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The immunohistochemical detection of epithelially derived cells in the bone marrow of patients with primary breast cancer has been shown to be associated with increased risk of distant relapse as well as higher rates of cancer-related death. Despite the correlation between bone marrow micrometastases and poor outcome in breast cancer patients, bone marrow status does not yet have an established role in patient management. In this prospective study, adjuvant therapy recommendations for 43 patients with stage I, II, or III breast cancer treated with lumpectomy or mastectomy, sentinel lymph node biopsy and/or axillary dissection, and intraoperative bone marrow aspiration were recorded. Recommendations were made by a multidisciplinary tumor board both blinded and unblinded to the results of the bone marrow aspiration. In our study, 10 of the 43 breast cancer patients were found to have bone marrow micrometastases. Four of these patients (40%) had axillary lymph node metastases. When blinded to the results of the bone marrow aspiration, the tumor board recommended adjuvant chemotherapy for these four node-positive patients, as well as two node-negative patients. When unblinded to the results of the bone marrow aspiration, the tumor board did not change its recommendations for any of these six patients. The remaining four node-negative, bone marrow-positive patients were not advised to have adjuvant chemotherapy by the tumor board when blinded to bone marrow status. However, once the tumor board was informed of the presence of bone marrow micrometastases, adjuvant chemotherapy was recommended for all of these patients. The results of this pilot study indicate that the presence of bone marrow micrometastases in breast cancer patients with stage I, II, or III disease does influence recommendations for adjuvant chemotherapy, particularly in patients with node-negative disease. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to provide follow-up data regarding the incidence of local breast cancer recurrence in patients undergoing skin-sparing mastectomy versus conventional non-skin-sparing mastectomy methods. PATIENTS AND METHODS: A retrospective follow-up study and analysis were performed of patients who underwent mastectomies for invasive breast cancer at The New York Presbyterian Hospital, Cornell University Medical College and Strang-Cornell Breast Center between 1990 and 1998. RESULTS: A total of 198 patients were identified in this study, and the mean follow-up was 49 months. This group included 71 patients who underwent skin-sparing mastectomy and 127 who underwent non-skin-sparing mastectomy procedures. No statistical differences in local recurrence rates were demonstrated between patients treated with skin-sparing mastectomy and those who underwent non-skin-sparing mastectomy. Local recurrence was present in four of 71 (5.6%) patients undergoing skin-sparing mastectomy and in five of 127 (3.9%) of those undergoing non-skin-sparing mastectomy. CONCLUSIONS: The use of skin-sparing mastectomy does not lead to an increase in local recurrence rates when compared with conventional non-sparing mastectomies and provides for improved aesthetic results after immediate reconstruction. [ABSTRACT FROM AUTHOR]

McCune-Albright syndrome (MAS) is a sporadic disorder characterized by the triad of irregularly edged hyperpigmented macules (café au lait spots); a slowly progressive bone disorder, polyostotic fibrous dysplasia, usually involving the base of the skull and the long bones; and luteinizing hormone-releasing hormone (LHRH)-independent precocious puberty. This case is the first report of a 27-year-old woman with ductal carcinoma in situ (DCIS) and Paget's disease of the nipple associated with MAS. The discussion focuses on two endocrine manifestations of this syndrome including precocious puberty and excess growth hormone secretion. In our patient, both her early puberty and pituitary adenoma, in association with MAS, resulted in excess production and secretion of estrogen and growth hormone. Both of these hormones function to stimulate breast growth and development. We hypothesize they are responsible for this patient's DCIS and Paget's disease of the nipple so early in life. [ABSTRACT FROM AUTHOR]

Background: The ICE3 trial evaluated the safety and efficacy of cryoablation in women aged ≥60 years with low-risk, early-stage breast cancers, aiming to provide a non-operative treatment option and avoid potential surgical risks. This study presents 5-year follow-up trial results., Methods: The ICE3 trial is an Institutional Review Board-approved, prospective, multicentered, non-randomized trial including women ≥ 60 years of age with unifocal, ultrasound visible, invasive ductal carcinoma ≤ 1.5 cm in size, histologic grade 1-2, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. The primary study endpoint of 5-year ipsilateral breast tumor recurrence (IBTR) was evaluated based on Kaplan-Meier estimates., Results: Overall, 194 patients meeting eligibility received successful cryoablation treatment per protocol and were included for analysis. The mean age was 74.9 years (55-94) with a mean tumor size of 7.4 mm transverse (2.8-14.0 mm) and 8.1 mm sagittal (2.5-14.9 mm). With a mean follow-up period of 54.16 months, the IBTR rate at 5 years was 4.3% and breast cancer survival was 96.7%. Of the 124 patients who received endocrine therapy only, the IBTR was 3.7%. No serious device-related adverse events were reported. Minor (88.2%) and moderate (9.6%) adverse events were mild in severity and resolved without residual effects. Quality-of-life score demonstrated statistically significant improvement (p < 0.001) in distress at 6 months as compared with baseline., Conclusions: Breast cryoablation presents a promising alternative to surgery in selected patients, offering the benefits of a minimally invasive procedure with minimal risks. Further studies are encouraged to confirm cryoablation as a viable alternative to surgical excision low-risk patients., (© 2024. The Author(s).)

Minimally invasive locoregional therapies have a growing role in the multidisciplinary treatment of primary and metastatic breast cancer. Factors contributing to the expanding role of ablation for primary breast cancer include earlier diagnosis, when tumors are small, and increased longevity of patients whose condition precludes surgery. Cryoablation has emerged as the leading ablative modality for primary breast cancer owing to its wide availability, the lack of need for sedation, and the ability to monitor the ablation zone. Emerging evidence suggests that in patients with oligometastatic breast cancer, use of locoregional therapies to eradicate all disease sites may confer a survival advantage. Evidence also suggests that transarterial therapies-including chemoembolization, chemoperfusion, and radioembolization-may be helpful to some patients with advanced liver metastases from breast cancer, such as those with hepatic oligoprogression or those who cannot tolerate systemic therapy. However, the optimal modalities for treatment of oligometastatic and advanced metastatic disease remain unknown. Finally, locoregional therapies may produce tumor antigens that in combination with immunotherapy drive anti-tumor immunity. Although key trials are ongoing, additional prospective studies are needed to establish the inclusion of interventional oncology in societal breast cancer guidelines to support further clinical adoption and improved patient outcomes.

Background: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks., Methods: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method., Results: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation., Conclusions: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients., (© 2021. Society of Surgical Oncology.)

Obesity is associated with altered glycine metabolism in humans. This study investigated the mechanisms regulating glycine metabolism in obese rats. Eight-week-old Zucker diabetic fatty rats (ZDF; a type-II diabetic animal model) received either 1% glycine or 1.19% L-alanine (isonitrogenous control) in drinking water for 6 weeks. An additional group of lean Zucker rats also received 1.19% L-alanine as a lean control. Glycine concentrations in serum and liver were markedly lower in obese versus lean rats. Enteral glycine supplementation restored both serum and hepatic glycine levels, while reducing mesenteric and internal white fat mass compared with alanine-treated ZDF rats. Blood glucose and non-esterified fatty acid (NEFA) concentrations did not differ between the control and glycine-supplemented ZDF rats (P > 0.10). Both mRNA and protein expression of aminomethyltransferase (AMT) and glycine dehydrogenase, decarboxylating (GLDC) were increased in the livers of obese versus lean rats (P < 0.05). In contrast, glycine cleavage system H (GCSH) hepatic mRNA expression was downregulated in obese versus lean rats, although there was no change in protein expression. These findings indicate that reduced quantities of glycine observed in obese subjects likely results from an upregulation of the hepatic glycine cleavage system and that dietary glycine supplementation potentially reduces obesity in ZDF rats.

Body temperature maintenance is one of the most important physiological processes initiated after birth. Brown adipose tissue (BAT) is an essential mediator of thermogenesis in many species and is responsible for 50% of the heat generated in the newborn lamb. To determine if maternal arginine supplementation could enhance thermogenesis in the neonate, we randomly assigned 31 multiparous Suffolk ewes, gestating singletons or twins, to receive intravenous injections of either l-arginine (27 mg/kg body weight; n = 17) or sterile saline (n = 14) three times daily from day 75 to 125 of gestation (term = 147). Following parturition, lambs were removed from their mothers and subjected to 0 °C cold challenges at 4 and 22 h of age. Rectal temperatures were higher for the duration of the cold challenges in lambs from arginine-treated ewes compared with lambs from saline-treated ewes (P < 0.05). Elevated rectal temperatures were associated with increased (P < 0.05) circulating glycine and serine concentrations in lambs. The mRNA expression of genes related to BAT function changed over time, but not between lambs from arginine-treated vs. saline-treated ewes. Results indicate that maternal arginine treatment increases neonatal thermogenesis after birth. Although the underlying mechanisms remain to be elucidated, these data are a first step in improving neonatal survival in response to cold., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells critical in mediating immune suppression in cancer patients. To develop an in vitro assay system that functionally mimics the tumor microenvironment, we cultured human monocytes with conditioned media from several cancer cell lines. Conditioned media from five tumor cell lines induced survival and differentiation of monocytes into cells characteristically similar to macrophages and MDSCs. Notably, media from the 786.O renal cell carcinoma line induced monocytes to acquire a monocytic MDSC phenotype characterized by decreased HLA-DR expression, increased nitric oxide production, enhanced proliferation, and ability to suppress autologous CD3 + T cell proliferation. We further demonstrated that these in vitro MDSCs are phenotypically and functionally similar to patient-derived MDSCs. Inhibitors of STAT3, CK2, and GM-CSF resulted in partial reversal of the MDSC phenotype. MDSCs generated in vitro from 786.O tumor conditioned media represent a platform to identify potential therapeutics that inhibit MDSC activities., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu 2/3 ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu 2/3 receptor agonist prodrug were investigated., Experimental Approach: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent and subtype-selective mGlu 2/3 receptor agonist LY2934747. Behavioural assessments of allodynia, hyperalgesia and nocifensive behaviours were determined in preclinical pain models after administration of LY2969822 0.3-10 mg·kg -1 . In addition, the ability of i.v. LY2934747 to modulate dorsal horn spinal cord wide dynamic range (WDR) neurons in spinal nerve ligated (SNL) rats was assessed., Key Results: Following treatment with LY2934747, the spontaneous activity and electrically-evoked wind-up of WDR neurons in rats that had undergone spinal nerve ligation and developed mechanical allodynia were suppressed. In a model of sensitization, orally administered LY2969822 prevented the nociceptive behaviours induced by an intraplantar injection of formalin. The on-target nature of this effect was confirmed by blockade with an mGlu 2/3 receptor antagonist. LY2969822 prevented capsaicin-induced tactile hypersensitivity, reversed the SNL-induced tactile hypersensitivity and reversed complete Freund's adjuvant - induced mechanical hyperalgesia. The mGlu 2/3 receptor agonist prodrug demonstrated efficacy in visceral pain models, including a colorectal distension model and partially prevented the nocifensive behaviours in the mouse acetic acid writhing model., Conclusions and Implications: Following oral administration of the prodrug LY2969822, the mGlu 2/3 receptor agonist LY2934747 was formed and this attenuated pain behaviours across a broad range of preclinical pain models., (© 2017 The British Pharmacological Society.)

Background: Cryoablation is a well-established technique to treat fibroadenomas. Pilot studies suggest this could be an effective non-surgical treatment for breast cancer. American College of Surgeons Oncology Group Z1072 is a phase II trial exploring the effectiveness of cryoablation in the treatment of breast cancers., Methods: The primary endpoint of Z1072 was the rate of complete tumor ablation, defined as no remaining invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) on pathologic examination of the targeted lesion. A secondary objective was to evaluate the negative predictive value of magnetic resonance imaging (MRI) to determine residual IBC or DCIS. Eligible patients included those with unifocal invasive ductal breast cancer ≤2 cm, with <25 % intraductal component and tumor enhancement on MRI. A total of 19 centers contributed 99 patients, of which 86 patients (87 breast cancers) were evaluable for data analysis., Results: Final pathology results, regardless of whether residual IBC/DCIS was in the targeted ablation zone or elsewhere in the breast, showed successful ablation in 66/87 (75.9 %) cancers. The 90 % confidence interval for the estimate of successful cryoablation was 67.1-83.2, with the one-sided lower-sided 90 % CI of 69.0. The negative predictive value of MRI was 81.2 % (90 % CI 71.4-88.8). When multifocal disease outside of the targeted cryoablation zone was not defined as an ablation failure, 80/87 (92 %) of the treated cancers had a successful cryoablation., Conclusion: Further studies with modifications on the Z1072 protocol could be considered to evaluate the role for cryoablation as a non-surgical treatment of early-stage breast cancer.

Context: Radial scars are benign sclerosing lesions that are routinely excised when diagnosed in a needle core biopsy. Optimal management for patients with incidental and small (≤5 mm) radial scars is uncertain., Objective: To assess pathologic upgrade of radial scars diagnosed in needle core biopsy samples and identify a subset of patients who could benefit from conservative management., Design: Patients with a diagnosis of radial scar in a needle core biopsy who underwent excision of the biopsied area were identified. Radial scars greater than 5 mm in size and those with coexisting atypia, carcinoma, and papillary lesions were excluded. After histologic-radiographic correlation, rates of pathologic upgrade were assessed., Results: Seventy-seven radial scars diagnosed in 66 patients were included. Overall, 9 of 77 (12%) showed upgrade to a high-risk lesion (6 lobular carcinoma in situ, 2 atypical ductal hyperplasia, 1 atypical lobular hyperplasia), while none (0%) showed upgrade to invasive carcinoma or ductal carcinoma in situ. One of 22 incidental radial scars (4.5%) showed upgrade on excision versus 6 of 36 (16.7%) for radial scars considered to be the radiographic target (P = .23). Older age was associated with upgrade (P < .001)., Conclusions: No incidental or small (≤5 mm) radial scars excised revealed invasive carcinoma or ductal carcinoma in situ on excision. Provided there is good pathologic-radiologic concordance, it appears reasonable for these patients to be managed conservatively.

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

Background: Pancreatic ductal adenocarcinoma (PDA) is characterised by a robust desmoplasia, including the notable accumulation of immunosuppressive cells that shield neoplastic cells from immune detection. Immune evasion may be further enhanced if the malignant cells fail to express high levels of antigens that are sufficiently immunogenic to engender an effector T cell response., Objective: To investigate the predominant subsets of immunosuppressive cancer-conditioned myeloid cells that chronicle and shape the progression of pancreas cancer. We show that selective depletion of one subset of myeloid-derived suppressor cells (MDSC) in an autochthonous, genetically engineered mouse model (GEMM) of PDA unmasks the ability of the adaptive immune response to engage and target tumour epithelial cells., Methods: A combination of in vivo and in vitro studies were performed employing a GEMM that faithfully recapitulates the cardinal features of human PDA. The predominant cancer-conditioned myeloid cell subpopulation was specifically targeted in vivo and the biological outcomes determined., Results: PDA orchestrates the induction of distinct subsets of cancer-associated myeloid cells through the production of factors known to influence myelopoiesis. These immature myeloid cells inhibit the proliferation and induce apoptosis of activated T cells. Targeted depletion of granulocytic MDSC (Gr-MDSC) in autochthonous PDA increases the intratumoral accumulation of activated CD8 T cells and apoptosis of tumour epithelial cells and also remodels the tumour stroma., Conclusions: Neoplastic ductal cells of the pancreas induce distinct myeloid cell subsets that promote tumour cell survival and accumulation. Targeted depletion of a single myeloid subset, the Gr-MDSC, can unmask an endogenous T cell response, disclosing an unexpected latent immunity and invoking targeting of Gr-MDSC as a potential strategy to exploit for treating this highly lethal disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Granular cell tumors (GCT) are generally benign soft tissue tumors. When located in the breast, they may be misdiagnosed as more typical tumors, such as invasive ductal carcinoma, based on misleading clinical or radiologic features. GCTs are frequently found in the setting of a known malignancy. We report the case of a patient with a large infra-mammary fold GCT, the management of which required a multidisciplinary operative approach due to extensive chest wall invasion., (© 2014 Wiley Periodicals, Inc.)

Background: The rat L5/L6 spinal nerve ligation model (SNL) has been widely used to investigate putative analgesics. Pursuit of novel therapies in preclinical settings requires models with consistent and reproducible phenotypes., New Method: We assessed the effects of repetitive stimulation of the hindpaws of SNL and Sham surgery rats during the 2 weeks immediately after surgery on the overall rate of achieving tactile hypersensitivity, as well as the magnitude of the hypersensitivity compared to unprimed rats. Beginning on day 2 post-surgery, and continuing on alternate days for a total of seven sessions, animals underwent light brushing/tapping (termed priming) of the hindpaws ipsilateral and contralateral to surgery., Results: Priming the ipsilateral hindpaw enhanced the magnitude of tactile hypersensitivity such that the baseline withdrawal threshold (BWT) for primed SNL animals was significantly lower than unprimed SNL animals over post-surgical days 15-29. BWT was not different between primed and unprimed Sham rats. The percentage of SNL primed animals meeting the a priori criterion for tactile hypersensitivity of paw withdrawal threshold less than 2.0 grams was 98.9%±1.1%., Comparison With Existing Method: SNL rats that did not receive stimulation (unprimed) showed significantly higher baseline hypersensitivity when evaluated on days 15-29, exemplified by only 34.5%±7.2% meeting the established <2.0g criterion., Conclusion: Our data indicate that tactile priming during the 2 weeks immediately after SNL surgery enhances the magnitude of tactile hypersensitivity in the SNL model, and provide an optimized assay for evaluating putative analgesics., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The presence of tumor cells at the margins of breast lumpectomy specimens is associated with an increased risk of ipsilateral tumor recurrence. Twenty to 30 % of patients undergoing breast-conserving surgery require second procedures to achieve negative margins. This study evaluated the adjunctive use of the MarginProbe device (Dune Medical Devices Ltd, Caesarea, Israel) in providing real-time intraoperative assessment of lumpectomy margins., Methods: This multicenter randomized trial enrolled patients with nonpalpable breast malignancies. The study evaluated MarginProbe use in addition to standard intraoperative methods for margin assessment. After specimen removal and inspection, patients were randomized to device or control arms. In the device arm, MarginProbe was used to examine the main lumpectomy specimens and direct additional excision of positive margins. Intraoperative imaging was used in both arms; no intraoperative pathology assessment was permitted., Results: In total, 596 patients were enrolled. False-negative rates were 24.8 and 66.1 % and false-positive rates were 53.6 and 16.6 % in the device and control arms, respectively. All positive margins on positive main specimens were resected in 62 % (101 of 163) of cases in the device arm, versus 22 % (33 of 147) in the control arm (p < 0.001). A total of 19.8 % (59 of 298) of patients in the device arm underwent a reexcision procedure compared with 25.8 % (77 of 298) in the control arm (6 % absolute, 23 % relative reduction). The difference in tissue volume removed was not significant., Conclusions: Adjunctive use of the MarginProbe device during breast-conserving surgery improved surgeons' ability to identify and resect positive lumpectomy margins in the absence of intraoperative pathology assessment, reducing the number of patients requiring reexcision. MarginProbe may aid performance of breast-conserving surgery by reducing the burden of reexcision procedures for patients and the health care system.

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Establishment of pregnancy in ruminants requires conceptus elongation and production of interferon tau (IFNT), the pregnancy recognition signal that maintains the corpus luteum and progesterone (P4) secretion. The enzymes hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1) and HSD11B2 catalyze the interconversion of inactive cortisone and active cortisol, which is a biologically active glucorticoid and ligand for the receptor subfamily 3, group C, member 1 (glucocorticoid receptor) (NR3C1). The activity of HSD11B1 is stimulated by P4, prostaglandins, and cortisol. These studies determined the effects of pregnancy, P4, and IFNT on HSD11B1, HSD11B2, prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (PTGS2), and nuclear NR3C1 in the ovine uterus. Endometrial HSD11B1 mRNA levels were more abundant between Days 12 and 16 of pregnancy than the estrous cycle, and HSD11B1 and PTGS2 expression in the endometrial luminal and superficial glandular epithelia was coincident with conceptus elongation. HSD11B1 mRNA was very low in the conceptus, whereas HSD11B2 mRNA was abundant in the conceptus but not in the uterus. Treatment of ewes with P4 induced, and intrauterine infusions of IFNT modestly stimulated, HSD11B1 expression in the endometrial luminal and superficial glandular epithelia. In all of the studies, HSD11B1 and PTGS2 expression was coincident in the endometrial epithelia, and NR3C1 was present in all endometrial cell types. Collectively, these results support hypotheses that endometrial epithelial HSD11B1 expression is induced by P4 as well as stimulated by IFNT and PTGS2-derived prostaglandins and that HSD11B1-regenerated cortisol acts via NR3C1 to regulate ovine endometrial functions during early pregnancy.

Establishment of pregnancy in ruminants requires blastocyst growth to form an elongated conceptus that produces interferon tau, the pregnancy recognition signal, and initiates implantation. Blastocyst growth and development requires secretions from the uterine endometrium. An early increase in circulating concentrations of progesterone (P4) stimulates blastocyst growth and elongation in ruminants. This study utilized sheep as a model to identify candidate genes and regulatory networks in the endometrium that govern preimplantation blastocyst growth and development. Ewes were treated daily with either P4 or corn oil vehicle from day 1.5 after mating to either day 9 or day 12 of pregnancy when endometrium was obtained by hysterectomy. Microarray analyses revealed many differentially expressed genes in the endometria affected by day of pregnancy and early P4 treatment. In situ hybridization analyses revealed that many differentially expressed genes were expressed in a cell-specific manner within the endometrium. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to identify functional groups of genes and biological processes in the endometrium that are associated with growth and development of preimplantation blastocysts. Notably, biological processes affected by day of pregnancy and/or early P4 treatment included lipid biosynthesis and metabolism, angiogenesis, transport, extracellular space, defense and inflammatory response, proteolysis, amino acid transport and metabolism, and hormone metabolism. This transcriptomic data provides novel insights into the biology of endometrial function and preimplantation blastocyst growth and development in sheep.

Establishment of pregnancy in ruminants requires conceptus elongation and production of interferon-tau (IFNT), the pregnancy recognition signal that maintains ovarian progesterone (P4) production. These studies determined temporal and spatial alterations in IGF binding protein (IGFBP)-1 and IGFBP3 in the ovine and bovine uterus; effects of P4 and IFNT on their expression in the ovine uterus; and effects of IGFBP1 on ovine trophectoderm cell proliferation, migration, and attachment. IGFBP1 and IGFBP3 were studied because they are the only IGFBPs specifically expressed by the endometrial luminal epithelia in sheep. In sheep, IGFBP1 and IGFBP3 expression was coordinate with the period of conceptus elongation, whereas only IGFBP1 expression was coordinate with conceptus elongation in cattle. IGFBP1 mRNA in the ovine endometria was between 5- and 29-fold more abundant between d 12 and 16 of pregnancy compared with the estrous cycle and greater on d 16 of pregnancy than nonpregnancy in the bovine uterus. In sheep, P4 induced and IFNT stimulated expression of IGFBP1 but not IGFBP3; however, the effect of IFNT did not mimic the abundant increase observed in pregnant ewes. Therefore, IGFBP1 expression in the endometrium is regulated by another factor from the conceptus. IGFBP1 did not affect the proliferation of ovine trophectoderm cells in vitro but did stimulate their migration and mediate their attachment. These studies reveal that IGFBP1 is a common endometrial marker of conceptus elongation in sheep and cattle and most likely regulates conceptus elongation by stimulating migration and attachment of the trophectoderm.

Background: Digital infrared thermal imaging (DITI) has resurfaced in this era of modernized computer technology. Its role in the detection of breast cancer is evaluated., Methods: In this prospective clinical trial, 92 patients for whom a breast biopsy was recommended based on prior mammogram or ultrasound underwent DITI. Three scores were generated: an overall risk score in the screening mode, a clinical score based on patient information, and a third assessment by artificial neural network., Results: Sixty of 94 biopsies were malignant and 34 were benign. DITI identified 58 of 60 malignancies, with 97% sensitivity, 44% specificity, and 82% negative predictive value depending on the mode used. Compared to an overall risk score of 0, a score of 3 or greater was significantly more likely to be associated with malignancy (30% vs 90%, P < .03)., Conclusion: DITI is a valuable adjunct to mammography and ultrasound, especially in women with dense breast parenchyma.

We recently demonstrated the pivotal role of the transcription factor (TF) activating TF 3 (ATF3) in dampening inflammation. We demonstrate that ATF3 also ameliorates allergen-induced airway inflammation and hyperresponsiveness in a mouse model of human asthma. ATF3 expression was increased in the lungs of mice challenged with ovalbumin allergen, and this was associated with its recruitment to the promoters of genes encoding Th2-associated cytokines. ATF3-deficient mice developed significantly increased airway hyperresponsiveness, pulmonary eosinophilia, and enhanced chemokine and Th2 cytokine responses in lung tissue and in lung-derived CD4(+) lymphocytes. Although several TFs have been associated with enhanced inflammatory responses in the lung, ATF3 attenuates the inflammatory responses associated with allergic airway disease.

We present a substantial series of behavioral and imaging experiments, which demonstrate, for the first time, that increasing AMPA receptor-mediated neurotransmission via administration of potent and selective biarylsulfonamide AMPA potentiators LY404187 and LY451395 reverses the central effects of an acutely intoxicating dose of ethanol in the rat. Using pharmacological magnetic resonance imaging (phMRI), we observed that LY404187 attenuated ethanol-induced reductions in blood oxygenation level dependent (BOLD) in the anesthetized rat brain. A similar attenuation was apparent when measuring local cerebral glucose utilization (LCGU) via C14-2-deoxyglucose autoradiography in freely moving conscious rats. Both LY404187 and LY451395 significantly and dose-dependently reversed ethanol-induced deficits in both motor coordination and disruptions in an operant task where animals were trained to press a lever for food reward. Both prophylactic and acute intervention treatment with LY404187 reversed ethanol-induced deficits in motor coordination. Given that LY451395 and related AMPA receptor potentiators/ampakines are tolerated in both healthy volunteers and elderly patients, these data suggest that such compounds may form a potential management strategy for acute alcohol intoxication.

Background: Sentinel lymph node biopsy (SLNB) is used to detect breast cancer axillary metastases. Some surgeons send the sentinel lymph node (SLN) for intraoperative frozen section (FS) to minimize delayed axillary dissections. There has been concern that FS may discard nodal tissue and thus underdiagnose small metastases. This study examines whether evaluation of SLN by FS increases the false-negative rate of SLNB., Methods: A retrospective analysis of SLNB from 659 patients was conducted to determine the frequency of node positivity among SLNB subjected to both FS and permanent section (PS) versus PS alone. Statistical analysis was performed by the chi(2) square test, and a logistic regression model was applied to estimate the effect of final node positivity between the two groups., Results: FS was performed in 327 patients and PS was performed in all 659 patients. Among patients undergoing both FS and PS (n = 327), the final node positivity rate was 33.0% compared with 19.6% among patients undergoing PS alone (n = 332). After adjustment for patient age, tumor diameter, grade, and hormone receptor status in a multivariate logistic regression model, there remained an increased likelihood of final node positivity for patients undergoing both procedures relative to PS alone (adjusted odds ratio, 2.1; 95% confidence interval, 1.3-3.6; P = .005)., Conclusions: There was a higher rate of SLN positivity in specimens evaluated by both FS and PS. Therefore, evaluating SLN by FS does not underdiagnose small metastases nor produce a higher false-negative rate. Intraoperative FS offers the advantage of less delayed axillary dissections.

Innate immune pattern recognition receptors play critical roles in pathogen detection and initiation of antimicrobial responses. We and others have previously demonstrated the importance of the beta-glucan receptor Dectin-1 in the recognition of pathogenic fungi by macrophages and dendritic cells and have elucidated some of the mechanisms by which Dectin-1 signals to coordinate the antifungal response. While Dectin-1 signals alone are sufficient to trigger phagocytosis and Src-Syk-mediated induction of antimicrobial reactive oxygen species, collaboration with TLR2 signaling enhances NF-kappaB activation and regulates cytokine production. In this study we demonstrate that Dectin-1 signaling can also directly modulate gene expression via activation of NFAT. Dectin-1 ligation by zymosan particles or live Candida albicans yeast triggers NFAT activation in macrophages and dendritic cells. Dectin-1-triggered NFAT activation plays a role in the induction of early growth response 2 and early growth response 3 transcription factors, and cyclooxygenase-2. Furthermore, we show that NFAT activation regulates IL-2, IL-10 and IL-12 p70 production by zymosan-stimulated dendritic cells. These data establish NFAT activation in myeloid cells as a novel mechanism of regulation of the innate antimicrobial response.

GLU(K5) kainate receptor subunits are abundant in pain pathways, including dorsal root ganglia and spinothalamic neurons, as well as in the thalamus and brain stem. A growing body of evidence indicates that the GLU(K5) kainate receptor subtype plays a prominent role in pain transmission, particularly in persistent pain. In the present studies, compounds from a novel series of amino acid GLU(K5) receptor antagonists were evaluated for their effectiveness in reversing capsaicin-induced mechanical allodynia as well as carrageenan-induced thermal hyperalgesia. In vitro, the amino acid compounds were efficacious in blocking glutamate-evoked calcium flux in cells expressing GLU(K5) but not GLU(K6) or GLU(A2), homomeric receptors. Electrophysiologically, the compounds exhibited selectivity for kainate receptors in dorsal root ganglion cells relative to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide and N-methyl-d-aspartate receptors in hippocampal pyramidal neurons. The amino acid compounds were poorly efficacious in the pain tests after s.c. or p.o. administration. However, compounds were highly efficacious after central intracisternal administration, and the rank order of potencies correlated with their rank order of affinities at GLU(K5) receptors determined in vitro, indicating that the lack of activity after systemic administration was due to poor oral bioavailability. To increase oral bioavailability, isobutyl or 2-ethyl-butyl ester prodrugs of the parent amino acids were prepared. The prodrugs, which produced robust plasma levels of parent amino acids, were highly efficacious in the capsaicin and carrageenan tests. The present studies provide further evidence that selective Glu(K5) kainate receptor subtype antagonists can reverse allodynia and hyperalgesia, particularly in persistent pain states.

Redevelopment of isometric force following shortening of skeletal muscle is thought to result from a redistribution of cross-bridge states. We varied the initial force and cross-bridge distribution by applying various length-change protocols to active skinned single fibres from rabbit psoas muscle, and observed the effect on the slowest phase of recovery ('late recovery') that follows transient changes. In response to step releases that reduced force to near zero ( approximately 8 nm (half sarcomere)(-1)) or prolonged shortening at high velocity, late recovery was well described by two exponentials of approximately equal amplitude and rate constants of approximately 2 s(-1) and approximately 9 s(-1) at 5 degrees C. When a large restretch was applied at the end of rapid shortening, recovery was accelerated by (1) the introduction of a slow falling component that truncated the rise in force, and (2) a relative increase in the contribution of the fast exponential component. The rate of the slow fall was similar to that observed after a small isometric step stretch, with a rate of 0.4-0.8 s(-1), and its effects could be reversed by reducing force to near zero immediately after the stretch. Force at the start of late recovery was varied in a series of shortening steps or ramps in order to probe the effect of cross-bridge strain on force redevelopment. The rate constants of the two components fell by 40-50% as initial force was raised to 75-80% of steady isometric force. As initial force increased, the relative contribution of the fast component decreased, and this was associated with a length constant of about 2 nm. The results are consistent with a two-state strain-dependent cross-bridge model. In the model there is a continuous distribution of recovery rate constants, but two-exponential fits show that the fast component results from cross-bridges initially at moderate positive strain and the slow component from cross-bridges at high positive strain.

Nipple discharge is not uncommon in women during their reproductive years. The etiology is benign in the majority of cases. Patients presenting with nipple discharge often require major duct excision (MDE) for accurate diagnosis and treatment. MDE is enhanced by the use of intraoperative injection of methylene blue dye into the discharging duct in order to aid visualization. Methylene blue dye-enhanced MDE has several advantages over traditional techniques. Methylene blue dye staining identifies the major discharging duct, as well as its side branches, which allows the surgeon to resect that specific ductal system only. This method allows neighboring major ducts to remain intact, preserving nipple function and permitting future cancer detection. Methylene blue-enhanced MDE allows the surgeon to more accurately determine the precise location and volume of tissue that needs to be excised. Lastly, methylene blue is both safe and inexpensive.

Phytocannabinoids, such as the principal bioactive component of marijuana, delta9-tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. delta9-Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase. Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.

Dectin-1 is a lectin receptor for beta-glucan that is important for innate macrophage recognition of fungi and contributes to phagocytosis, reactive oxygen production, and induction of inflammatory cytokines. The mechanisms by which Dectin-1 mediates intracellular signaling are just beginning to be defined. Spleen tyrosine kinase (Syk) is a protein tyrosine kinase that is critical for adaptive immune responses where it mediates signaling through B-cell receptors, T-cell receptors, and Fc receptors. Here we report that Dectin-1 activates Syk in macrophages and is important for Dectin-1-stimulated reactive oxygen production, but not for phagocytosis. Syk activation is restricted to a subpopulation of macrophages that is in equilibrium with cells that cannot activate the pathway. The proportion of macrophages using this signaling pathway can be modulated by cytokine treatment. Thus, Dectin-1 signaling reveals dynamic macrophage heterogeneity in inflammatory activation potential.

Inflammatory local recurrence after breast-conserving therapy for noninflammatory breast cancer is uncommon and carries a poor prognosis. Over a 5-year period, 7 such cases were treated at the New York-Presbyterian Hospital/Weill-Cornell Medical Center. The characteristics of these 7 patients were compiled and are reviewed along with a discussion of inflammatory recurrence. Tumor size, location, histologic type, grade, stage, margin status, lymphovascular invasion (LVI), estrogen receptor (ER) status, progesterone receptor (PgR) status, adjuvant therapy, and/or radiation therapy at the time of primary treatment and at recurrence were analyzed. The median survival time was 79 months (range, 26-130 months) for patients initially ER-positive, compared with 23 months (range, 0-67 months) for initially ER-negative patients. The median survival for patients without lymph node involvement was 78 months (range, 26-130 months) compared with 41 months (range, 0-79 months) for those with nodal metastases. Survival time in this series of inflammatory local recurrences correlated with the ER status and lymph node involvement of the primary lesion. The optimal management for inflammatory local recurrence is a multimodality approach combining preoperative chemotherapy and surgery.

Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.

Background: Because widespread screening for breast cancer is detecting more women at younger ages and earlier stages, the need for minimally invasive, cosmetically preferable approaches to its treatment is growing. Ablative techniques are now being applied to the treatment of primary breast tumors, perhaps offering an alternative to surgical excision. Techniques available for breast cancer treatment include radiofrequency ablation, cryoablation, interstitial laser ablation, microwave thermotherapy, and focused ultrasound ablation., Data Sources: Literature searches for breast and cryoablation, focused ultrasound ablation, interstitial laser ablation, microwave thermotherapy, and radiofrequency ablation were performed. Over 30 articles were identified and analyzed., Conclusions: It is cautiously optimistic that these therapies can be used as a routine adjunct in the treatment of selected breast cancers. The challenge will lie in the ability to identify multifocal disease and in situ carcinoma as well as to ensure complete and effective eradication of the breast cancer.

Background: Persistently involved margins following breast conservation surgery (BCS) create a diagnostic dilemma regarding the recommendation of further BCS or mastectomy., Methods: A retrospective review of 276 breast cancer patients who underwent BCS and required additional surgical treatment between 1990-2002 was performed., Results: For treatment of persistently involved margins, 63% of subjects underwent re-excision the first time, 49% the second time, and 37% the third time. The incidence of residual carcinoma increased linearly with the number of initially involved margins (P = .03). Ductal carcinoma-in-situ (DCIS) or infiltrating lobular carcinoma (IFLC) primary histology was associated with a higher rate of residual cancer compared to invasive ductal carcinoma (IFDC) (62% vs. 69% vs. 54%, respectively, P = .56). A trend towards an increased risk of residual cancer in primary tumors > or =2 cm versus tumors under 2 cm was also evident (63%% vs. 50%, respectively, P = .38)., Conclusions: Approximately half of patients repeatedly selected BCS over mastectomy. It is important to realistically discuss the probability of definitive resection with patients who are undergoing breast conservation with re-excision.

Background: Sentinel lymph node biopsies (SLNB) are used to detect axillary metastases as an important prognostic indicator for breast cancer patients. Bone marrow micrometastases (BMM) have also been shown to predict prognosis. This study examines whether SLNB and BMM are associated., Study Design: A retrospective analysis was performed on 124 stages I to III breast cancer patients treated with mastectomy or lumpectomy, SLNB, and bone marrow aspiration between 1997 and 2003. SLNB were examined for the presence of metastases by hematoxylin and eosin (H&E) stains and also by immunohistochemistry (IHC) for lymph nodes negative by H&E. The kappa statistic was used to evaluate the association (agreement) between SLNB and BMM., Results: In this study population, 36 patients (29%) had micrometastases detected in their bone marrow, and 51 patients (41%) had positive sentinel lymph nodes. Of the patients with positive BMM (n = 36), 53% (19 of 36) had positive SLNB (14 of 19 by H&E and 5 of 19 by IHC). In patients with negative BMM (n = 88), 36% (32 of 88) had a positive SLNB (27 of 32 by H&E and 5 of 32 by IHC). The kappa statistic and associated 95% confidence interval indicated poor agreement between SLNB and BMM (kappa = 0.15; 95% CI = -0.03, 0.32)., Conclusions: There was poor agreement between axillary metastases and micrometastases detected in the bone marrow. This study suggests that BMM and axillary metastases are not concordant findings in most patients.

The ability of Candida albicans to rapidly and reversibly switch between yeast and filamentous morphologies is crucial to pathogenicity, and it is thought that the filamentous morphology provides some advantage during interaction with the mammalian immune system. Dectin-1 is a receptor that binds beta-glucans and is important for macrophage phagocytosis of fungi. The receptor also collaborates with Toll-like receptors for inflammatory activation of phagocytes by fungi. We show that yeast cell wall beta-glucan is largely shielded from Dectin-1 by outer wall components. However, the normal mechanisms of yeast budding and cell separation create permanent scars which expose sufficient beta-glucan to trigger antimicrobial responses through Dectin-1, including phagocytosis and activation of reactive oxygen production. During filamentous growth, no cell separation or subsequent beta-glucan exposure occurs, and the pathogen fails to activate Dectin-1. The data demonstrate a mechanism by which C. albicans shape alone directly contributes to the method by which phagocytes recognize the fungus.

Background: Sentinel lymph node biopsy (SLNB) is an established means of staging the axilla in patients with breast cancer. Recently, methylene blue dye has been shown to be an efficacious and cost-effective alternative to isosulfan blue. With the increasing popularity of SLNB, the potential complications of isosulfan blue use must be appreciated., Methods: A literature search for English language articles available on MEDLINE from 1985 to November 2002 using the search terms allergy, allergic reaction, anaphylactic reactions, anaphylaxis, blue dye, breast cancer, isosulfan blue, methylene blue, and sentinel lymph node biopsy identified 24 reports., Conclusions: The use of isosulfan blue due for SLNB is associated with a significant number of allergic reactions, some of which are life-threatening. Because methylene blue dye has been shown to be equally effective and does not pose a serious risk of serious allergic reactions, it offers an improved technique above isosulfan blue dye for SLNB.

Background: Today, the majority of small invasive and noninvasive breast cancers are treated with breast conservation therapy (BCT). The incidence of local-regional recurrence (LRR) after BCT for stage 0, I, and II patients ranges between 5% and 22%., Methods: A literature search for BCT, local recurrence, and regional recurrence was performed. Data from over 50 articles pertaining to the characteristics, risk factors, detection, management, and prognosis of these patients with LRR after BCT were collected and analyzed., Results: Positive margins, high-grade ductal carcinoma in situ (DCIS), young age, and the absence of radiation therapy after BCT increase the risk for LRR. Prognosis at LRR is impacted by invasive versus noninvasive histology, size and stage, method of detection, and involvement of skin and/or axillary lymph nodes. The standard treatment is salvage mastectomy., Conclusions: The prognosis for LRR after BCT is favorable compared with patients with postmastectomy chest wall recurrence.

5-Hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in para-chloramphetamine-treated rats was comparable with that of paroxetine, a selective serotonin reuptake inhibitor (SSRI), whereas its ability to antagonize NE depletion in alpha-methyl-m-tyrosine-treated rats was similar to norepinephrine reuptake inhibitors (NRIs), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI paroxetine or the NRI thionisoxetine alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran, and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain. Duloxetine (3-30 mg/kg oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states.

Objective: Areola-sparing mastectomy (ASM) is defined as resecting the nipple and any existing surgical biopsy scar, removing all breast parenchyma, and leaving a natural envelope of skin (including the areola), which improves the aesthetic result of immediate reconstruction. We previously demonstrated a <1% incidence of malignant involvement of the areola in a retrospective mastectomy series. Subsequently, we performed ASM on selected patients undergoing mastectomy. We report here our results from an ongoing study of ASM at our institution., Methods: During a 20-month period, 17 ASMs with immediate reconstruction were performed on 12 patients. Patients were followed-up prospectively by the surgical oncologist for complications and recurrence., Results: ASM was performed for breast cancer prophylaxis (n = 10), ductal carcinoma in situ (DCIS) (n = 4), and <2-cm peripheral infiltrating carcinoma (n = 3). The mean patient age was 47.7 years (range 37 to 61). Thirteen patients were reconstructed with tissue expanders and 4 with pedicle transverse rectus abdominus myocutaneous flaps. Ten patients underwent sentinel lymph node biopsy. None of the ten patients showed sentinel lymph node metastasis. Two patients with DCIS and microinvasion underwent subareolar touch-prep cytology, both of which were negative for malignancy. All mastectomy specimens had negative histologic margins. No patient received chemotherapy or radiation therapy. One postoperative consisted of a localized wound infection that resolved with oral antibiotics. At a median follow-up of 24 months (range 11 to 28), there were no instances of local or distant recurrence., Conclusions: Overall, we found that ASM with immediate reconstruction provides excellent aesthetic results with infrequent complications. Furthermore, in this small series we showed no recurrence at 2 years. We continue to offer ASM for selected patients including those desiring surgical breast cancer prophylaxis as well as those with DCIS or small peripheral infiltrating ductal carcinoma.

Macrophages play a critical role in both innate and acquired immunity because of their unique ability to internalize, kill, and degrade bacterial pathogens through the process of phagocytosis. The adaptor protein, amphiphysin IIm, participates in phagocytosis and is transiently associated with early phagosomes. Certain pathogens, including Chlamydia pneumoniae, have evolved mechanisms to subvert macrophage phagosome maturation and, thus, are able to survive within these cells. We report here that, although amphiphysin IIm is usually only transiently associated with the phagosome, it is indefinitely retained on vacuoles containing C. pneumoniae. Under these wild-type conditions, C. pneumoniae do not elicit significant nitric oxide (NO) production and are not killed. Abrogation of amphiphysin IIm function results in C. pneumoniae-induced NO production and in the sterilization of the vacuole. The data suggest that C. pneumoniae retains amphiphysin IIm on the vacuole to survive within the macrophage.