Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy with high recurrence and poor prognosis duo to the lack of effective biomarkers. TBC1 domain family member 16 (TBC1D16), a GTPase-activating protein, is involved in regulating intracellular trafficking in tumorigenesis and metastasis. However, the clinical significance of TBC1D16 in EOC remains unknown. In the present study, we investigated the expression and prognostic significance of TBC1D16 in EOC and its relationship with the expression of vascular endothelial growth factor (VEGF). The tissue specimens included 156 histologically confirmed EOC and 30 normal ovarian tissues. The expression of TBC1D16 and VEGF was detected by immunohistochemistry (IHC), and the immunoreactive score was calculated with signal intensity and percentage of positive cells. IHC results showed that TBC1D16 and VEGF were both mainly localized in cytoplasm of epithelial cells in normal ovarian tissues and were expressed in cancer cells. Based on the immunoreactive score, TBC1D16 expression in EOC was categorized as “high expression,” compared with normal ovarian tissues (P < 0.05). The Chi-square test showed that high TBC1D16 expression was related to advanced pT stages (P = 0.029), but not correlated with other clinical features. Moreover, the TBC1D16 expression was significantly higher in EOC specimens with low VEGF expression (P < 0.001). Importantly, in both univariate and multivariate survival analyses, high expression of TBC1D16 was significantly correlated with good overall survival (OS). In conclusion, TBC1D16 is a predictive marker for favorable prognosis of EOC.

Tubulointerstitial nephritis is primary injury to renal tubules and interstititum which could be resulting in decreased renal function. The acute and chronic forms are most often due to allergic drug reactions or to infections. Tubulointerstitial nephritis in Crohn’s disease has rarely been reported. Imaging findings of a striated nephrogram on enhanced computed tomography (CT) could represent the clinical state of tubulointerstitial nephritis. This is the first report of tubulointerstitial nephritis caused by infliximab, monoclonal antibody against human tumor necrosis factor-α, showing striated nephrograms in Crohn’s disease. The case of a 28-year-old man treated with infliximab for Crohn’s disease is described. Infliximab was added to his maintenance therapy, and bowel symptoms were stable. The patient presented with a 2-month history of fever and an elevated C-reactive protein after infliximab administration for 4.5 years. Contrast-enhanced CT showed striated nephrograms in both kidneys. Urinalysis showed no abnormal findings. The pathological diagnosis on CT-guided percutaneous renal needle biopsy was drug-induced tubulointerstitial nephritis because of eosinophilic infiltration with neutrophils mainly in the tubulointerstitial areas. The imaging findings of striated nephrogram are important for the diagnosis of tubulointerstitial nephritis. Tubulointerstitial nephritis could be caused by drug-induced inflammation or direct extension of Crohn’s disease as an extra-interstitial manifestation. The treatment strategies for these two diseases are contradictory to each other and inappropriate treatment could worsen the renal function. Needle biopsy is therefore indispensable for differential diagnosis.

Access to day-care services for children with mild acute illness is important for working parents, because infants and toddlers often suddenly become ill, and most Japanese nursery schools do not accept children with even mild illnesses. Actual travel time to nurseries providing such day-care services is one of the indicators for measuring accessibility. However, this variable has not been well analyzed in previous work. To clarify practical access to such nurseries, this study used a car navigation algorithm to calculate the percentage of the population of children in Japan who can access nurseries providing services for children with mild acute illnesses within 15 to 30 minutes and compared this with the proportion of children living within a linear distance of 10 km of such nurseries. Of the 4,987,706 children younger than 5 years in 2015, 51.7% lived in areas from which the nearest nursery for children with mild acute illness was accessible within 0-15 minutes by automobile. In addition, 81.5% lived within 0-30 minutes of such nurseries, and the same percentage (81.5%) lived within a linear distance of 10 km of such nurseries. Both calculation methods (travel time and linear distance) showed inter-regional differences in accessibility, and the proportion of children with access to these nurseries was higher in heavily populated regions (e.g., Kanto and Kinki) than in less populated regions (e.g., Hokkaido and Tohoku). Children and caregivers throughout Japan should have equal access to these nurseries, because the national government subsidizes such services.

Primary gastrointestinal lymphoma (PGIL) has been reported in many studies of lymphomas of the gastrointestinal tract worldwide. However, there have been few accurate population-based reports on lymphomas, and it is difficult to apply the strict definition of PGIL to all lymphomas occurring in the gastrointestinal tract. Accordingly, instead of using PGIL, this study included newly diagnosed lymphomas with biopsy or excision specimens obtained from the gastrointestinal tract (GI-related lymphomas) and aimed at presenting the incidence rate, subtype frequency, and occurrence site of GI-related lymphomas. Additionally, we examined GI-related lymphomas diagnosed using flow cytometry (FCM) analysis, cytogenetics analysis, and molecular analysis (multimetric and/or integrated analysis). We extracted data on GI-related lymphomas from 2,098 lymphoma cases registered from the entire Miyagi Prefecture in Japan. The number of GI-related lymphomas was 350, and the incidence rate was 2.97 per 100,000 persons. Diffuse large B-cell lymphoma was the most common subtype (47.4%), followed by extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (32.6%) and follicular lymphoma (8.3%). The stomach was the most common site (62.6%), followed by the large intestine (15.4%), small intestine (14.3%), and duodenum (6.0%). Of the 350 included cases, 111 were diagnosed using multimetric and/or integrated analysis, in which the proportions of positive results for FCM analysis, cytogenetics analysis, and molecular analysis were 81%, 33%, and 51%, respectively. These results may provide a representation of lymphomas occurring in the gastrointestinal tract in Japan. Multimetric and/or integrated analysis of GI-related lymphomas could enable us to acquire useful information for the diagnosis.

Shortage of healthcare workers is a global problem. It is important to clarify factors, including job stress, that influence workplace resignation and factors that cause burnout among rural physicians. The study was designed as a cross-sectional questionnaire survey. We sent questionnaires to town or village hospitals and clinics (n = 1,898) in Hokkaido, Tohoku, Shikoku, and Kyushu and Okinawa. The number of participants was 509. Of these 7.7% were female and 21.6% were < 50 years. Internal or general medicine physicians were asked about personal and job factors, job stress based on the demand-control-support model, intention to resign from current position, and burnout evaluated using the Maslach Burnout Inventory-General Survey. Overall, 10.4% of the participants intended to resign, and 21.8% was defined as burnout positive. In the multivariate logistic regression analysis, dissatisfaction with income (OR, 3.63; 95% CI, 1.63-8.10), having one’s hometown in another town or village in the same prefecture (OR, 3.53; 95% CI, 1.18-10.62) were significantly related to intention to resign, while high job control (OR, 0.72; 95% CI, 0.58-0.88) had a significantly protective effect. In the multivariate analysis, high job demand (OR, 1.48; 95% CI, 1.28-1.72) was significantly related to burnout, and high job control (OR, 0.66; 95% CI, 0.55-0.78) and high support from co-workers (OR 0.88, 95% CI, 0.78-1.00) had a significantly protective effect. Improving job stress factors, especially job control, and taking into consideration physicians’ hometown and income may be important factors to prevent resignation from a current position and burnout among Japanese rural physicians.

Thoracic epidural anesthesia (TEA) and paravertebral block (PVB) have been performed for perioperative regional anesthesia in the trunk. However, TEA and PVB are associated with a risk of serious complications, such as pneumothorax, hypotension, or nerve damage. Retrolaminar paravertebral block (RLB) was introduced as a new alternative to PVB. This new approach might lower the risk of serious complications, but its use has not been well established yet. Therefore, we conducted a double-masked, placebo-controlled, randomized clinical trial to evaluate the efficacy of a double-level RLB for postoperative analgesia after breast cancer surgery. A total of 122 women who underwent breast cancer surgery with axillary lymph node dissection under general anesthesia were allocated into RLB group (60 patients) and Control group (62 patients). RLB was performed upon surgery completion with 15 ml ropivacaine (0.5%) for each lamina of the T2 and T4 vertebrae. In Control group, the same volume of normal saline was injected at each level. The time to first postoperative analgesic administration was significantly longer in RLB group than that in Control group (161.5 min vs. 64.0 min). The pain score in RLB group was significantly lower immediately after surgery. However, the number of patients requiring analgesics during the 12-hour post-surgical period was similar between RLB group (20 patients) and Control group (22 patients). In conclusion, the double-level RLB could delay the time to initial administration of analgesics, but this technique may be insufficient to reduce the analgesic requirement within the 12-hour postoperative period following breast cancer surgery.

Campomelic dysplasia (CD) is a skeletal dysplasia characterized by shortened and bowed long bones, airway instability, the potential for disorders of sexual differentiation (DSD), and Pierre Robin Sequence (PRS) with cleft palate, midface hypoplasia and laryngotrachemomalacia. CD is caused by alterations in the Sex-determining region of the Y chromosome (SRY)-related-box 9 (SOX9), which has important roles in tissue and sexual differentiation. The SOX9 gene and the enhancer regions of SOX9 are located at chromosome 17q24.3. We report a 6-year-old phenotypically female referred to our department because of precocious puberty. The patient was born with Tetralogy of Fallot (TOF) and PRS. Skeletal X-ray examination showed only 11 pairs of ribs and bilateral bowed radiuses. Endocrine evaluations showed that increased levels of serum testosterone, and chromosomal analysis revealed a 46, XY, t(2;17)(p15;q24.2) karyotype. The patient was diagnosed with peripheral precocious puberty caused by over-secretion of testosterone by gonadoblastoma originating from dysgenetic gonads with Y-chromosome-related DSD. Multiple somatic abnormalities and DSD indicated that the patient might have CD. Laparoscopy revealed bilateral dysgenetic gonads, and these were removed in the successive operation to prevent malignant transformation and virilization, caused by dysgenetic gonads with Y chromosomal materials. It is highly suggestive that the chromosomal translocation of 17q 24.2 may cause DSD and multiple somatic abnormalities, including CD, although the identified 17q breakpoint was located outside of known SOX9 enhancer regions. Thus, a hitherto unknown enhancer may be present at 17q24.2. This is the first reported case of CD with a translocation breakpoint at 17q24.2.

Immunoparalysis is a common cause of death for critical care patients with sepsis, during which comprehensive suppression of innate and adaptive immunity plays a significant pathophysiological role. Although the underlying mechanisms are unknown, damage-associated molecular patterns (DAMPs) from septic tissues might be involved. Therefore, we surveyed sera from septic patients for factors that suppress the innate immune response to DAMPs, including adenosine triphosphate (ATP), monosodium urate, and high mobility group box-1. Macrophages, derived from THP-1 human acute monocytic leukemia cells, were incubated with each DAMP, in the presence or absence of sera that were collected from critically ill patients. Secreted cytokines were then quantified, and cell lysates were assayed for relevant intracellular signaling mediators. Sera from septic patients who ultimately did not survive significantly suppressed IL-1β production only in response to extracellular ATP. This effect was most pronounced with sera collected on day 3, and persisted with sera collected on day 7. However, this effect was not observed when THP-1 cells were treated with sera from survivors of sepsis. Septic sera collected at the time of admission (day 1) also diminished intracellular levels of inositol 1,4,5-triphosphate and cytosolic calcium (P < 0.01), both of which are essential for ATP signaling. Finally, activated caspase-1 was significantly diminished in cells exposed to sera collected on day 7 (P < 0.05). In conclusion, the sera of septic patients contain certain factors that persistently suppress the immune response to extracellular ATP, thereby leading to adverse clinical outcomes.

Receptor for activated C kinase 1 (RACK1) plays an important role in regulating the immune response and cytokine expression. However, little is known about its role in acute pancreatitis (AP). We therefore investigated the role of RACK1 in AP and explored its relationship with interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), both of which are related to AP severity. Two rat models of chemically induced AP with different severities were used: acute edematous pancreatitis (AEP) and acute necrotizing pancreatitis (ANP). The expression levels of IL-6 and TNF-α mRNAs and proteins were significantly increased in leukocytes from AEP and ANP rats, compared with the levels in the control animals, while the expression levels of RACK1 mRNA and protein were significantly decreased in leukocytes from these AP rats. Moreover, the RACK1 levels in leukocytes were significantly lower in ANP rats than those in AEP rats. Consequently, AP patients and healthy volunteers (HVs) were enrolled in this study. Compared with the HVs (n = 5), the expression levels of IL-6 and TNF-α mRNAs and proteins were significantly higher in leukocytes from 15 AP patients, including patients with mild AP (n = 5). By contrast, the expression levels of RACK1 mRNA and protein in leukocytes were significantly lower among patients with severe AP (n = 5) and with moderately severe AP (n = 5), compared with the HVs. The expression levels of RACK1 mRNA were negatively correlated with the IL-6 and TNF-α mRNA levels. Thus, RACK1 may alleviate the severity of AP.

The most important risk factor for severe respiratory syncytial virus (RSV) infection is considered young age due to the immature immune system. The risk at young age is reported greater for RSV than for other respiratory infectious agents. Based on the strong association between young age and severity of RSV infection due to immature immunity, we aimed to assess whether there were any age-related differences in fever responses, as one clinical aspect of the immune response. In our observational study over two seasons (2014-2015 and 2015-2016), daily body temperatures of children under 3 years old with RSV infection were recorded from the first medical visit during the acute phase to defervescence. The body temperature records were analyzed among 171 children of four age groups (< 6, < 12, < 24 and ≥ 24 months), in terms of fever development, degrees of fever onset, the highest fever during the period, and fever duration. There were 54 patients in the group of < 6 months, 41 in the group of < 12 months, 58 in the group of < 24 months, and 18 in the group of ≥ 24 months. We thus found the correlation between age and fever responses under 24 months old; namely, the more the age advanced, the more frequently high and prolonged fever was experienced. Importantly, infants under 6 months old tend to show the suppressed fever responses. In conclusion, young infants with reduced fever response during RSV infection do not implicate less severity and needs attentive management.