A Single-Year Cosmic Ray Event at 5410 BCE Registered in 14C of Tree Rings.

The annual 14C data in tree rings is an outstanding proxy for uncovering extreme solar energetic particle (SEP) events in the past. Signatures of extreme SEP events have been reported in 774/775 CE, 992/993 CE, and ∼660 BCE. Here, we report another rapid increase of 14C concentration in tree rings from California, Switzerland, and Finland around 5410 BCE. These 14C data series show a significant increase of ∼6‰ in 5411-5410 BCE. The signature of 14C variation is very similar to the confirmed three SEP events and points to an extreme short-term flux of cosmic ray radiation into the atmosphere. The rapid 14C increase in 5411/5410 BCE rings occurred during a period of high solar activity and 60 years after a grand 14C excursion during 5481-5471 BCE. The similarity of our 14C data to previous events suggests that the origin of the 5410 BCE event is an extreme SEP event.

The accuracy of fine needle aspiration cytology in the clinical diagnosis of minor salivary gland tumours.

The objective of this study was to investigate the accuracy of fine needle aspiration cytology (FNAC) and biopsy for the clinical diagnosis of minor salivary gland tumours (MSGTs). This retrospective study of 32 MSGT cases was conducted over a 5-year period. Clinical features including age, sex, and location of the tumour were obtained from the patient clinical records. All cases were also assessed histologically according to the 2017 World Health Organization Classification of Head and Neck Tumours. The results of FNAC and biopsy were correlated with those of histopathology, and their sensitivity, specificity, and diagnostic efficacy were calculated using histopathology as the gold standard. Eighteen malignant MSGTs (56.3%) and 14 benign MSGTs (43.8%) were diagnosed by pathological diagnosis. The most common malignant tumour was mucoepidermoid carcinoma (seven cases, 38.9%). Most benign cases were pleomorphic adenomas (13 cases, 92.9%). FNAC was performed for 23 cases and biopsy for 13 cases. The sensitivity and specificity of FNAC were 66.7% and 91.0%, respectively, while those of biopsy were 90.0% and 100.0%, respectively. Although FNAC is a minimally invasive and cost-effective procedure, it is less accurate than biopsy in the assessment of MSGTs. Repeated FNAC or biopsy should be considered in negative and unsatisfactory FNAC cases.

A hot and fast ultra-stripped supernova that likely formed a compact neutron star binary.

Compact neutron star binary systems are produced from binary massive stars through stellar evolution involving up to two supernova explosions. The final stages in the formation of these systems have not been directly observed. We report the discovery of iPTF 14gqr (SN 2014ft), a type Ic supernova with a fast-evolving light curve indicating an extremely low ejecta mass (≈0.2 solar masses) and low kinetic energy (≈2 × 1050 ergs). Early photometry and spectroscopy reveal evidence of shock cooling of an extended helium-rich envelope, likely ejected in an intense pre-explosion mass-loss episode of the progenitor. Taken together, we interpret iPTF 14gqr as evidence for ultra-stripped supernovae that form neutron stars in compact binary systems.

A surge of light at the birth of a supernova.

It is difficult to establish the properties of massive stars that explode as supernovae. The electromagnetic emission during the first minutes to hours after the emergence of the shock from the stellar surface conveys important information about the final evolution and structure of the exploding star. However, the unpredictable nature of supernova events hinders the detection of this brief initial phase. Here we report the serendipitous discovery of a newly born, normal type IIb supernova (SN 2016gkg), which reveals a rapid brightening at optical wavelengths of about 40 magnitudes per day. The very frequent sampling of the observations allowed us to study in detail the outermost structure of the progenitor of the supernova and the physics of the emergence of the shock. We develop hydrodynamical models of the explosion that naturally account for the complete evolution of the supernova over distinct phases regulated by different physical processes. This result suggests that it is appropriate to decouple the treatment of the shock propagation from the unknown mechanism that triggers the explosion.

Regulatory T cells with superior immunosuppressive capacity emigrate from the inflamed colon to draining lymph nodes.

Foxp3+ Regulatory T cells (Tregs) play a critical role in the maintenance of colon homeostasis. Here we utilized photoconvertible KikGR mice to track immune cells from the caecum and ascending (proximal) colon in the steady state and DSS-induced colitis. We found that Tregs from the proximal colon (colonic migratory Tregs) migrated exclusively to the distal part of mesenteric lymph nodes (dMLN) in an S1PR1-dependent process. In the steady state, colonic migratory CD25+ Tregs expressed higher levels of CD103, ICOS, LAG3 and CTLA-4 in comparison with pre-existing LN Tregs. Intestinal inflammation led to accelerated Treg replacement in the colon, bidirectional Treg migration from the colon to dMLN and vice versa, as well as increases in Treg number, proliferation and expression of immunosuppressive molecules. This was especially apparent for CD25 very high Tregs induced in colitis. Furthermore, colonic migratory Tregs from the inflamed colon included more interleukin (IL)-10 producing cells, and demonstrated greater inhibition of T-cell proliferation in comparison with pre-existing LN Tregs. Thus, our results suggest that Tregs with superior immunosuppressive capacity are increased both in the colon and dMLN upon inflammation. These Tregs recirculate between the colon and dMLN, and are likely to contribute to the downregulation of intestinal inflammation.

Severe hypoglycaemia is a major predictor of incident diabetic retinopathy in Japanese patients with type 2 diabetes.

AIM: Hypoglycaemia is a common complication in diabetes patients. However, its relationship with retinopathy has not been well documented in patients with type 2 diabetes (T2D). This study aimed to investigate the associations between hypoglycaemia and the incidence and progression of diabetic retinopathy (DR). METHODS: In this longitudinal cohort study, which was part of the Japan Diabetes Complications Study (JDCS), adult patients with T2D were recruited at 59 diabetes clinics across Japan. Their history of hypoglycaemia was assessed by standardized self-reported questionnaires. Severe hypoglycaemia was defined as having at least one episode with coma requiring an outpatients visit or hospitalization. Adjusted hazard ratios (HRs) for incidence and progression of DR over 8 years of follow-up were determined. RESULTS: Of 1221 patients without DR, 127 (10.4%) had experienced non-severe hypoglycaemia within the previous year, whereas 10 (0.8%) reported severe hypoglycaemia episodes. During the 8-year follow-up involving 8492 person-years, 329 patients developed DR. In 410 patients with prevalent DR, the adjusted HRs for incident DR were 4.35 (95% CI: 1.98-9.56; P<0.01) and, for progression of DR, 2.29 (95% CI: 0.45-11.78; P=0.32) with severe hypoglycaemia. CONCLUSION: Having a history of severe hypoglycaemia was one of the strongest predictors of incident DR in patients with T2D, with a fourfold increased risk. Identifying patients with greater risks of DR based on their history of hypoglycaemia may help to personalize risk evaluation in patients with diabetes.

Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology.

Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients' outcomes.

Usefulness of immunocytochemistry using a Breast Marker antibody cocktail targeting P63/cytokeratin7/18/cytokeratin5/14 for fine needle aspiration of the breast: a retrospective cohort study of 139 cases.

OBJECTIVE: The Breast Marker Cocktail from Biocare Medical comprises five antibodies recognising p63, and cytokeratins (CKs) 7, 18, 5 and 14. Immunohistochemistry using this cocktail is useful for diagnosing proliferative intraductal breast lesions. However, cytology using the cocktail has not been reported. METHODS: We report 139 cases of mammary samples collected by fine needle aspiration (FNA) for which histological diagnoses were available. After cell transfer, immunocytochemistry was performed using the cocktail, and clusters of cells were classified. A cluster with no or limited CK5/14 expression (<20% of cells) was classified as a monotonous cluster. One with more than 20% of cells showing CK5/14 expression was defined as a mosaic cluster. When at least one p63-positive cell was present, we defined it as a cluster with p63. We also evaluated background p63-positive myoepithelial cell densities. RESULTS: The diagnostic sensitivity and specificity for carcinomas were 97.8% (89/91) and 91.7% (11/12), respectively, using the criterion of two or more monotonous clusters lacking p63. Two false-negative cases were triple-negative cancers; one false-positive was an apocrine papilloma. The numbers of monotonous clusters with p63 differed significantly between benign lesions, ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS) and invasive carcinomas (P < 0.001). The background myoepithelial cell density was significantly higher in fibroepithelial tumours than in other lesions (P < 0.001). CONCLUSIONS: Immunocytochemistry using this antibody cocktail showed good sensitivity and specificity for diagnosing breast cancers. Thus, this method is useful for mammary cytology using FNA.

Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma.

BACKGROUND: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b: a randomized controlled trial.

Chronic HCV-infected patients tend to have vitamin D deficiency, suggesting that vitamin D supplementation may enhance the efficacy of treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV). We therefore assessed the effects of vitamin D supplementation on viral response to PEG-IFN/RBV. Eighty-four patients with HCV genotype 1b were randomized, 42 to oral vitamin D supplementation (1000 IU/day) and 42 to nonsupplementation (control), from week 8 to the end of PEG-IFN/RBV therapy. The primary end point was undetectable HCV RNA at week 24 (viral response [VR]). VR rate at week 24 was significantly higher in the vitamin D than in the control group (78.6% vs 54.8% P = 0.037). Adverse events were similar in both groups. When patients were subdivided by IL28B SNP rs8099917 genotype, those with the TT genotype group showed a significantly higher VR rate at week 24 with than without vitamin D supplementation (86.2% vs 63.3% vs P = 0.044). Although patients with the TG/GG genotype, who were relatively resistant to PEG-IFN treatment, had similar VR rates at week 24 with and without vitamin D supplementation, the decline in viral load from week 8 to week 24 was significantly greater with than without vitamin D supplementation. Multivariate analysis showed that rs8099917 genotype and vitamin D supplementation contributed significantly to VR at week 24. SVR rates were similar in the vitamin D and control groups [64.3% (27/42) vs 50% (21/42), P = 0.19]. Vitamin D supplementation may enhance the effects of PEG-IFN/RBV in HCV genotype 1b-infected patients.

The effect of core suture flexor tendon repair techniques on gliding resistance during static cycle motion and load to failure: a human cadaver study.

The purpose of this study was to describe a modification of the Massachusetts General Hospital (MMGH) tendon repair and to compare it with three other suture techniques. Twenty human flexor digitorum profundus (FDP) tendons were randomly assigned to the modified Pennington (MP) suture and the MMGH suture. These were compared to the modified Kessler (MK) and Massachusetts General Hospital (MGH) sutures, using data from a previous study. All tendons were repaired with a similar epitendinous stitch and core sutures of 4-0 FiberWire. There was no significant difference in the normalized gliding resistance within the two-strand or four-strand core repair groups. The MP suture had significantly higher 2 mm gap force and ultimate load to failure than the MK suture. The MMGH suture had significantly higher 2 mm gap force and maximum failure ultimate load than the MGH suture. All repairs failed by knot unravelling.

Low transition rate from normo- and low microalbuminuria to proteinuria in Japanese type 2 diabetic individuals: the Japan Diabetes Complications Study (JDCS).

AIMS/HYPOTHESIS: The aim of the study was to determine the transition rate and factors associated with the progression of normo- and low microalbuminuria to diabetic nephropathy (overt proteinuria). METHODS: For 8 years we prospectively observed 1,558 Japanese patients with type 2 diabetes mellitus whose basal urinary albumin:creatinine ratio (UACR) had been measured as <17.0 mg/mmol at entry. The incidence of nephropathy (UACR >33.9 mg/mmol) was determined by measuring UACR twice a year. RESULTS: Progression to nephropathy occurred in 74 patients. The annual transition rate was 0.67%, and was substantially higher for the low-microalbuminuric group than for the normoalbuminuric group (1.85% and 0.23%, respectively; hazard ratio for the low-microalbuminuric group 8.45, p < 0.01). The hazard ratio for an HbA(1c) of 7-9% or ≥9% was 2.72 (p < 0.01) or 5.81 (p < 0.01) relative to HbA(1c) <7.0%, respectively. In comparison with individuals with a systolic blood pressure (SBP) of <120 mmHg, the hazard ratios for patients with an SBP of 120-140 mmHg or ≥140 mmHg were 2.31 (p = 0.06) and 3.54 (p < 0.01), respectively. Smoking also affected progression to proteinuria (hazard ratio 1.99, p < 0.01). In contrast, 30.3% of the low-microalbuminuric group returned to normoalbuminuria (i.e. were in remission). CONCLUSIONS/INTERPRETATION: These results suggest that if patients with type 2 diabetes mellitus are receiving treatment from diabetologists for hyperglycaemia and hypertension when they are in the early stages of nephropathy (i.e. normo- or low microalbuminuria), their rate of transition to proteinuria is considerably lowered, and that differentiating patients with low microalbuminuria from those with high microalbuminuria might be clinically useful. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000222.

Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis.

BACKGROUND: Silencing of genes using small interfering RNA (siRNA) is a recently developed strategy to regulate the synthesis of target molecules. Signal transducer and activator of transcription 6 (STAT6) is a nuclear transcription factor that mediates Th2-type immunity. METHODS: To elucidate the therapeutic potential of using siRNA to inhibit STAT6 in allergic reactions, we determined the nucleotide sequences of siRNA specific for STAT6. RESULTS: The selected sequences of STAT6 siRNA specifically inhibited the generation of STAT6 synthesis in dermal fibroblasts and eotaxin (CCL11) production in response to IL-4/TNF-α in vitro. Local administration of STAT6 siRNA in vivo alleviated contact hypersensitivity responses to chemical haptens. This was accompanied by reduced local production of IL-4, IL-13, eotaxin (CCL11), TARC (CCL17) and MDC (CCL22). Similarly, consecutive intranasal instillation of STAT6 siRNA markedly inhibited inflammatory cellular infiltration of mucosal tissues in allergic rhinitis responses in association with reduced IL-4 and IL-5 production from regional lymph node cells. Immediate responses, such as sneezing and nasal rubbing behaviors, were also improved by STAT6 siRNA. CONCLUSIONS: Local administration of STAT6 siRNA is thus a promising therapeutic strategy for both Th2-mediated cutaneous diseases and allergic rhinitis.

Androgen receptor and 5alpha-reductase immunohistochemical profiles in extramammary Paget disease.

BACKGROUND: Extramammary Paget disease is an uncommon skin tumour occurring mostly in the genitoperineal region. Previous reports have shown frequent expression of androgen receptor, suggesting a tumour-proliferative effect of androgens on Paget cells. Androgen-converting enzymes such as 5alpha-reductase, which locally produces a bioactive androgen, have recently gained attention in studies of the intratumoral actions of androgens. OBJECTIVES: We investigated correlations between the androgenic microenvironment and invasiveness in extramammary Paget disease, particularly in terms of sex differences. METHODS: We examined 58 cases of extramammary Paget disease (32 men, 26 women; 42 noninvasive, 16 invasive) using immunohistochemistry for androgen receptor and 5alpha-reductase. RESULTS: In all 58 cases, expression rates were 57% for androgen receptor and 55% for 5alpha-reductase, with 38% double-positivity for androgen receptor and 5alpha-reductase. Only 5alpha-reductase expression rate was significantly higher in invasive cases (81%) than in noninvasive cases (45%; P = 0.042). For invasive cases, numbers of double-positive results for androgen receptor and 5alpha-reductase were significantly higher in men (70%) than in women (17%; P = 0.039). CONCLUSIONS: Double positivity for androgen receptor and 5alpha-reductase in Paget cells suggests autocrine synthesis of androgens in extramammary Paget disease. The different hormonal microenvironments in male and female cases and intratumoral androgen levels affect the invasiveness of extramammary Paget disease.

Significance of collagenous and mucinous spherulosis in breast cytology specimens.

OBJECTIVE: Spherulosis of the breast is a rare but distinct benign morphological entity. As there are few cytological reports of breast spherulosis, the significance of spherulosis among cytological specimens is unclear. The objective was to document cytological aspects of spherulosis. METHODS: A total of 3491 consecutive breast fine needle aspiration cytology (FNAC) samples and 69 nipple discharge cytology samples were reviewed. Papanicolaou-stained slides with or without Romanowsky staining were analysed. The corresponding 1926 histological specimens were also reviewed. RESULTS: We detected 17 cases of collagenous spherulosis (CS) and/or mucinous spherulosis (MS) among 3560 breast cytology specimens (0.48%). All samples were from women, who varied in age from 22 to 69 years. CS and/or MS were present in 15 of 3491 FNAC specimens (0.43%) and in two of 69 nipple discharge cytology specimens (2.9%). Corresponding histological specimens were available for 14 of the 17 specimens. Of the 14 specimens, 12 consisted of intraductal papilloma, one of fibroadenoma, and one of fibrocystic change. There was no spherulosis among the 1251 cytological specimens of malignant diseases. CONCLUSIONS: Cytological evidence of spherulosis is a good indicator of intraductal papilloma.

Nicotine enhances skin necrosis and expression of inflammatory mediators in a rat pressure ulcer model.

BACKGROUND: Many bedridden patients develop pressure ulcers, not only in hospital but also at home. Clinical studies have indicated cigarette smoking to be a risk factor for pressure ulcers. However, the contribution of nicotine to pressure ulcer formation has not been identified. OBJECTIVES: We aimed to clarify the effect of nicotine on pressure ulcer formation, and its mechanism. METHODS: Ischaemia-reperfusion (I/R) was performed in rat dorsal skin to induce pressure ulcers. The extent of the resulting necrotic area was determined. To clarify the mechanism of the effect of nicotine, mRNA levels of cyclooxygenase-2 (COX-2), interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase (iNOS) and protein expression of COX-2 and iNOS in the necrotic area were investigated by real-time reverse transcription-polymerase chain reaction and Western blotting, respectively. Furthermore, the effects of the COX-2 inhibitor NS-398 and the iNOS inhibitor aminoguanidine on necrosis were examined. RESULTS: Skin necrosis in the I/R-treated area was significantly increased by intraperitoneal administration of nicotine (0.175 mg kg(-1) daily). Repeated nicotine administration had little effect on systolic and diastolic blood pressure. I/R treatment increased mRNA levels of COX-2, IL-1beta, IL-6 and iNOS, which were further augmented by nicotine in a dose-dependent manner. Correspondingly, nicotine (0.35 mg kg(-1) daily) markedly enhanced the protein expression of COX-2 and iNOS. Moreover, NS-398 and aminoguanidine showed a tendency to abrogate the increase of I/R-induced skin necrosis caused by nicotine. CONCLUSIONS: These results suggest that the increased risk of pressure ulcers due to cigarette smoking is mediated, in part, by nicotine. They also indicated that the effect of nicotine is not mediated by a change in blood pressure, but is elicited via an increase of inflammatory mediators in the I/R-treated skin.

Effect of triangular ligament tears on distal radioulnar joint instability and evaluation of three clinical tests: a biomechanical study.

Using 11 fresh/frozen cadaver specimens, instability of the distal radioulnar joint (DRUJ) during passive wrist motion was measured by motion analysis and three clinical tests (ulno-carpal stress test, piano-key test, and DRUJ ballottement test) were performed. Release of the triangular ligament from the palmar approach was performed to simulate instability of the DRUJ. Displacement of the distal radius against the ulnar head was measured at various degrees of forearm rotation. Release of the triangular ligament at the ulnar fovea and around the base of the ulnar styloid process caused various degrees of DRUJ instability during passive wrist motion. After complete triangular ligament release, only the DRUJ ballottement test demonstrated a statistically significant degree of accuracy in the evaluation of distal radioulnar joint instability.

The role of immunohistochemistry in the differential diagnosis of papillary lesions of the breast.

Papillary lesions of the breast represent a heterogeneous group with differing biological behaviour. Correct diagnosis is crucial but may be difficult, as many benign and malignant papillary lesions have similar appearances. Immunohistochemistry plays a useful role in their differentiation. Myoepithelial markers can help in differentiating papilloma from papillary carcinoma, as the former usually shows a continuous layer of myoepithelial cells. In intracystic papillary carcinoma, there is controversy as to the presence of a complete myoepithelial cell layer around these lesions. p63 is the marker of choice as the staining is nuclear, cross-reactivity is minimal, and sensitivity is high. Papilloma may frequently be complicated by superimposed different types of epithelial hyperplasia, which range from usual to atypical or even ductal carcinoma in situ, and they many be morphologically similar. Basal cytokeratins (CKs) are useful to differentiate these entities; as usual hyperplasia is positive for basal CKs with a mosaic staining pattern. CK5/6 is probably the best marker. Neuroendocrine markers (chromogranin A and synaptophysin) may be positive in papillary carcinoma, particularly in the solid type, and there may be some overlap with the ductal carcinoma in situ with spindle cells or endocrine ductal carcinoma in situ. A panel of CK5/6, p63 and neuroendocrine markers can be useful in the diagnostic investigation of problematic papillary lesions of the breast. As the experience with these markers remains rather limited, it is too early to recommend basing treatment choices on these marker studies alone. Complete removal of lesion is probably still the treatment of choice.

Involvement of cyclooxygenase-2 in lipopolysaccharide-induced impairment of the newborn cell survival in the adult mouse dentate gyrus.

There is growing evidence indicating that neurogenesis in adulthood is influenced by certain types of the central diseases such as neuroinflammation, however, its mechanism is not fully understood. This study was, therefore, designed to examine the effects of lipopolysaccharide (LPS), a bacterial endotoxin known to cause the neuroinflammation, on the neurogenesis in the dentate gyrus of adult mice using the bromodeoxyuridine (BrdU) -pulse chase method. LPS failed to affect the number of BrdU-labeled cells in the dentate gyrus 2 h after BrdU injection, indicating no effects of LPS on the proliferation of the neural stem cells (NSCs). On the other hand, we found that LPS dose-dependently (0.1, 0.5, 1 mg/kg) decreased the number of BrdU-labeled cells 7 and 21 days after BrdU injection. We also observed that LPS increased cell death in the dentate gyrus using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, suggesting that LPS impaired the survival of newborn cells derived from the NSCs. The double-immunostaining for BrdU and specific cell type markers revealed that LPS did not alter the commitment of the NSCs to the neurons and astrocytes. The systemic injection of indomethacin, a non-selective cyclooxygenase (COX) inhibitor, and NS398, a selective COX-2 inhibitor, but not SC560, a selective COX-1 inhibitor, did not only ameliorate LPS-induced suppression of the newborn cell survival, they fully protected against the LPS effect. Furthermore, the central injection of NS398 also ameliorated LPS-induced suppression of the newborn cell survival in the dentate gyrus. The treatment with LPS increased the expression of COX-2 protein 7 h and 7 days after the injection in the dentate gyrus. These results suggest that LPS impairs the survival of newly generated cells derived from the NSCs in the dentate gyrus without affecting the differentiation fate, and these effects of LPS were mediated presumably by COX-2 expression in the dentate gyrus.