Prevalence and characteristics of Palestine refugee mothers at risk of postpartum depression in Amman, Jordan: a cross-sectional study.

BACKGROUND: Postpartum depression (PPD) is a major public health concern because it adversely affects maternal health and children's physical and mental development. The prevalence of PPD in Arab countries is higher than the worldwide prevalence. Additionally, refugee women are more likely to develop PPD than women in the general population, but little research of refugee women in Arab countries is available. The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) have provided primary health care to Palestine refugees since 1950 and began the Mental Health and Psychosocial (MHPSS) programme in Jordan in 2017 to enhance the psychosocial and social wellbeing of Palestine refugees. We assessed the prevalence of PPD and examined associated factors among Palestine refugee women living in Amman, Jordan. METHODS: This cross-sectional descriptive study was done between April 21 and May 21, 2018. Eligible participants were Palestine refugee mothers who had given birth 3-16 weeks previously and were attending any of five UNRWA health centres in Amman that were launching the MHPSS programme. Data were gathered in face-to-face structured interviews that included the Edinburgh Postpartum Depression Scale (EPDS) to assess PPD, the Maternal Social Support Scale to assess levels of perceived social support, and a structured questionnaire about sociodemographic, obstetric or paediatric, psychological, and social factors. Participants with scores greater than 12 in the EPDS were classified as having depressive symptoms. Logistic regression was used to identify factors associated with depressive symptoms. The study protocol was approved by the Department of Health, UNRWA Headquarters, Amman, Jordan, and Nagasaki University. Each participant provided written informed consent. FINDINGS: 251 women participated in the study, with a mean age of 27·2 years (range 18-42, SD 5·43). 123 (49%) women were classified as having PPD. Logistic regression showed that factors associated with PPD were perceived low levels of social support (adjusted odds ratio 3·76, 95% CI 1·92-10·93) and experiencing stressful life events (one event 3·92, 1·51-9·91; two events 5·77, 2·33-14·27; and three or more events 14·8, 5·23-41·89). INTERPRETATION: The prevalence of PPD among Palestine refugee women in Amman was higher than that reported in a previous study of the general childbearing population (women aged 18-45 years) in Irbid in Jordan (22%, Mohammad et al. Midwifery 2011; 27: e238-45) but similar to findings in the West Bank (47%, Quandil et al. BMC Pregnancy Childbirth 2016; 16: 375) and in Syrian refugee women in Jordan (49·6%, Mohammad et al. Res Nurs Health 2011; 41: 519-245). Our findings highlight the need to address this disorder in Palestine refugee mothers. Periodical PPD screening, raising awareness about PPD, providing information to husbands and families, and building a support system for mothers could alleviate the risk of PPD. Future studies should examine whether factors of antenatal depression, which were not assessed in this study, correlate with having PPD to clarify the need for early intervention in mothers. FUNDING: Nagasaki University.

Morbidity patterns among hospitalised Palestine refugees from Syria in Jordan: a population-based study.

BACKGROUND: Palestine refugees from Syria (PRS) are among the most vulnerable refugee groups for adverse health outcomes and require assistance from humanitarian agencies. As the armed conflict in Syria has continued, most Palestinians have been displaced from that country to neighbouring countries, where they have experienced difficulties in accessing essential services. More than 17 000 PRS are in Jordan as of 2018 and have received assistance from the United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA), including free primary care and subsidised secondary and tertiary care through contracted governmental hospitals. In this study, we investigated the morbidity patterns among PRS in Jordan receiving UNRWA-supported hospital care. METHODS: We assessed cross-sectional data extracted from the UNRWA Hospitalization Database in Jordan on Oct 18, 2018, for PRS who used UNRWA hospitalisation support between May 31, 2012, and Dec 9, 2017. The database records demographic and medical characteristics of patients and financial information for the care sought. We used descriptive statistics to reveal morbidity patterns. Analyses were done with Microsoft Excel 2016 and Stata/IC (version 15). No ethics approval was required for this study as it was conducted as a part of routine internal monitoring by UNRWA. FINDINGS: 889 PRS were included in analysis, among whom 637 (72%) were girls or women and 252 (28%) were boys or men. The age range was 1-78 years, with girls and women being younger than boys and men (28·1 years [SD 15·1] vs 31·0 years [SD 21·3], p=0·02). The most common reasons for seeking care were pregnancy, childbirth, and the puerperium (381 [60%] of 637 girls and women). Diseases of the circulatory system, digestive system, and musculoskeletal system and connective tissue were the most common diagnoses among boys and men (34 cases [14%] of 252 for each diagnosis). The mean length of stay for women (1·8 days [SD 2·0]) was slightly shorter than that for men (2·0 days [SD 2·2]) but the difference was not significant. The cost was significantly higher for boys and men (mean US$729·7 [SD 557·4] per person) than for girls and women ($326·0 [SD 1190·4], p<0·001). Of all, 886 (>99%) patients were discharged from hospital, two died, and one was transferred to another hospital. INTERPRETATION: More girls and women than boys and men sought care through the UNRWA support programme during the study period, mostly for pregnancy, childbirth, and the puerperium. However, the conditions seen in boys and men led to longer stays in hospitals and significantly higher costs. Diagnoses based on International Classification of Diseases standards should be investigated further, but this study highlights the demand for health-care services and types of care required by the PRS population. Future research should focus on identifying similarities and differences in hospital admissions for PRS compared with other Palestine refugees to inform future preventive public health efforts by UNRWA. The study examined PRS who accessed to UNRWA services only, thus the findings are not representative of PRS in general. However, this is to our knowledge the first study to present morbidity patters and differences in female and male PRS patients receiving care at UNRWA in Jordan. FUNDING: None.

Appropriate Surgical Timing of Salter Innominate Osteotomy for Residual Acetabular Dysplasia in Children.

BACKGROUND: Salter innominate osteotomy (SIO) provides favorable results for treating residual acetabular dysplasia in young children. In this study, we examined the midterm results of SIO according to the age at surgery to determine the optimal timing of this procedure. METHODS: We retrospectively examined 50 hips of 42 patients (8 boys and 34 girls) with acetabular dysplasia who underwent SIO and were followed up until skeletal maturity. The center-edge angle (CEA) was measured based on the anteroposterior radiographs of the hip obtained before surgery, 5 weeks after surgery, and at the latest follow-up. Severin classification was evaluated at the latest follow-up. Patients were categorized into 3 groups according to age at surgery: younger than 7 years of age (group A), 7 to 8 years of age (group B), and 9 years of age or older (group C). RESULTS: The mean preoperative CEA level of 0.9 degrees improved to 17.1 degrees postoperatively, which was increased to 28.1 degrees at the latest examination. Overall, 45 hips (90%) were classified as Severin I or II, with 96% in group A, 94% in group B, and 57% in group C. In group C, postoperative acetabular coverage was similar to that in the other groups (16.6 degrees in group A, 14.8 degrees in group B, and 18.1 degrees in group C), although the final outcome was unsatisfactory. The average improvement in CEA from postoperative to skeletal maturity was significantly smaller in group C than in the other groups (12.7 degrees in group A, 11.3 degrees in group B, and 3.0 degrees in group C). CONCLUSIONS: SIO showed favorable outcomes with satisfactory acetabular coverage at skeletal maturity. However, satisfactory acetabular coverage could not be obtained in some older patients because of limited postoperative remodeling capacity and smaller secondary improvement of CEA. We recommend that SIO should be performed in patients aged 8 years or younger. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Exploring health literacy and its associated factors among Palestinian university students: a cross-sectional study.

Health literacy plays an important role in personal and community health. Since university is a turning point when young adults begin to take responsibility for their own health, understanding university students' health literacy levels is crucial. To this end, we aimed to explore health literacy and its associated factors among Palestinian university students. We conducted a cross-sectional study at Birzeit University in the Ramallah district. We recruited 472 students using convenience sampling at six on-campus cafeterias. The 44-item Arabic version of the Health Literacy Questionnaire was used to measure students' health literacy levels, while a locally developed distress scale was used to measure students' distress levels. We stratified the multiple regression model for the health literacy score by gender. Students' average total health literacy score was 135.3 (SD 20.9), with male students scoring significantly higher than female students. A higher health literacy score was significantly associated with having a father with a higher level of education, a higher frequency of medical checkups, higher self-reported health status, and consulting a higher number of sources for health-related information. High distress levels were associated with lower levels of health literacy, especially among female students. This study provides the first evidence on Palestinian university students' health literacy levels. Tailored health education and promotion are required for students with low parental education and moderate to high distress. Future research is required to explain the gender differences in health literacy and distress among university students.

Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity.

The acquisition of cytotoxic effector function by CD8(+) T cells is crucial for the control of intracellular infection and tumor invasion. However, it remains unclear which signaling pathways are required for the differentiation of CD8(+) cytotoxic T lymphocytes. We show here that Notch2-deficient T cells had impaired differentiation into cytotoxic T lymphocytes. In addition, dendritic cells with lower expression of the Notch ligand Delta-like 1 induced the differentiation of cytotoxic T lymphocytes less efficiently. We found that the intracellular domain of Notch2 interacted with a phosphorylated form of the transcription factor CREB1, and together these proteins bound the transcriptional coactivator p300 to form a complex on the promoter of the gene encoding granzyme B. Our results suggest that the highly regulated, dynamic control of T cell cytotoxicity depends on the integration of Notch2 and CREB1 signals.

Health and dignity of Palestine refugees at stake: a need for international response to sustain crucial life services at UNRWA.

The UN Sustainable Development Goals affirm equality and dignity as essential to the enjoyment of basic human rights, including the right to the highest attainable standard of physical and mental health, which promotes global solidarity among all people, including refugees. The UN Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) has provided support to Palestine refugees in Jordan, Lebanon, Syria, the Gaza Strip, and the West Bank since the 1950s. Today, however, conflict and violence, occupation, high levels of poverty, and other social determinants of health jeopardize the wellbeing of Palestine refugees. Health concerns include non-communicable diseases, mental health conditions, and access to hospital care. Additionally, UNRWA is continuing to face a severe funding crisis. Using a historical and health policy perspective, this Health Policy examines UNRWA strategies that facilitate continuous provision of health-care services for Palestine refugees. Given the increasingly volatile environment faced by this population, a multifaceted international response is needed to enable UNRWA to deliver sustainable services to Palestine refugees and avert further loss of life, dignity, and hope, pending a just and lasting solution to their plight in accordance with applicable international law and UN General Assembly resolutions.

Notch Balances Th17 and Induced Regulatory T Cell Functions in Dendritic Cells by Regulating Aldh1a2 Expression.

Dendritic cells (DCs) are important for adaptive immune responses through the activation of T cells. The molecular interplay between DCs and T cells determines the magnitude of T cell responses or outcomes of functional differentiation of T cells. In this study, we demonstrated that DCs in mice that are Rbpj deficient in CD11c+ cells (Rbpj-/- mice) promoted the differentiation of IL-17A-producing Th17 cells. Rbpj-deficient DCs expressed little Aldh1a2 protein that is required for generating retinoic acid. Those DCs exhibited a reduced ability for differentiating regulatory T cells induced by TGF-ß. Rbpj protein directly regulated Aldh1a2 transcription by binding to its promoter region. The overexpression of Aldh1a2 in Rbpj-deficient DCs negated their Th17-promoting ability. Transfer of naive CD4+ T cells into Rag1-deficient Rbpj-/- mice enhanced colitis with increased Th17 and reduced induced regulatory T cells (iTreg) compared with control Rag1-deficient mice. The cotransfer of iTreg and naive CD4+ T cells into Rag1-deficient Rbpj-/- mice improved colitis compared with transfer of naive CD4+ T cell alone. Furthermore, cotransfer of DCs from Rbpj-/- mice that overexpressed Aldh1a2 or Notch-stimulated DCs together with naive CD4+ T cells into Rbpj-/-Rag1-deficient mice led to reduced colitis with increased iTreg numbers. Therefore, our studies identify Notch signaling in DCs as a crucial balancer of Th17/iTreg, which depends on the direct regulation of Aldh1a2 transcription in DCs.

Three species of Dendromonocotyle Hargis, 1955 (Monogenea: Monocotylidae) collected from Japanese rays.

Eighteen species of Dendromonocotyle Hargis, 1955 (Monogenea: Monocotylidae) have so far been described from elasmobranchs worldwide. In this paper, two new species are described; Dendromonocotyle tsutsumii n. sp. from the skin of the Japanese eagle ray, Myliobatis tobijei Bleeker from Tokyo Bay and the pitted stingray, Dasyatis matsubarai Miyosi, from Ooarai, Ibaraki Prefecture, Japan, and Dendromonocotyle fukushimaensis n. sp. from the skin of the cow stingray, Dasyatis ushiei (Jordan & Hubbs) reared at an aquarium in Fukushima Prefecture, Japan. Dendromonocotyle tsutsumii is distinguished from the congeners by the presence of a sclerotised duct connecting the vagina with the seminal receptacle, and De. fukushimaensis by the large body size and the presence of a donut-shaped structure encircling the male copulatory organ near its distal end. Additionally, the reproductive system of Dendromonocotyle akajeii Ho & Perkins, 1980 is redescribed, based on specimens from the skin of the whip stingray, Hemitrygon akajei (Müller & Henle) (syn. Dasyatis akajei) caught in Hamana Lake, Shizuoka Prefecture, Japan. A key to the 20 species of Dendromonocotyle including the present new species is provided.

Assessment of mental health and psycho-social support pilot program's effect on intended stigmatizing behavior at the Saftawi Health Center, Gaza: a cross-sectional study.

Background: In the midst of a global refugee crisis, addressing mental health is critical for refugee health care delivery. Understanding efficacy of mental health interventions is more important than ever. Aims: In this study, we aim to assess the efficacy of comprehensive mental health and psychosocial support services for refugees in Gaza by comparing intended stigmatizing behavior toward mental health disorders between two health centers (HCs)(Saftawi and Nasser). Methods: One year after these services by the United Nations Relief and Works Agency (UNRWA) for Palestine Refugees in the Near East were implemented at Saftawi HC, a randomly selected sample of HC patrons (n = 205) from Saftawi, and a comparable number from a control HC (n = 203 at Nasser) completed the Reported and Intended Behavior Scale (RIBS) regarding stigma towards mental illnesses. Multivariable linear regressions were used to determine the impact of these services in the HC on attitudes against mental health. Results: Saftawi respondents endorsed significantly less intended stigmatizing behavior compared to Nasser respondents (p < 0.001). Multivariable analysis demonstrated significantly less intended stigmatizing behavior at Saftawi compared to Nasser (p < 0.01) while controlling for demographic covariables. Conclusions: UNRWA primary care services and education implemented for refugees in Gaza was associated with reduced stigmatizing behavior toward mental health, which can help guide efficacious mental health care interventions within the Palestine refugee community and in other simiilar communities.

Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome.

The nuclear pore complex (NPC) is a huge protein complex embedded in the nuclear envelope. It has central functions in nucleocytoplasmic transport, nuclear framework, and gene regulation. Nucleoporin 107 kDa (NUP107) is a component of the NPC central scaffold and is an essential protein in all eukaryotic cells. Here, we report on biallelic NUP107 mutations in nine affected individuals who are from five unrelated families and show early-onset steroid-resistant nephrotic syndrome (SRNS). These individuals have pathologically focal segmental glomerulosclerosis, a condition that leads to end-stage renal disease with high frequency. NUP107 is ubiquitously expressed, including in glomerular podocytes. Three of four NUP107 mutations detected in the affected individuals hamper NUP107 binding to NUP133 (nucleoporin 133 kDa) and NUP107 incorporation into NPCs in vitro. Zebrafish with nup107 knockdown generated by morpholino oligonucleotides displayed hypoplastic glomerulus structures and abnormal podocyte foot processes, thereby mimicking the pathological changes seen in the kidneys of the SRNS individuals with NUP107 mutations. Considering the unique properties of the podocyte (highly differentiated foot-process architecture and slit membrane and the inability to regenerate), we propose a "podocyte-injury model" as the pathomechanism for SRNS due to biallelic NUP107 mutations.

Malignant mesothelioma with squamous differentiation.

AIMS: We report the autopsy findings of a 58-year-old man with malignant mesothelioma in the left pleural cavity. METHODS AND RESULTS: The patient had a history of asbestos exposure, and the chest computed tomography scan on initial admission demonstrated an extrapleural sign, suggesting a nodular lesion in the chest wall. However, no nodular lesions were detectable in either of his lungs. In spite of chemotherapy, he died 4 months after the initial admission. An autopsy revealed markedly thickened pleura in a large section of the left pleural cavity without visible intrapulmonary primary tumour lesions. Histological examination of a biopsy specimen obtained prior to chemotherapy and that of an autopsy specimen showed that the pleural tumour was composed of a mixture of mesothelioma and tumour cells with squamous differentiation mimicking squamous cell carcinoma. CONCLUSIONS: To the best of our knowledge, this is the first case report of mesothelioma with extensive squamous differentiation in the English-language literature. The extensive squamous differentiation reminiscent of squamous cell carcinoma can be a pitfall in the pathological diagnosis of pleural cytology and that of biopsy specimens from patients with mesothelioma. Here, we report autopsy findings of a case of malignant mesothelioma with portions of extensive squamous differentiation, mimicking a squamous cell carcinoma.

Early radiographic risk factors for rigid relapse in idiopathic clubfoot treated with the Ponseti method.

BACKGROUND: This study aimed at identifying early risk factors for rigid relapse in idiopathic clubfoot using foot radiographs. METHODS: Thirty-four patients with 43 idiopathic clubfeet treated with the Ponseti method were retrospectively reviewed. RESULTS: There were seven rigid relapse recalcitrant to manipulation and requiring extensive soft-tissue release. Three radiograabphic measurements on the maximum dorsiflexion lateral (MD-Lat) radiograph, talocalcaneal (TaloCalc-Lat), tibiocalcaneal (TibCalc-Lat), and calcaneus-first metatarsal (CalcMT1-Lat) angles, showed significant differences between patients with and without rigid relapse. The TaloCalc-Lat and CalcMT1-Lat angles showed significant hazard ratio for rigid relapse by multivariate survival analysis. Clubfeet demonstrating TibCalc-Lat>90° and CalcMT1-Lat<5° have a 24.9-fold odds ratio to develop rigid relapse compared to those demonstrating TibCalc-Lat≤90° or CalcMT1-Lat≥5°. CONCLUSIONS: The TaloCalc-Lat, TibCalc-Lat, and CalcMT1-Lat angles on the MD-Lat radiograph immediately before the tenotomy, probably representing intrinsic tightness of the midfoot and/or hindfoot, are significant risk factors for rigid relapse in patients treated with the Ponseti method.

Retrospective analysis of antiretroviral therapy uptake and retention of male clients receiving methadone maintenance therapy in two provinces in Vietnam: potential synergy of the two therapies.

BACKGROUND: Vietnam has a concentrated HIV epidemic with injection drug use being the dominant mode of HIV transmission. Vietnam has rapidly expanded antiretroviral therapy (ART) and methadone maintenance therapy (MMT). This study aims to analyze ART uptake and retention among male clients receiving MMT in Vietnam in the early phase of the MMT program. METHODS: The male clients (age ≥18) who were newly enrolled in care or started ART at two HIV clinics in Hanoi (2009 to 2011) and three HIV clinics in Can Tho (2010 to 2012) were included for the analysis. The CD4 lymphocyte count at HIV care enrollment and ART initiation and retention on ART were retrospectively analyzed. The values of those receiving MMT were compared with the values of two groups: those in whom injection drug use (IDU) status was documented, but were not receiving MMT, and all male clients not receiving MMT. To analyze retention, survival analysis with log rank test and Cox proportional hazard model was used. RESULTS: During the study period, 663 adult men were newly enrolled in HIV care (237 had IDU status documented) and 456 initiated ART (167 had IDU status documented). Among those who initiated ART, 28 were receiving MMT. At care enrolment, those receiving MMT had a median CD4 count of 230 (IQR 57-308) cells/mm3, while men self-reporting IDU and not receiving MMT and all men not receiving MMT had a median CD4 count of 158 (IQR 50-370) cells/mm3 and 143 (IQR 35-366) cells/mm3, respectively. At ART initiation, men receiving MMT had significantly higher CD4 count with median at 203 (IQR 64-290) cells/mm3 than men self-reporting IDU and not receiving MMT (80, IQR 40-220, cells/mm3, p = 0.038) and all men not receiving MMT (76, IQR 20-199, cells/mm3, p = 0.009). Those receiving MMT had a significantly higher retention rate than those self-reporting IDU but not receiving MMT (hazard ratio = 0.18, p = 0.019) and men not receiving MMT (hazard ratio = 0.20, p = 0.041). CONCLUSIONS: Our analysis suggests that men receiving MMT in Vietnam are achieving relatively early uptake and high retention rates on ART. The findings support potential benefits of integrating MMT and ART services in Vietnam.

CD98hc regulates the development of experimental colitis by controlling effector and regulatory CD4(+) T cells.

CD4(+) T cell activation is controlled by signaling through the T cell receptor in addition to various co-receptors, and is also affected by their interactions with effector and regulatory T cells in the microenvironment. Inflammatory bowel diseases (IBD) are caused by the persistent activation and expansion of auto-aggressive CD4(+) T cells that attack intestinal epithelial cells. However, the molecular basis for the persistent activation of CD4(+) T cells in IBD remains unclear. In this study, we investigated how the CD98 heavy chain (CD98hc, Slc3a2) affected the development of colitis in an experimental animal model. Transferring CD98hc-deficient CD4(+)CD25(-) T cells into Rag2(-/-) mice did not cause colitis accompanied by increasing Foxp3(+) inducible regulatory T cells. By comparison, CD98hc-deficient naturally occurring regulatory T cells (nTregs) had a decreased capability to suppress colitis induced by CD4(+)CD25(-) T cells, although CD98hc-deficient mice did not have a defect in the development of nTregs. Blocking CD98hc with an anti-CD98 blocking antibody prevented the development of colitis. Our results indicate that CD98hc regulates the expansion of autoimmune CD4(+) T cells in addition to controlling nTregs functions, which suggests the CD98hc as an important target molecule for establishing strategies for treating colitis.

Manipulation of CD98 resolves type 1 diabetes in nonobese diabetic mice.

The interplay of CD4(+) and CD8(+) T cells targeting autoantigens is responsible for the progression of a number of autoimmune diseases, including type 1 diabetes mellitus (T1D). Understanding the molecular mechanisms that regulate T cell activation is crucial for designing effective therapies for autoimmune diseases. We probed a panel of Abs with T cell-modulating activity and identified a mAb specific for the H chain of CD98 (CD98hc) that was able to suppress T cell proliferation. The anti-CD98hc mAb also inhibited Ag-specific proliferation and the acquisition of effector function by CD4(+) and CD8(+) T cells in vitro and in vivo. Injection of the anti-CD98hc mAb completely prevented the onset of cyclophosphamide-induced diabetes in NOD mice. Treatment of diabetic NOD mice with anti-CD98hc reversed the diabetic state to normal levels, coincident with decreased proliferation of CD4(+) T cells. Furthermore, treatment of diabetic NOD mice with CD98hc small interfering RNA resolved T1D. These data indicate that strategies targeting CD98hc might have clinical application for treating T1D and other T cell-mediated autoimmune diseases.

Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor.

CD4(+) helper T (Th) cells differentiate toward distinct effector cell lineages characterized by their distinct cytokine expression patterns and functions. Multiple Th cell populations secrete IL-22 that contributes to both protective and pathological inflammatory responses. Although the differentiation of IL-22-producing Th cells is controlled by the aryl hydrocarbon receptor (AhR), little is known about the regulatory mechanisms inducing physiological stimulators for AhR. Here, we show that Notch signaling enhances IL-22 production by CD4(+) T cells by a mechanism involving AhR stimulation. Notch-mediated stimulation of CD4(+) T cells increased the production of IL-22 even in the absence of STAT3. CD4(+) T cells from RBP-J-deficient mice had little ability to produce IL-22 through T cell receptor-mediated stimulation. RBP-J-deficient mice were highly susceptible to the detrimental immunopathology associated with ConA-induced hepatitis with little IL-22 production by CD4(+) T cells. Exogenous IL-22 protected RBP-J-deficient mice from ConA-induced hepatitis. Notch signaling promoted production of endogenous stimulators for AhR, which further augmented IL-22 secretion. Our studies identify a Notch-AhR axis that regulates IL-22 expression and fine-tunes immune system control of inflammatory responses.

Guided growth for coronal lower limb deformities in skeletal dysplasia.

Coronal angular deformities of the lower limbs are common in young children with skeletal dysplasia . The guided growth technique has been applied to correct deformities in children, but there are few comprehensive reports on the effectiveness of the procedure in skeletal dysplasia. We reviewed 44 limbs of 22 patients with various types of skeletal dysplasias who underwent guided growth surgery. Fifteen varus and 29 valgus limbs were treated with 102 epiphysiodesis. The average age at surgery, at implant removal, and at the latest examination was 10.4 ± 3.6 years, 11.8 ± 3.7 years and 14.1 ± 4.4 years, respectively. The mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (mMPTA), lateral distal tibial angle (mLDTA) and mechanical axis deviation (MAD) were measured from standing anteroposterior radiographs of both lower limbs. The mLDTA, mMPTA and MAD were successfully improved after surgery. Moderate or severe deformities were observed in 100% of the varus and 83% of the valgus limbs preoperatively, whereas only 14% of the varus and 20% of the valgus limbs had residual deformities at the latest examination. Correction of deformities was limited in some older children. Fifteen limbs (34%) required repeated implantations due to recurrence or inverted deformity. The guided growth surgery is effective in correcting coronal angular deformities in children with skeletal dysplasia with a limited risk of complications. The timing of surgery and implant removal is critical in obtaining satisfactory correction and preventing recurrence or inverted deformities.

Notch signaling regulates the development of a novel type of Thy1-expressing dendritic cell in the thymus.

Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) required for T-cell activation and are classified into several subtypes by phenotypic and functional characteristics. However, it remains unclear if distinct transcription factors control the development of each DC subpopulation. In this report, we demonstrate that Notch signaling controls the development of a novel DC subtype that expresses Thy1 (Thy1(+) DCs). Overstimulation of bone marrow cells with the Notch ligand Delta-like 1 promoted the development of Thy1(+) DCs. Thy1(+) DCs are characterized as CD11c(+) MHC class II(+) NK1.1(-) B220(-) CD8α(+) , and are present in the thymus but not in the spleen and lymph nodes. Thymic Thy1(+) DCs are able to capture exogenous proteins and delete CD4(+) CD8(+) T cells. Transplantation experiments demonstrated that CD44(+) CD25(-) and CD44(+) CD25(+) thymocytes can differentiate into Thy1(+) DCs. Recombination signal binding protein for immunoglobulin kappa J region (RBP-J) deficiency in lineage-negative bone marrow cells, but not CD11c(+) cells, disrupted Thy1(+) DC development in the thymus. Our data indicate that Notch signaling controls the development of a novel type of Thy1-expressing DC in the thymus that possibly controls negative selection, and indicates that there may be highly regulated, differential transcriptional control of DC development. Furthermore, our findings suggest that Notch signaling regulates T-cell development not only by intrinsically inducing T-cell lineage-specific gene programs, but also by regulating negative selection through Thy1(+) DCs.

Notch2 regulates the development of marginal zone B cells through Fos.

B cells are classified into several subsets depending on their functions, marker expression pattern and localization. Marginal zone B (MZB) cells are a distinct lineage from follicular B cells, and regulate host defenses against blood-borne pathogens. Notch2/RBP-J signaling regulates the development of MZB cells by interacting with delta-like 1 ligand, although the target genes for Notch2 signaling remain unclear. We identified Fos as an upregulated gene in LPS-stimulated B cells that received Notch2 signaling. Fos is expressed in CD21(high)CD23(low) MZB cells at a higher level compared to CD21(Int)CD23(high) follicular B cells. Deleting the Notch2 gene in CD19(+) B cells decreased Fos expression in B cells. Overexpression of Fos in Notch2-deficient B cells or bone marrow cells partially restored MZB development. Fos promoter activity was upregulated by Notch2 signaling, indicating that Notch2 directly controls Fos transcription associated with MZB development. These data identify Fos as one of the target genes for Notch2 signaling that is crucial for MZB development.