss. Conclusion: In conclusion, prenatal inflammation sensitizes the underdeveloped preterm lung to subsequent postnatal inflammation, resulting in injury, disturbed development and functional impairment. MAPC therapy partially prevents these changes and is therefore a promising approach for preterm infants to prevent adverse pulmonary outcomes.

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin condition. The pathogenesis involves genetic, environmental, and immunological factors as well as a barrier dysfunction of the epidermis. Biomarkers may play a significant role in diagnosis, severity assessment, and treatment monitoring of AD. They are categorizable into diagnostic and prognostic as well as severity and stratification biomarkers, offering the potential for a more personalized treatment approach. Although there have been tremendous therapeutic advancements with interleukin (IL) antagonists and Janus kinase (JAK) inhibitors, the domain of biomarkers still requires further research to clarify their place in the diagnosis and prognosis of AD to unravel a better scientific basis for personalized medical care for patients with AD. This article reviews the various biomarkers in relation to the different AD phenotypes and endotypes.

Abstract Background With the increasing incidence of skin cancer and limited access to specialised care, teledermoscopy (TDS) may represent a useful triage tool for skin cancer detection. Objectives An evaluation of a 3‐year TDS project in primary healthcare centres (PHCs) in Belgium (TELESPOT project). Methods A total of nine PHCs were trained to use an in‐house developed smartphone‐based application for macroscopic and dermoscopic acquisition of skin lesions, subsequently analysed independently by two investigators in a tertiary university skin cancer centre. The primary outcome was the proportion of high‐priority management (HPM) recommendations. Secondary outcomes included the TDS diagnoses, the quality of image acquisition, the mean time between HPM recommendations and subsequent surgery, the correlation between HPM reports and histopathology after surgery as well as patient and general practitioner satisfaction scores. All the endpoints were compared between the initial year of the TDS project and the subsequent 2‐year extension period of the study. Results Over 3 years, a total of 478 lesions were analysed in 335 patients: initial phase (105 lesions from 76 patients in six PHCs) and extension phase (373 lesions from 259 patients in nine PHCs). An HPM was recommended in 9.2% (initial and extension phases: 7.6% and 15.7%, respectively). The dermoscopic‐histological correlation achieved 84.1%. The median delay between HPM and surgery was 9 days. Conclusions This TDS project avoided unnecessary tertiary care visits in about 9 out of 10 cases, increased the HPM by a ninefold in comparison with the conventional care pathway and provided excellent satisfaction levels for PHCs and patients. Long‐term participation improved the triage quality for suspect skin lesions by 2.24‐fold.

We thank the authors of [...]

Background Neonates with congenital heart disease are at risk for impaired brain development in utero, predisposing children to postnatal brain injury and adverse long‐term neurodevelopmental outcomes. Given the vital role of the placenta in fetal growth, we assessed the incidence of placental pathology in fetal congenital heart disease and explored its association with total and regional brain volumes, gyrification, and brain injury after birth. Methods and Results Placentas from 96 term singleton pregnancies with severe fetal congenital heart disease were prospectively analyzed for macroscopic and microscopic pathology. We applied a placental pathology severity score to relate placental abnormalities to neurological outcome. Postnatal, presurgical magnetic resonance imaging was used to analyze brain volumes, gyrification, and brain injuries. Placental analyses revealed the following abnormalities: maternal vascular malperfusion lesions in 46%, nucleated red blood cells in 37%, chronic inflammatory lesions in 35%, delayed maturation in 30%, and placental weight below the 10th percentile in 28%. Severity of placental pathology was negatively correlated with cortical gray matter, deep gray matter, brainstem, cerebellar, and total brain volumes (r=−0.25 to −0.31, all P

Abstract Background Oxygen‐flow‐assisted topical administration of 5% methotrexate (OFAMTX5%) was recently described as a painless therapeutic option with good cosmetic results for superficial basal cell carcinoma (sBCC). Objectives To assess the efficacy and cosmetic outcome of OFAMTX5% for small (2 cm) sBCCs of the trunk. Methods Patients with a least two sBCCs, as diagnosed by clinical, dermatoscopic and optical coherence tomography (OCT) examination, were included. One target lesion was treated 2×/week for 2 weeks. Complete (CR), partial (PR) and no (NR) responses, respectively defined as a total absence, improvement or a similar OCT aspect compared to baseline, were evaluated by OCT at 3 and 12 months postprocedure. Cosmetic outcome was evaluated at 1 year. Results At 3 months in a cohort of 32 patients (mean age: 54 years, min: 44 years, max: 89 years), the small sBCC lesion group presented a 94.4% (17/18) CR and a 5.5% PR (1/18), whereas the large lesion group revealed a CR of 64.3% (9/14) and PR of 35.7% (5/14). At 12 months, 3/14 large lesions presented recurrent sBCC at the border of the target lesion, but none in the small lesion group (0/18). No treatment‐related cutaneous nor systemic adverse events were observed. No OCT changes were noted at 3 and 12 months in control sBCC lesions. Cosmetic results were scored as good and excellent in 19.4% and 80.1%, respectively. Conclusions OFAMTX5% represents an interesting therapeutic alternative for sBCC on the trunk, without pain sensations and treatment‐related adverse effects. The place of OFAMTX5% in the therapeutic armamentarium against sBCC remains to be determined in larger series.

AbstractBackground The diagnostic value of C-reactive protein (CRP) for appendicitis in children has not been evaluated in primary care. As biochemical responses and differential diagnoses vary with age, separate evaluation in children and adults is needed.Objectives To determine whether adding CRP to symptoms and signs improves the diagnosis of appendicitis in children with acute abdominal pain in primary care.Methods A retrospective cohort study in Dutch general practice. Data was collected from the Integrated Primary Care Information database between 2010 and 2016. We included children aged 4–18 years, with no history of appendicitis, presenting with acute abdominal pain, and having a CRP test. Initial CRP levels were related to the specialist’s diagnosis of appendicitis, and the test’s characteristics were calculated for multiple cut-offs. The value of adding CRP to signs and symptoms was analysed by logistic regression.Results We identified 1076 eligible children, among whom 203 were referred for specialist evaluation and 70 had appendicitis. The sensitivity and specificity of a CRP cut-off ≥10 mg/L were 0.87 (95%CI, 0.77–0.94) and 0.77 (95%CI, 0.74–0.79), respectively. When symptoms lasted > 48 h, this sensitivity increased to 1.00. Positive predictive values for CRP alone were low (0.18–0.38) for all cut-off values (6–100 mg/L). Adding CRP increased the area under the curve from 0.82 (95%CI, 0.78–0.87) to 0.88 (95%CI, 0.84–0.91), and decision curve analysis confirmed that its addition provided the highest net benefit.Conclusion CRP adds value to history and physical examination when diagnosing appendicitis in children presenting acute abdominal pain in primary care. Appendicitis is least likely if the CRP value is < 10 mg/L and symptoms have been present for > 48 h.

Abstract Background Given the high prevalence of Cluster-C Personality Disorders (PDs) in clinical populations, disease burden, high societal costs and poor prognosis of comorbid disorders, a major gain in health care can be achieved if Cluster-C PDs are adequately treated. The only controlled cost-effectiveness study published so far found Individual Schema Therapy (IST) to be superior to Treatment as Usual (TAU). Group ST (GST) might improve cost-effectiveness as larger numbers can be treated in (>50%) less time compared to IST. However, to date there is no RCT supporting its (cost-) effectiveness. The overall aim of this study is to assess the evidence for GST for Cluster-C PDs and to improve treatment allocation for individual patients. Three main questions are addressed: 1) Is GST for Cluster-C PDs (cost-)effective compared to TAU? 2) Is GST for Cluster-C PDs (cost-) effective compared to IST? 3) Which patient-characteristics predict better response to GST, IST, or TAU? Methods In a multicenter RCT, the treatment conditions GST, IST, and TAU are compared in 378 Cluster-C PD patients within 10 sites. GST and IST follow treatment protocols and are completed within 1 year. TAU is the optimal alternative treatment available at the site according to regular procedures. Severity of the Cluster-C PD is the primary outcome, assessed with clinical interviews by independent raters blind for treatment. Functioning and wellbeing are important secondary outcomes. Assessments take place at week 0 (baseline), 17 (mid-GST), 34 (post-GST), 51 (post-booster sessions of GST), and 2 years (FU). Patient characteristics predicting better response to a specific treatment are studied, e.g., childhood trauma, autistic features, and introversion. A tool supporting patients and clinicians in matching treatment to patient will be developed. An economic evaluation investigates the cost-effectiveness and cost-utility from a societal perspective. A process evaluation by qualitative methods explores experiences of participants, loved ones and therapists regarding recovery, quality of life, and improving treatment. Discussion This study will determine the (cost-)effectiveness of treatments for Cluster-C PDs regarding treatment type as well as optimal matching of patient to treatment and deliver insight into which aspects help Cluster-C-PD patients recover and create a fulfilling life. Trial registration Dutch Trial Register: NL9209 . Registered on 28-01-2021,

Abstract Scabies is a very common ectoparasitosis and is responsible for a real scourge worldwide. The infestation leads to a highly contagious and pruritic dermatosis. Clinical diagnosis is not always easy; dermoscopy is a very useful diagnostic tool. Treatment relies on hygienic measures and specific acaricidals, either for topical application or oral administration. Ivermectin, permethrin and benzyl benzoate are the most frequently used therapies. Treatment failure is on the rise and could be attributed to noncompliance, treatment costs or to resistance to these agents. A series of novel agents are currently under investigation.

Preeclampsia and fetal growth restriction (PE/FGR) are pregnancy complications known to be associated with poor utero-placental function due to abnormal "physiological" remodeling of spiral arteries and unfavorable maternal cardiovascular health. However, the prevalence and degree of impaired spiral artery remodeling has not been clearly established. Prospective, multi-center observational cohort study to assess the prevalence of lesions associated with abnormal development of spiral arteries in placental bed biopsies systematically obtained from 121 women undergoing Caesarian section for PE/FGR compared with a reference group of 149 healthy controls. PE/FGR was associated with a high prevalence of impaired spiral artery remodeling compared with controls (63.6 vs 10.1 %, p < 0.001), and a higher prevalence of non-remodeled spiral arteries without the presence of intramural trophoblast (45.5 vs 6.7 %, p < 0.001), despite abundant interstitial trophoblast invasion in surrounding decidua and myometrium. Normal remodeling was associated with circumferential presence of intramural trophoblast and hardly any trophoblast in surrounding tissue. Acute atherosis (28.9 vs 3.4 %, p < 0.001) and thrombosis (16.5 vs 5.4 %, p = 0.003) lesions were significantly more prevalent in PE/FGR. Impaired remodeling, acute atherosis and thrombosis lesions were equally present in both decidual and myometrial segments of the spiral arteries in both groups. Impaired remodeling was most prominent in the groups with FGR (with or without PE) and thrombosis was most often seen in the group with PE and FGR. PE/FGR is associated with a high prevalence of impaired physiological remodeling and vascular lesions of the uterine spiral arteries in the placental bed. [Display omitted] • Preeclampsia and fetal growth restriction are associated with inefficient trophoblast invasion. • Acute atherosis and thrombosis are more prevalent in spiral arteries of women with preeclampsia and/or FGR. • Normal remodeling is associated with circumferential intramural trophoblast. • Abnormal remodeling is associated with abundant extravascular trophoblast invasion. • Spiral artery lesions are more severe in the FGR group than in the preeclampsia alone group. [ABSTRACT FROM AUTHOR]

Finding infant rib fractures was for many years an almost undisputed proof that physical child abuse took place. Yet, these rib fractures are virtually always occult and asymptomatic and are only identified when looked for, usually with X-rays, from physical child abuse accusations related to, e.g., suspicion of the shaken baby syndrome. In a recent systematic literature review (searched in Cochran, Embase, PubMed and Sociological Abstracts), Güvensel questioned the diagnostic accuracy of rib fractures to be caused by abuse, due to lack of sufficient scientific evidence. Further, there is currently a world-wide disagreement between physicians considering themselves child abuse specialized, and physicians that explore non-abuse-related symptoms that may mimic physical abuse, which, it is hoped, will significantly reduce current unjustified child abuse diagnoses. In an attempt to help resolving this disagreement, we hypothesize that the probability of physical child abuse-related infant rib fractures is significantly lower than the probability of all other possible non-abuse-related causes of occult asymptomatic infant rib fractures, e.g., from birth trauma, prematurity, osteogenesis imperfecta, hypermobile Ehlers-Danlos Syndrome, severe chronic placental pathology (e.g., massive perivillous fibrin depositions and severe chronic histiocytic intervillositis), and vitamin-D deficiency. As method, we attempted to assess the incidence of these various causes of infant rib fractures, in the Netherlands and the USA. The results are that the estimated Dutch and USA physical abuse-related infant rib fracture incidences are at least about 250 and 45 times lower than the sum of all the non-abuse-related estimates. Because these latter rib fractures are occult and asymptomatic, it is likely that (many) more could be out there. In conclusion, occult asymptomatic rib fractures develop perinatally, virtually always as birth trauma, in infants with sufficiently weak bones due to vitamin D deficiency, transmitted by their vitamin D deficient pregnant mothers. This group also includes cortical rib cracks due to deformation forces, with an estimated 186/100,000 incidence. And, despite obvious uncertainties in all estimated incidences, we provided strong evidence that our hypothesis has relevance, implying that the abundant occult asymptomatic rib fractures, when found in infants, should not be used to assess potential physical child abuse.

The development of the normal human heart, ranging from gestational age to the mature adult heart, relies on a very delicate and timely orchestrated order of processes. One of the most striking alterations in time is the gradual extinction of the ability for cardiomyocytes to proliferate. Once passing this event, cardiomyocytes grow and increase in contractile strength by means of physiological hypertrophy. This process, importantly, seems to depend on an adequate development of electromechanical coupling that is achieved by the appropriate formation of the intercellular junction named the intercalated disc (ICD). In this report, we describe two sudden death cases of young and apparently healthy-born individuals without external abnormalities compared to an age-matched control. Histological examination, including the comparison with the age-matched and histology-matched controls, showed a disturbed formation of the protein machinery composing the electromechanical junctions at the ICD and an increased nuclei count for both patients. As a cause or consequence, cardiomyocytes in both sudden death cases showed signs of a delayed developmental stage, presumably resulting in an exaggerated degree of hyperplasia.

Vitamin D status is influenced by well-known determinants, but factors associated with low 25-hydroxyvitamin D levels in the cutaneous melanoma population are not well defined. The aim of this study was to confirm the well-known determinants and to assess new determinants for 25-hydroxyvitamin D levels in a cutaneous melanoma population. In a prospectively included cohort of 387 patients with cutaneous melanoma the association of 25-hydroxyvitamin D levels with sex, age, body mass index, time of blood withdrawal, Fitzpatrick phototype, vitamin D supplementation, score for intensity of lifetime sun exposure, smoking, education level, hair and skin colour, eye colour, total number of benign naevi, freckles and parameters of chronic sun damage was investigated. In addition, 25-hydroxyvitamin D levels were correlated with pathological parameters of the primary tumour and melanoma stage (8th edition of the American Joint Committee on Cancer (AJCC). Univariate and multivariate logistic regressions were performed using R software. The following factors had a significant effect on vitamin D status: body mass index, seasonal time of blood sampling, vitamin D supplementation, and a subtype of skin, and hair colour.

Abstract Introduction Teledermoscopy using smartphone-based applications is becoming more and more important in a setting of increasing frequency of skin cancer and difficult access to specialized care. The TELESPOT project aimed to provide rapid diagnosis and speed up patient flow between primary healthcare centers and a tertiary care center in Belgium. The aim of the present study is to describe the development of an in-house smartphone-based dermoscopy application, evaluate its real-life value in a series of primary healthcare centers, and present preliminary diagnostic data. Methods Modified Likert scales were used to assess patient and general practitioner (GP) satisfaction rates for the system. Furthermore, a total of 105 photographic and dermoscopic images were acquired in a series of 80 patients at participating centers. Results Overall, patient and GP satisfaction levels were 89% and 94%, respectively. High-priority management was recommended in 7.6% of cases (8/105: 3 basal cell carcinoma, 1 primary cutaneous B-cell lymphoma, 1 Spitz melanocytic nevus, 1 congenital nevus, 1 in situ melanoma, and 1 invasive melanoma, proven by histology). Conclusions The primary healthcare centers were highly satisfied with the TELESPOT project in terms of user-friendliness, efficacy, and reliability as well as in providing a reinforced image of first-line medicine efforts in combating skin cancer.

Abstract Risankizumab, an interleukin (IL)-23 antagonist, is a highly effective treatment for moderate to severe psoriasis. Crusted scabies (CS) is a rare and severe form of scabies, occurring mainly in immunosuppressed patients and/or neurologically or mentally ill patients. A young girl with Down syndrome was diagnosed with a hyperkeratotic form of psoriasis. As treatment with topical dermocorticosteroids, UVB-phototherapy and acitretin for 6 weeks did not improve the lesions, two injections of risankizumab were administered. Following these injections, the lesions became rapidly even more severely crusted, and new lesions appeared on the extremities and the face of the patient. There was histological evidence of a high charge of scabies, leading to a diagnosis of CS. The patient was hospitalized and successfully treated by local permethrine and systemic ivermectine. This case suggests that even though anti-IL23 antagonists display an excellent overall safety profile, a particular caution for infections should still be respected in patients with underlying risk factors.

Abstract Introduction Cutaneous metastases of breast cancer remain a therapeutic challenge. Oxygen flow-assisted topical administration of methotrexate 5% (OFAMTX, 5% methotrexate in a carrier solution) has recently been proven to be an efficacious alternative treatment for extramammary Paget’s disease, which is considered to be an in situ mammary adenocarcinoma of the epidermis. Case Report A 51-year-old patient with triple negative breast cancer presenting with biopsy-proven skin metastases on the chest agreed to a treatment with OFAMTX5%. The treatment duration was 2 weeks and consisted of twice-weekly sessions with OFAMTX5% applied to an area of skin of approximately 40 cm2. Skin biopsies were performed before and 2 months after procedure. The tolerance to the treatment was excellent, and no pain sensations were experienced. Two months post-procedure the treated area presented a post-inflammatory hyperpigmentation. No residual metastatic lesions were detectable on the control skin biopsy. Six months post-procedure the patient is still in clinical remission. Discussion OFAMTX5% represents an alternative skin-directed, painless, patient-friendly and efficacious adjuvant treatment for superficial metastatic lesions of breast cancer. Larger series are required to evaluate the potential of OFAMTX5% for the treatment of superficial metastatic lesions of breast cancer.

Local prophylaxis with antibiotic-loaded bone cement is a successful method to prevent post-operative infections in patients receiving orthopaedic implants. No comparable method is available for uncemented implants. Therefore, a hydrogel consisting of hyaluronic and polylactic acids was evaluated in a rabbit model for delivery of antimicrobial agents to prevent post-operative infections. In a pilot study, the suitability of the in vivo model was assessed by testing the hydrogel as carrier material for antimicrobial agents.In the main study, the antimicrobial-agent-loaded hydrogel was evaluated for infection prophylaxis. Rabbits received a titanium rod intramedullary in the tibia after contamination with Staphylococcus aureus. The rods were coated with unloaded hydrogel (Gel), hydrogel loaded with 2 % (Van2) or 5 % vancomycin (Van5), bioactive glass (BAG) or N-acetyl-L-cysteine (NAC). To analyse the infection severity after 28 d, histopathological, bacteriological, micro-computed tomographic and haematological analyses were performed. In the pilot study, the Van5 group had less infection (0/6 infected) as compared to the Gel group (5/5, p = 0.000) and the in vivo model was deemed suitable. In the main study, in the Van2 and Van5 groups, the number of infected animals was lower [1/6 (p = 0.006) and 2/6 (p = 0.044) infected, respectively]. In contrast, BAG and NAC groups showed no infection reduction (5/6 both groups, p = 0.997). The hydrogel can be used as a local carrier of vancomycin for prophylaxis of implant-related infections.The present study showed promising results for local delivery of antibacterial agents by hydrogel to prevent implant-related infections.

Abstract Background Massive perivillous fibrin deposition (MPFD) is associated with adverse pregnancy outcomes and is mainly caused by maternal factors with limited involvement of fetal or genetic causes. We present one consanguineous couple with six fetuses developing Fetal Akinesia Deformation Sequence (FADS) and MPFD, with a possible underlying genetic cause. This prompted a literature review on prevalence of FADS and MPFD. Methods Fetal ultrasound examination, motor assessment, genetic testing, postmortem examination, and placenta histology are presented (2009–2019). Literature was reviewed for the association between congenital anomalies and MPFD. Results All six fetuses developed normally during the first trimester. Thereafter, growth restriction, persistent flexed position, abnormal motility, and contractures in 4/6, consistent with FADS occurred. All placentas showed histologically confirmed MPFD. Genetic analyses in the five available cases showed homozygosity for two variants of unknown significance in two genes, VARS1 (OMIM*192150) and ABCF1 (OMIM*603429). Both parents are heterozygous for these variants. From 63/1999 manuscripts, 403 fetal outcomes were mobilized. In 14/403 fetuses, congenital abnormalities in association with MPFD were seen of which two fetuses with contractures/FADS facial anomalies. Conclusion The low prevalence of fetal contractures/FADS facial anomalies in association with MPFD in the literature review supports the possible fetal or genetic contribution causing FADS and MPFD in our family. This study with literature review supports the finding that fetal, fetoplacental, and/or genetic components may play a role in causing a part of MPFDs.

Introduction: The cholinergic anti-inflammatory pathway (CAIP) has been proposed as an efferent neural pathway dampening the systemic inflammatory response via the spleen. The CAIP activates the splenic neural plexus and a subsequent series of intrasplenic events, which at least require a close association between sympathetic nerves and T cells. Knowledge on this pathway has mostly been derived from rodent studies and only scarce information is available on the innervation of the human spleen. This study aimed to investigate the sympathetic innervation of different structures of the human spleen, the topographical association of nerves with T cells and age-related variations in nerve distribution.Materials and Methods: Spleen samples were retrieved from a diagnostic archive and were allocated to three age groups; neonates, 10–25 and 25–70 years of age. Sympathetic nerves and T cells were identified by immunohistochemistry for tyrosine hydroxylase (TH) and the membrane marker CD3, respectively. The overall presence of sympathetic nerves and T cells was semi-automatically quantified and expressed as total area percentage. A predefined scoring system was used to analyze the distribution of nerves within different splenic structures.Results: Sympathetic nerves were observed in all spleens and their number appeared to slightly increase from birth to adulthood and to decrease afterward. Irrespective to age, more than halve of the periarteriolar lymphatic sheaths (PALSs) contained sympathetic nerves in close association with T cells. Furthermore, discrete sympathetic nerves were observed in the capsule, trabeculae and red pulp and comparable to the total amount of sympathetic nerves, showed a tendency to decrease with age. No correlation was found between the number of T cells and sympathetic nerves.Conclusion: The presence of discrete sympathetic nerves in the splenic parenchyma, capsule and trabecular of human spleens could suggest a role in functions other than vasoregulation. In the PALS, sympathetic nerves were observed to be in proximity to T cells and is suggestive for the existence of the CAIP in humans. Since sympathetic nerve distribution shows interspecies and age-related variation, and our general understanding of the relative and spatial contribution of splenic innervation in immune regulation is incomplete, it remains difficult to estimate the anti-inflammatory potential of targeting splenic nerves in patients.

Summary:. Necrobiosis lipoidica (NL) is a rare granulomatous skin disorder of unknown physiopathology that is frequently associated with diabetes mellitus. The typical skin lesions of NL present as chronic, bilateral, well-defined red to yellow-brown plaques with telangectasias, a violaceous border and a waxy atrophic center. The lower legs are the most often involved areas, but NL may exceptionally develop on scar tissue following surgery. The treatment is very challenging and notoriously difficult. We report a 60-year-old diabetic woman who developed NL all along the surgical scars following breast reduction, without presenting NL on the lower legs. NL should be considered among the rare but possible skin healing complications of surgery.

Early utero-placental vascular development impacts placental development and function throughout pregnancy. We investigated whether impaired first-trimester utero-placental vascular development is associated with pathologic features of the postpartum placenta. In this prospective observational study of 65 ongoing pregnancies, we obtained three-dimensional power Doppler ultrasounds of the placenta at 7, 9 and 11 weeks of gestation. We applied VOCAL software to measure placental volume (PV), virtual reality based segmentation to measure utero-placental vascular volume (uPVV) and applied a skeletonization algorithm to generate the utero-placental vascular skeleton (uPVS). Vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-, crossing- or vessel point). Following delivery, placentas were measured and histologically examined according to the Amsterdam criteria to assess maternal vascular malperfusion (MVM). We used linear mixed models to estimate trajectories of PV, uPVV and uPVS development. Multivariable linear regression analysis with adjustments for confounders was used to evaluate associations between PV, uPVV and uPVS development and features of the postpartum placenta. We observed no associations between first-trimester PV development and measurements of the postpartum placenta. Increased first-trimester utero-placental vascular development, reflected by uPVV (β = 0.25 [0.01; 0.48]), uPVS end points (β = 0.25 [0.01; 0.48]), bifurcation points (β = 0.22 [0.05; 0.37]), crossing points (β = 0.29 [0.07; 0.52]) and vessel points (β = 0.09 [0.02; 0.17]) was positively associated with the postpartum placental diameter. uPVV was positively associated with postpartum placental weight. No associations were found with MVM. Development of the first-trimester utero-placental vasculature is associated with postpartum placental size, whereas placental tissue development contributes to a lesser extent. [Display omitted] • New imaging markers of early placental vascular development using 3D power Doppler. • Placental vascular imaging markers and histologic evaluation of the human placenta. • First-trimester vascular development is associated with postpartum placental size. [ABSTRACT FROM AUTHOR]

BRAF inhibitors may present several cutaneous adverse effects, including actinic keratosis, squamous cell carcinoma, keratoacanthoma, rashes, increased photosensitivity, panniculitis, palmoplantar and capillary involvement, pruritus and xerosis as well as granulomatous reactions. A 30-year-old patient with multiple tattoos received dabrafenib and trametinib for metastatic melanoma. After 4 months, he developed an induration and thickening strictly limited to several tattoos. Histopathology revealed nonnecrotizing granulomas in the dermis. Topical steroids relieved pruritus but not the granulomatous aspect of the tattoos. As far as we know, this is the first description of granulomatous reactions restricted to preexisting tattoos following BRAF inhibitor therapy.

Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelial stem/progenitor cells and vascular maturation, which are crucial drivers of lung development. Therefore, a translational ovine model of antenatal infection/inflammation with consecutive exposures to chronic and acute stimuli was used. Ovine fetuses were exposed intra-amniotically to Ureaplasma parvum 42 days (chronic stimulus) and/or to lipopolysaccharide 2 or 7 days (acute stimulus) prior to preterm delivery at 125 days of gestation. Pulmonary inflammation, endogenous epithelial stem cell populations, vascular modulators and morphology were investigated in preterm lungs. Pre-exposure to UP attenuated neutrophil infiltration in 7d LPS-exposed lungs and prevented reduction of SOX-9 expression and increased SP-B expression, which could indicate protective responses induced by re-exposure. Sequential exposures did not markedly impact stem/progenitors of the proximal airways (P63+ basal cells) compared to single exposure to LPS. In contrast, the alveolar size was increased solely in the UP+7d LPS group. In line, the most pronounced reduction of AEC2 and proliferating cells (Ki67+) was detected in these sequentially UP + 7d LPS-exposed lambs. A similar sensitization effect of UP pre-exposure was reflected by the vessel density and expression of vascular markers VEGFR-2 and Ang-1 that were significantly reduced after UP exposure prior to 2d LPS, when compared to UP and LPS exposure alone. Strikingly, while morphological changes of alveoli and vessels were seen after sequential microbial exposure, improved lung function was observed in UP, 7d LPS, and UP+7d LPS-exposed lambs. In conclusion, although sequential exposures did not markedly further impact epithelial stem/progenitor cell populations, re-exposure to an inflammatory stimulus resulted in disturbed alveolarization and abnormal pulmonary vascular development. Whether these negative effects on lung development can be rescued by the potentially protective responses observed, should be examined at later time points.

Background: Pachyderma is defined as severely thickened skin with deep folds and is occasionally observed with primary cutaneous NK and T-cell lymphoma (pCNKTCL), primary cutaneous B-cell lymphoma (pCBCL), and leukemia cutis (LC). Aim: To describe the clinical, histological, and therapeutic particularities of a series of pCNKTCL, pCBCL, and LC patients with pachyderma. Results: In a series of pCNKTCL (n = 70), pCBCL (n = 12), and LC (n = 2) patients followed up during 9 years, 6 cases of pachyderma were observed. Pachyderma occurred on the arms (n = 2), thighs (n = 1), forehead (n = 1), and face (n = 2). The mean age of the patients was 69 years (51–82). The stages were erythrodermic (T4) mycosis fungoides (MF) (n = 1), folliculotropic MF (FMF) (n = 2), classic (T2) MF (n = 2), and chronic myeloid leukemia (n = 1). The erythrodermic MF patient with acute pachyderma on the right arm responded rapidly to oral steroids. The other cases were indolent, appeared progressively, and were highly treatment resistant. Histology revealed dense dermal neoplastic infiltration. The immunohistological profile of the pachydermic lesions was similar to common MF and LC. Conclusion: Pachyderma is an atypical manifestation of MF and LC and may occur on the face (FMF) or the extremities (MF). The rapidly appearing pachyderma may be transitory and responds readily to oral steroids.

Tregs are crucial for maintaining maternal immunotolerance against the semiallogeneic fetus. We investigated the elusive transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy. Uterine biopsies, from placental bed (materno-fetal interface) and incision site (control) and blood were obtained from women with uncomplicated pregnancies undergoing cesarean section. Tregs and CD4+ non-Tregs were isolated for transcriptomic profiling by Cel-Seq2. Results were validated on protein and single cell levels by flow cytometry. Placental bed uTregs showed elevated expression of Treg signature markers, including FOXP3, CTLA-4, and TIGIT. Their transcriptional profile was indicative of late-stage effector Treg differentiation and chronic activation, with increased expression of immune checkpoints GITR, TNFR2, OX-40, and 4-1BB; genes associated with suppressive capacity (HAVCR2, IL10, LAYN, and PDCD1); and transcription factors MAF, PRDM1, BATF, and VDR. uTregs mirrored non-Treg Th1 polarization and tissue residency. The particular transcriptional signature of placental bed uTregs overlapped strongly with that of tumor-infiltrating Tregs and was remarkably pronounced at the placental bed compared with uterine control site. In conclusion, human uTregs acquire a differentiated effector Treg profile similar to tumor-infiltrating Tregs, specifically at the materno-fetal interface. This introduces the concept of site-specific transcriptional adaptation of Tregs within 1 organ.

Abstract Background Posttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP-seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes. Results Analysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. Of the corresponding transcription factors, four were upregulated, SP1, ARNT2, HEY2, and VDR, and two downregulated, FOSL and NR4A1. Conclusion We demonstrate a key role for genome-wide alterations in H3K27ac in FGR placentas corresponding with changes in transcription profiles of regions relevant to placental function. Future studies on the role of H3K27ac in FGR and placental-fetal development may help to identify novel targets for therapy of this currently incurable disease.

circumvallate placenta, placental abruption and acute chorioamnionitis separately are associated with unfavourable clinical outcomes. We aimed to determine the prevalence and define whether an association exists between the three abnormalities. 16,042 placenta pathology reports between 1997 and 2020 from a tertiary care centre in the Netherlands were retrospectively analysed. For the statistical analysis, the chi-square test and bootstrapping were used to evaluate an association. In our cohort the prevalence of circumvallate placenta is 2.2 %, placental abruption cases 4.0 % and acute chorioamnionitis 20.6 %. We observed a statistically significant association between all three placental abnormalities: circumvallate placenta, placental abruption and acute chorioamnionitis. In addition, there was also an association between circumvallate placenta and acute chorioamnionitis. Our results show that combined presence of circumvallate placenta, placental abruption and acute chorioamnionitis are associated in preterm birth (p = 0.001). A remarkable finding is that the combination of all three abnormalities (circumvallate placenta, placental abruption and acute chorioamnionitis) was not observed in term pregnancies >37 weeks. • Prevalence of circumvallate placenta 2.2 %, abruption 4.0 %, chorioamnionitis 20.6 %. • Significant association of all three abnormalities combined. • Association between circumvallate placenta and chorioamnionitis. • Combination of all three abnormalities was not observed pregnancies >37 wks. [ABSTRACT FROM AUTHOR]