Arf1 and Arf6 Synergistically Maintain Survival of T Cells during Activation.

ADP-ribosylation factor (Arf) family consisting of six family members, Arf1-Arf6, belongs to Ras superfamily and orchestrates vesicle trafficking under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins. It is well established that brefeldin A, a potent inhibitor of ArfGEFs, blocks cytokine secretion from activated T cells, suggesting that the Arf pathway plays important roles in T cell functions. In this study, because Arf1 and Arf6 are the best-characterized members among Arf family, we established T lineage-specific Arf1-deficient, Arf6-deficient, and Arf1/6 double-deficient mice to understand physiological roles of the Arf pathway in the immune system. Contrary to our expectation, Arf deficiency had little or no impact on cytokine secretion from the activated T cells. In contrast, the lack of both Arf1 and Arf6, but neither Arf1 nor Arf6 deficiency alone, rendered naive T cells susceptible to apoptosis upon TCR stimulation because of imbalanced expression of Bcl-2 family members. We further demonstrate that Arf1/6 deficiency in T cells alleviates autoimmune diseases like colitis and experimental autoimmune encephalomyelitis, whereas Ab response under Th2-polarizing conditions is seemingly normal. Our findings reveal an unexpected role for the Arf pathway in the survival of T cells during TCR-induced activation and its potential as a therapeutic target in the autoimmune diseases.

Laparoscopic or transanal repair of rectocele? Comparison of a reduction in rectocele size.

PURPOSE: This study aimed to compare the reduction in rectocele size after laparoscopic ventral rectopexy (LVR) with that after transanal repair (TAR). METHODS: Forty-six patients with rectocele who underwent LVR and 45 patients with rectocele who received TAR between February 2012 and December 2022 were included. This was a retrospective analysis of prospectively collected data. All patients had clinical evidence of a symptomatic rectocele. Bowel function was evaluated using the constipation scoring system (CSS) and fecal incontinence severity index (FISI). Substantial symptom improvement was defined as at least a 50% reduction in the CSS or FISI scores. Evacuation proctography was performed before surgery and 6 months postoperatively. RESULTS: Constipation was substantially improved in 40-70% of the LVR patients and 70-90% of the TAR patients over 5 years. Fecal incontinence was markedly improved in 60-90% of the LVR patients across 5 years and in 75% of the TAR patients at 1 year. Postoperative proctography showed a reduction in rectocele size in the LVR patients (30 [20-59] mm preoperatively vs. 11 [0-44] mm postoperatively, P < 0.0001) and TAR patients (33 [20-55] mm preoperatively vs. 8 [0-27] mm postoperatively, P < 0.0001). The reduction rate of rectocele size in the LVR patients was significantly lower than that in the TAR patients (63 [3-100] % vs. 79 [45-100] %, P = 0.047). CONCLUSION: The reduction in rectocele size was lower in the patients who underwent LVR than in those who received TAR.

PC3-Secreted Microprotein Is Expressed in Glioblastoma Stem-Like Cells and Human Glioma Tissues.

Glioblastoma multiforme (GBM) is the most prevalent malignant primary brain tumor with a high recurrence rate. Despite multimodal therapy including surgical resection, chemotherapy, and radiotherapy, the median survival time after the initial diagnosis of GBM is approximately 14 months. Since cancer stem cells (CSCs) are considered the leading cause of cancer recurrence, glioblastoma stem cell-targeted therapy is a promising strategy for the treatment of GBM. However, because CSC heterogeneity has been implicated in the difficulties of CSC-target therapy, more in-depth knowledge of CSC biology is still required to develop novel therapies. In this study, we established single cell-derived tumorspheres from human glioblastoma U87MG cells. One of these tumorspheres, P4E8 clone, showed CSC-like phenotypes, such as self-renewal capacity, expression of CSC markers, resistance to anti-cancer agents, and in vivo tumorigenicity. Therefore, we used P4E8 cells as a cell-based model of glioblastoma stem cells (GSCs). Gene expression analysis using microarray indicated that the most highly expressed genes in P4E8 cells compared to the parental U87MG were PC3-secreted microprotein (MSMP). Furthermore, MSMP was expressed in patient-derived GSCs and human glioma tissues at the protein level, implying that MSMP might contribute to glioma development and progression.

PI3K-Akt pathway enhances the differentiation of interleukin-27-induced type 1 regulatory T cells.

Interleukin 27 (IL-27) has been identified as a potent cytokine in the differentiation of type 1 regulatory T (Tr1) cells through interactions with several key elements, including transcription factors such as aryl hydrocarbon receptor and IL-21. Autocrine production of IL-21 is known to be important for maintaining IL-10 expression by Tr1 cells. Although previous studies have shown that the phosphoinositide 3-kinase (PI3K) -Akt axis contributes to the differentiation of helper T-cell subsets, the role of the PI3K pathway on Tr1 cell differentiation remains to be elucidated. Here, we demonstrate that suppression of the PI3K-Akt pathway results in impairment of IL-27-induced Tr1 (IL-27-Tr1) cell differentiation in vitro and in vivo. Furthermore, this suppression down-regulates IL-21 receptor expression by Tr1 cells, followed by suppression of IL-10 expression by IL-27-Tr1 cells. These results suggest that the PI3K pathway enhances IL-10 expression by IL-27-Tr1 cells through up-regulation of IL-21 receptors.

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells.

mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-context-dependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.

Influence of family dynamics on burden among family caregivers in aging Japan.

BACKGROUND: Long-term care for the elderly is largely shouldered by their family, representing a serious burden in a hyper-aging society. However, although family dynamics are known to play an important role in such care, the influence of caring for the elderly on burden among caregiving family members is poorly understood. OBJECTIVE: To examine the influence of family dynamics on burden experienced by family caregivers. METHODS: We conducted a cross-sectional study at six primary care clinics, involving 199 caregivers of adult care receivers who need long-term care. Participants were divided into three groups based on tertile of Index of Family Dynamics for Long-term Care (IF-Long score), where higher scores imply poorer relationships between care receivers and caregiving family: best, <2; intermediate, 2 to <5; worst, ≥5. The mean differences in burden index of caregivers (BIC-11) between the three groups were estimated by linear regression model with adjustment for care receiver's activity of daily living and cognitive function. RESULTS: Mean age of caregivers was 63.2 years (with 40.7% aged ≥ 65 years). BIC-11 scores were higher in the worst IF-Long group (adjusted mean difference: 4.4, 95% confidence interval: 1.2 to 7.5) than in the best IF-Long group. We also detected a positive trend between IF-Long score and BIC-11 score (P-value for trend <0.01). CONCLUSION: Our findings indicate that family dynamics strongly influences burden experienced by caregiving family members, regardless of the care receiver's degree of cognitive impairment. These results underscore the importance of evaluating relationships between care receivers and their caregivers when discussing a care regimen for care receivers.

MTF Measurement of MR Blurring in Liver Dynamic MRI with Gd-EOB-DTPA.

During the arterial phase acquisition of Gd-EOB-DTPA examinations, use of a small volume of the Gd-EOB-DTPA may make it difficult the encoding center of the k-space, and produce blurring. The previous studies revealed the encoding technique of the k-space was one of the most important reasons. However, there is no report to discuss the reasons with quantitative evaluations. The purpose of this study was to quantitatively evaluate the characteristics of the artifacts using different k-space encoding techniques (centric-view ordering (CVO) and sequential-view ordering (SVO)) for liver dynamic MRI in computer simulation study. This simulation study consists of the following steps. First of all, the creation of a time intensity curve, and original simulation images at certain points among the one phase dynamic scanning. Secondly, creation-simulated MR echo data from the created original images using FFT, and encoding simulated k-space using the simulated MR echo data. Finally, a reconstruction of simulated dynamic MR images from the simulated k-space, and to evaluate each simulated MR images, we measured modulation transfer functions (MTFs) from the bar patterns of the reconstructed images. The results of the CVO simulation indicated that the bar patterns were blurring compared to the images encoded by the SVO. The results of the SVO simulation indicated that the bar patterns were not enhanced at late scan timings. In addition, the results of MTFs indicated that there was no edge enhancement at all scan timings and both encoding techniques. In conclusion, it is possible to quantitatively evaluate the characteristics of artifacts using MTF, which was measured by the bar patterns, in liver dynamic MRI.

TAK1-JNK axis mediates survival signal through Mcl1 stabilization in activated T cells.

TAK1, a member of MAPK kinase kinase (MAPKK-K) family, can activate JNK, p38 MAPK, and NF-κB signaling pathways. Although targeted gene disruption studies have demonstrated that TAK1 plays a critical role in T cell functions, precise functions of downstream mediators remain elusive. We used the chemical compound LL-Z1640-2, which preferentially suppressed MAPK activation but not NF-κB signal downstream of TAK1. LL-Z1640-2 blocked TCR-induced T cell proliferation and activation, confirming that a TAK1-mediated MAPK signal is essential for T cell activation. LL-Z1640-2 induced apoptosis of activated mouse splenic T cells in a caspase- and caspase-activated DNase-dependent manner. TAK1-JNK pathway, which is activated downstream of IL-2R, induced the phosphorylation of antiapoptotic protein Mcl1 in activated T cells, resulting in the stabilization of Mcl1 protein. Our data uncover that among signal transduction pathways downstream of TAK1, JNK mediates a survival program through Mcl1 stabilization downstream of IL-2R in activated T cells and that blockade of TAK1-JNK pathway can eliminate activated T cells by apoptosis.

Class I PI3K-mediated Akt and ERK signals play a critical role in FcεRI-induced degranulation in mast cells.

Class IA and IB phosphoinositide 3-kinases (PI3Ks) have been shown to regulate mast cell functions such as proliferation, development, survival and degranulation, but the functional redundancy between these two PI3K signaling pathways in mast cells remains unclear. Here, we have generated mice deficient in both class IA regulatory subunit p85α and class IB catalytic subunit p110γ, and show that p85α(-/-)p110γ(-/-) mice exhibit a more severe defect in mast cell development than single-knockout mice. In addition, the in vivo passive cutaneous anaphylaxis reaction of p85α(-/-)p110γ(-/-) mice was nearly completely abrogated, whereas single-knockout mice exhibit just marginal reduction. Pharmacological inactivation of Akt in wild-type bone marrow-derived mast cells (BMMCs) led to partial reduction of degranulation, while over-expression of a constitutively active Akt partially restored the impaired degranulation in p85α(-/-)p110γ(-/-) BMMCs. We also found that the extracellular signal-regulated kinase (ERK) signaling pathway was activated in a PI3K-dependent manner upon FcεRI stimulation and that simultaneous inhibition of Akt and ERK resulted in nearly complete blockade of FcεRI-induced degranulation. Our data provide evidence that Akt and ERK pathways play redundant roles in FcεRI-induced degranulation.

Cutting edge: mTORC1 in intestinal CD11c+ CD11b+ dendritic cells regulates intestinal homeostasis by promoting IL-10 production.

The mammalian target of rapamycin (mTOR) controls cell growth and survival through two distinct complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Although several reports have suggested the involvement of mTORC1 in development and function of dendritic cells (DCs), its physiological roles remain obscure. We therefore established mTORC1 signal-deficient mice lacking Raptor, an essential component of mTORC1 signal, specifically in DC lineage (referred to here as Raptor(DC-/-)). Raptor(DC-/-) mice exhibited cell expansion in specific subsets of DCs such as splenic CD8(+) DCs and intestinal CD11c(+)CD11b(+) DCs. We also found that impaired mTORC1 signal resulted in the suppression of IL-10 production along with enhanced CD86 expression in intestinal CD11c(+)CD11b(+) DCs and that Raptor(DC-/-) mice were highly susceptible to dextran sodium sulfate-induced colitis. Our results uncover mTORC1-mediated anti-inflammatory programs in intestinal CD11c(+)CD11b(+) DCs to limit the intestinal inflammation.

Developing a scale to measure family dynamics related to long-term care, and testing that scale in a multicenter cross-sectional study.

BACKGROUND: As Japan's population ages, more frail elderly people are cared for by members of their family. The dynamics within such families are difficult to study, in part because they are difficult to quantify. We developed a scale for assessing family dynamics related to long-term care. Here we report on the development of that scale, and we present the results of reliability testing and validation testing. METHODS: Two primary-care specialists drafted questions about family dynamics, and discussed them with other primary-care physicians and clinical researchers. The final questionnaire asked about four problems or undesirable situations: disengagement (emotional distance), scapegoating (inappropriate blame), transfer of problems across generations (transfer of unnecessary burden from older to younger generations, trans-generationally displaced revenge), and undesirable behavior (co-dependence). Next, at six general-medicine clinics, doctors evaluated families that had a caregiver and a patient requiring long-term care. The results were analyzed by factor analysis. Cronbach's α was computed, and criterion-related validation tests were done with three types of criteria: relationship before caregiving, ability to do activities of daily living (ADL), and the duration of care. RESULTS: Results were obtained from 199 families. Among the caregivers, 79% were women and their mean age was 63 years. Among the patients, 71% were women and their mean age was 84 years. The results of factor analysis indicated that the scale was unidimensional. Cronbach's α was 0.73. Not having a good relationship before caregiving was associated with significantly worse family dynamics scores, as was greater dependence regarding ADL. CONCLUSIONS: We developed a scale that enables physicians to assess the dynamics of families with a patient and a family caregiver. The scale's scores are reliable and the results of validation testing were generally good. This scale holds promise as a tool both for research and for primary-care practice.

Significance of KRAS mutation in patients receiving mFOLFOX6 with or without bevacizumab for metastatic colorectal cancer.

BACKGROUND/AIMS: KRAS mutation is an important prognostic factor for patients with metastatic colorectal cancer receiving anti-epidermal growth factor receptor therapy. However, the influence of KRAS mutation on the response to mFOLFOX6 ± bevacizumab remains unclear. METHODOLOGY: We retrospectively analyzed 49 patients who received modified FOLFOX6 (mFOLFOX6) ± bevacizumab as first-line therapy. Genetic analysis showed that 30 patients had wild-type (WT) KRAS and 19 patients hadKRAS mutations (MT). These two groups were compared with regard to the response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: The RR was not significantly different between the WT and MT groups, but PFS and OS were significantly better in the WT group than the MT group (PFS: 11.8 months vs. 8.7 months, p<0.01; OS: 37.8 months vs. 29.3 months, p<0.0385). A similar analysis of 27 patients who were treated with mFOLFOX6 + bevacizumab showed a better prognosis for WT patients. Multivariate analysis also revealed that KRAS mutation was an independent factor with a significant relation to PFS. CONCLUSIONS: These results suggest that KRAS mutation may be a useful prognostic marker for patients with metastatic colorectal cancer receiving mFOLFOX6 ± bevacizumab therapy, especially for patients treated with mFOLFOX6 + bevacizumab.

Potential tumor spread of lateral pelvic lymphatic flow in low rectal cancer.

BACKGROUND/AIMS: In Japan lateral pelvic lymph node dissection has been actively performed with total mesorectal excision for low rectal cancer. However, its definitive efficacy remains unclear. This study is to evaluate clinical significance of lateral pelvic lymphatic drainage in low rectal cancer patients by 99mTc-Sn colloid radioactive tracers. METHODOLOGY: Intraoperatively detecting rectal lymphatic drainage using 99mTc-Sn colloid radioactive tracer in 39 low rectal cancer patients, we performed lateral pelvic lymph node dissection in lateral pelvic lymphatic flow-positive patients. RESULTS: Lateral pelvic lymphatic flow was detected in 11 patients (28%). In four (36%) of 11 patients, tumor cells were histologically identified in lateral pelvic lymph nodes. A median size of metastatic lateral pelvic lymph nodes was 7.5 (range, 2-150) mm, and all but one overlooked patient could not be detected by routine preoperative imaging scans retrospectively. The five-year disease-free survival rate of lateral pelvic lymphatic flow-positive patients was significantly poorer (45% vs. 75%, p = 0.0044). CONCLUSIONS: Tumor cells potentially extended beyond the fascia propria recti in low rectal cancer with lateral pelvic lymphatic flow. Preoperative chemoradiation therapy and adjuvant therapy are considered to be reasonable to improve a poor prognosis of low rectal cancer patients with lateral pelvic lymphatic flow.

Risk factors for parastomal hernia in Japanese patients with permanent colostomy.

PURPOSE: Although the definitive risk factors for parastomal hernia development remain unclear, potential contributing factors have been reported from Western countries. The aim of this study was to identify the risk factors for parastomal hernia in Japanese patients with permanent colostomies. METHODS: All patients who received abdominoperineal resection or total pelvic exenteration at our institution between December 2004 and December 2011 were reviewed. Patient-related, operation-related and postoperative variables were evaluated, in both univariate and multivariate analyses, to identify the risk factors for parastomal hernia formation. RESULTS: Of the 80 patients who underwent colostomy, 22 (27.5 %) developed a parastomal hernia during a median follow-up period of 953 days (range 15-2792 days). Hernia development was significantly associated with increasing patient age and body mass index, a laparoscopic surgical approach and the transperitoneal route of colostomy formation. In the multivariate analysis, the body mass index (p = 0.022), the laparoscopic approach (p = 0.043) and transperitoneal stoma creation (p = 0.021) retained statistical significance. CONCLUSIONS: Our findings in Japanese ostomates match those from Western countries: a higher body mass index, the use of a laparoscopic approach and a transperitoneal colostomy are significant independent risk factors for parastomal hernia formation. The precise role of the stoma creation route remains unclear.

Positive C4d staining of the portal vein endothelium in the liver of patients with biliary atresia: a role of humoral immunity in ongoing liver fibrosis.

PURPOSE: This study aimed to clarify the role of complement activation in fibrogenesis in BA. METHODS: In total, 27 paraffin-embedded liver biopsy samples were immunohistochemically analyzed using C4d polyclonal antibody, vascular cell adhesion molecule-1 (VCAM-1), and CD45. The liver samples were obtained from 25 patients during Kasai operation, and two additional specimens were obtained from 2 patients by needle biopsy later at the time of liver function deterioration. The degree of liver fibrosis was histologically graded 1-3. RESULTS: Among the 25 samples, 9 showed C4d-positive immunostaining localized on the endothelia of a few portal veins in the portal tract. The degree of fibrosis was correlated with C4d staining (p = 0.025). The age at Kasai operation correlated with the degree of fibrosis and the C4d positivity. Two needle biopsy samples were positive for C4d. Among 13 samples submitted for VCAM-1 staining, 2 negative samples were C4d negative and all positive C4d samples were VCAM-1 positive with CD45 mononuclear cell infiltration. CONCLUSION: These findings suggest that ongoing cirrhosis could be a result of progressive "vasculopathy" of the portal vein caused by humoral and cell-mediated immune interaction.

Comparison of Safety and Efficacy between Laparoscopic Ventral Rectopexy and Delorme's Procedure for External Rectal Prolapse in Nonagenarians.

Objectives: This study evaluates the safety and efficacy of laparoscopic ventral rectopexy (LVR) in nonagenarian patients with external rectal prolapse (ERP) compared to Delorme's procedure. Methods: We conducted a retrospective analysis of prospectively collected data, including nonagenarian patients who underwent either LVR or Delorme's procedure, comparing outcomes such as morbidity, length of hospital stay (LOS), and recurrence rates. Results: Between September 2009 and August 2023, 22 patients (median age 91, range 90-94 years) underwent LVR, while 12 patients (median age 91, range 90-96 years) received Delorme's procedure. Baseline characteristics, including sex ratio, parity, American Society of Anesthesiology grade, and Body Mass Index, did not significantly differ between the groups. LVR had a significantly longer operating time but lower blood loss than Delorme's procedure. Postoperative LOS was significantly shorter for LVR patients (median 1, range 1-3 days) compared to Delorme's procedure patients (median 2.5, range 1-13 days; P = 0.001). Notably, no significant morbidity occurred in the LVR group, while one case of delirium and another of solitary rectal ulcer syndrome were observed in the Delorme's procedure group. Recurrence rates were lower in the LVR group, with no recurrences during a median follow-up of 23 months (range 1-65 months), compared to one recurrence at 2 months during a median follow-up of 34 months (range 1-96 months) in the Delorme's procedure group. Conclusions: LVR is a safe and effective surgical option for nonagenarian ERP patients, showing favorable outcomes in terms of morbidity, LOS, and recurrence rates compared to Delorme's procedure.

Oncogenic K-RasG12V cannot overcome proliferation failure caused by loss of Ppp6c in mouse embryonic fibroblasts.

Protein phosphatase 6 is a Ser/Thr protein phosphatase and its catalytic subunit is Ppp6c. Ppp6c is thought to be indispensable for proper growth of normal cells. On the other hand, loss of Ppp6c accelerates growth of oncogenic Ras-expressing cells. Although it has been studied in multiple contexts, the role(s) of Ppp6c in cell proliferation remains controversial. It is unclear how oncogenic K-Ras overcomes cell proliferation failure induced by Ppp6c deficiency; therefore, in this study, we attempted to shed light on how oncogenic K-Ras modulates tumor cell growth. Contrary to our expectations, loss of Ppp6c decreased proliferation, anchorage-independent growth in soft agar, and tumor formation of oncogenic Ras-expressing mouse embryonic fibroblasts (MEFs). These findings show that oncogenic K-RasG12V cannot overcome proliferation failure caused by loss of Ppp6c in MEFs.

The effect of a prostaglandin E1 derivative on the symptoms and quality of life of patients with lumbar spinal stenosis.

BACKGROUND: Quality of life (QOL) is a concern for patients with lumbar spinal stenosis (LSS). In this study, QOL was examined using the 5-item EuroQol (EQ-5D). METHODS: QOL and activities of daily living (ADL) were surveyed for 91 patients who visited 18 medical institutions in our prefecture and were diagnosed with LSS-associated intermittent claudication. A second survey was performed after ≥6 weeks for 79 of the subjects to evaluate therapy with limaprost (an oral prostaglandin E1 derivative) or etodolac (an NSAID). Symptoms, maximum walking time, QOL, ADL items, and relationships among these variables were investigated for all 91 patients. Leg pain, leg numbness, and low back pain while walking were surveyed by use of VAS scores (0-100). RESULTS: Leg pain, leg numbness, and low back pain while walking (VAS ≥25) were present in 83.5, 62.6, and 54.9 % of the patients in the first survey, and approximately half of the patients had a maximum walking time <15 min. The mean EQ-5D utility value for QOL was 0.59 ± 0.12. This value was significantly associated with maximum walking time (p = 0.030) based on classification of patients into groups with walking times <7.5, 7.5-15, 15-30, and >30 min, showing that maximum walking time affected health-related QOL. Of the 79 patients who completed the second survey, 56 had taken limaprost and 23 (control group) had received etodolac. Limaprost improved possible walking time, reduced ADL interference, and significantly increased the EQ-5D utility score, whereas no significant changes occurred in the control group. Maximum walking time was prolonged by ≥10 min and the EQ-5D utility value was improved by ≥0.1 points in significantly more patients in the limaprost group than in the control group. CONCLUSION: According to the findings of this survey, at an average of 8 weeks after administration limaprost improved symptoms, QOL, and ADL in LSS patients whereas treatment with an NSAID reduced pain but did not have any other effects.

A Case of Pediatric Breast Abscess Caused by Rarely Observed Bacteria in a Three-Year-Old Boy With an Inverted Nipple: Peptoniphilus harei, Actinotignum sanguinis, and Porphyromonas somerae.

Mastitis and breast abscesses are most common in lactating women but can also be observed in non-lactating women, adolescent girls, and neonates. However, breast abscesses are extremely rare in young boys. Herein, we report the case of a three-year-old boy with a swollen and painful right nipple, later diagnosed with a breast abscess. In this case, we suspected that the patient's inverted nipple was the possible site of the infection. To our best knowledge, this is the first case report of breast abscess in a young boy after the neonatal period. Although Staphylococcus aureus is the most common pathogen, our patient showed three rare bacteria, namely, Peptoniphilus harei, Actinotignum sanguinis, and Porphyromonas somerae, in the culture of the aspirated pus. Furthermore, this case study is the first report of a breast abscess caused by Porphyromonas somerae.

Mechanism of cystogenesis by Cd79a-driven, conditional mTOR activation in developing mouse nephrons.

Polycystic kidney disease (PKD) is a common genetic disorder arising from developmental and postnatal processes. Defects in primary cilia and their signaling (eg, mTOR) underlie the pathogenesis. However, how mTOR regulates tubular integrity remains unclear. The paucity of faithful models has limited our understanding of pathogenesis and, therefore, the refinement of therapeutic targets. To understand the role of mTOR in early cystogenesis, we studied an in-house mouse model, Cd79a-Cre;Tsc1ff. (Cd79a-Tsc1 KO hereafter), recapitulating human autosomal-dominant PKD histology. Cre-mediated Tsc1 depletion driven by the promoter for Cd79a, a known B-cell receptor, activated mTORC1 exclusively along the distal nephron from embryonic day 16 onward. Cysts appeared in the distal nephron at 1 weeks of age and mice developed definite PKD by 4 weeks. Cd79a-Tsc1 KO tubule cells proliferated at a rate comparable to controls after birth but continued to divide even after postnatal day 14 when tubulogenesis is normally completed. Apoptosis occurred only after 9 weeks. During postnatal days 7-11, pre-cystic Cd79a-Tsc1 KO tubule cells showed cilia elongation, aberrant cell intercalation, and mitotic division, suggesting that defective cell planar polarity (PCP) may underlie cystogenesis. mTORC1 was activated in a portion of cyst-lining cells and occasionally even when Tsc1 was not depleted, implying a non-autonomous mechanism. Our results indicate that mTORC1 overactivation in developing distal tubules impairs their postnatal narrowing by disrupting morphogenesis, which orients an actively proliferating cell toward the elongating axis. The interplay between mTOR and cilium signaling, which coordinate cell proliferation with PCP, may be essential for cystogenesis.