Protective Mechanism of Stem Cells from Human Exfoliated Deciduous Teeth in Treating Spinal Cord Injury.

Spinal cord injury (SCI) induces devastating permanent deficits. Recently, cell transplantation therapy has become a notable treatment for SCI. Although stem cells from human exfoliated deciduous teeth (SHED) are an attractive therapy, their precise mechanism of action remains to be elucidated. In this study, we explored one of the neuroprotective mechanisms of SHED treatment at the subacute stage after SCI. We used a rat clip compression SCI model. The animals were randomly divided into three groups: SCI, SCI + phosphate-buffered saline (PBS), and SCI + SHED. The SHED or PBS intramedullary injection was administered immediately after SCI. After SCI, we explored the effects of SHED on motor function, as assessed by the Basso-Beattie-Bresnahan score and the inclined plane method, the signal transduction pathway, especially the Janus kinase (JAK) and the signal transducer and activator of transcription 3 (STAT3) pathway, the apoptotic pathway, and the expression of neurocan, one of the chondroitin sulfate proteoglycans. SHED treatment significantly improved functional recovery from Day 14 relative to the controls. Western blot analysis showed that SHED significantly reduced the expression of glial fibrillary acidic protein (GFAP) and phosphorylated STAT3 (p-STAT3) at Tyr705 on Day 10 but not on Day 5. However, SHED had no effect on the expression levels of Iba-1 on Days 5 or 10. Immunohistochemistry revealed that p-STAT3 at Tyr705 was mainly expressed in GFAP-positive astrocytes on Day 10 after SCI, and its expression was reduced by administration of SHED. Moreover, SHED treatment significantly induced expression of cleaved caspase 3 in GFAP-positive astrocytes only in the epicenter lesions on Day 10 after SCI but not on Day 5. The expression of neurocan was also significantly reduced by SHED injection on Day 10 after SCI. Our results show that SHED plays an important role in reducing astrogliosis and glial scar formation between Days 5 and 10 after SCI, possibly via apoptosis of astrocytes, ultimately resulting in improvement in neurological functions thereafter. Our data revealed one of the neuroprotective mechanisms of SHED at the subacute stage after SCI, which improved functional recovery after SCI, a serious condition.

Platelet-derived Growth Factor Activates Pericytes in the Microvessels of Chronic Subdural Hematoma Outer Membranes.

Angiogenesis is one of the growth mechanisms of chronic subdural hematoma (CSDH). Pericytes have been implicated in the capillary sprouting during angiogenesis and are involved in brain ischemia and diabetic retinopathy. This study examined the pericyte expressions in CSDH outer membranes obtained during trepanation surgery. Eight samples of CSDH outer membranes and 35 samples of CSDH fluid were included. NG2, N-cadherin, VE-cadherin, Tie-2, endothelial nitric oxide synthase (eNOS), platelet-derived growth factor (PDGF) receptor-ß (PDGFR-ß), a well-known marker of pericytes, phosphorylated PDGFR-ß at Tyr751, and ß-actin expressions, were examined using western blot analysis. PDGFR-ß, N-cadherin, and Tie-2 expression levels were also examined using immunohistochemistry. The concentrations of PDGF-BB in CSDH fluid samples were measured using enzyme-linked immunosorbent assay kits. NG2, N-cadherin, VE-cadherin, Tie-2, eNOS, PDGFR-ß, and eNOS expressions in CSDH outer membranes were confirmed in all cases. Furthermore, phosphorylated PDGFR-ß at Tyr751 was also detected. In addition, PDGFR-ß, N-cadherin, and Tie-2 expressions were localized to the endothelial cells of the vessels within CSDH outer membranes by immunohistochemistry. The concentration of PDGF-BB in CSDH fluids was significantly higher than that in cerebrospinal fluid. These findings indicate that PDGF activates pericytes in the microvessels of CSDH outer membranes and suggest that pericytes are crucial in CSDH angiogenesis through the PDGF/PDGFR-ß signaling pathway.

Angiogenesis in the Outer Membrane of Chronic Subdural Hematomas through Thrombin-Cleaved Osteopontin and the Integrin α9 and Integrin ß1 Signaling Pathways.

BACKGROUND: A chronic subdural hematoma (CSDH) is considered to be an inflammatory and angiogenic disease. The CSDH outer membrane, which contains inflammatory cells, plays an important role in CSDH development. Osteopontin (OPN) is an extracellular matrix protein that is cleaved by thrombin, generating the N-terminal half of OPN, which is prominently involved in integrin signal transduction. We explored the expression of the N-terminal half of OPN in CSDH fluid and the expression of integrins α9 and ß1 and the downstream components of the angiogenic signaling pathways in the outer membrane of CSDHs. METHODS: Twenty samples of CSDH fluid and eight samples of CSDH outer membrane were collected from patients suffering from CSDHs. The concentrations of the N-terminal half of OPN in CSDH fluid samples were measured using ELISA kits. The expression levels of integrins α9 and ß1, vinculin, talin-1, focal adhesion kinase (FAK), paxillin, α-actin, Src and ß-actin were examined by Western blot analysis. The expression levels of integrins α9 and ß1, FAK and paxillin were also examined by immunohistochemistry. We investigated whether CSDH fluid could activate FAK in cultured endothelial cells in vitro. RESULTS: The concentration of the N-terminal half of OPN in CSDH fluid was significantly higher than that in the serum. Western blot analysis confirmed the presence of these molecules. In addition, integrins α9 and ß1, FAK and paxillin were localized in the endothelial cells of vessels within the CSDH outer membrane. FAK was significantly phosphorylated immediately after treatment with CSDH fluid. CONCLUSION: Our data suggest that the N-terminal half of OPN in CSDH fluid promotes neovascularization in endothelial cells through integrins α9 and ß1. The N-terminal half of OPN, which is part of the extracellular matrix, plays a critical role in the promotion of CSDHs.

Mechanism for control of ball spin rate by the upper limb in baseball pitching based on singular value decomposition.

This study aims to examine the mechanism by which the ball spin rate during fastball pitching is controlled by synergistic joint torque. The participants were seven baseball players. The kinematics and kinetics of the fingers, wrist, elbow, and shoulder were calculated using the inverse dynamics method. The synergistic relationship between the joint torques was calculated using singular value decomposition. The similarity of the spatial pattern of the joint torque in each participant was evaluated using cosine similarity. The results indicated that there were three types of synergistic torque control: (1) two pitchers had a synergistic torque control that was primarily based on shoulder internal rotation torque, (2) two pitchers had a synergistic torque control that was primarily based on elbow extension torque, and (3) three pitchers had a synergistic torque control that was primarily based on shoulder horizontal adduction torque. In particular, pitchers with a high spin rate relative to the ball velocity (SPV) had a torque control of the shoulder internal rotation type. In contrast, pitchers with a low SPV had a torque control of the shoulder horizontal adduction type. It is considered that pitchers with a high SPV execute shoulder internal rotation torque, which has the same direction as that of ball spin, based on hierarchical control to increase the ball spin rate. These results suggest that pitchers with high and low SPVs exhibit different motor patterns. Pitchers and coach need to focus on the shoulder joint as well as the fingers when they throw fastball.

Preschool children aged 4 to 5 years show discomfort with trypophobic images.

The fear or disgust of clustered patterns, such as honeycomb or lotus seed pods, is known as trypophobia. A previous developmental study reported that 4-year-old children prefer neutral images over clustered images. However, whether those results indicated higher rating scores for trypophobic images has been controversial. In this study, we examined discomfort with trypophobic images in adults and children aged 4-9 years using an identical experimental procedure. A modified rating scale applicable for children was used that was based on the established Trypophobia Scale for adults. The participants were required to rate five trypophobic and five neutral images on four rating items (disgusting, fear, feel itchiness, and like) on a 4-point scale ranging from 1 (not at all) to 4 (very much). The participants in all age groups indicated higher rate scores for trypophobic images than for neutral images in terms of 'disgust', 'fear', and 'feeling itchiness', whereas they indicated higher scores for neutral images than for trypophobic images in terms of 'like'. These results suggest that children aged 4-5 years have responses comparable to the responses of adults with respect to trypophobic and neutral images; thus, trypophobia appears to emerge at least by the age of 4-5 years.

Memantine ameliorates the impairment of social behaviors induced by a single social defeat stress as juveniles.

Clinically, juveniles are more sensitive to stress than adults, and exposure to stress as juveniles prolongs psychiatric symptoms and causes treatment resistance. However, the efficacy of antidepressants for juveniles with psychiatric disorders is unknown. In the present study, we investigated whether the expression or development of impaired social behavior was attenuated by memantine, a non-competitive NMDA receptor antagonist. In addition, we clarified the molecular mechanisms related to intracellular signal transduction through NMDA receptors and the ameliorating effect of memantine in mice with impaired social behavior. Acute administration of memantine before the social interaction test, but not before exposure to social defeat stress, attenuated social behavioral impairment. A single social defeat stress increased the phosphorylation of NMDA receptor subunit GluN2A and extracellular-signal-related kinase 1/2 (ERK1/2). Memantine inhibited the increase of phosphorylated GluN2A and ERK1/2 resulting from social interaction behavior. In both GluN2A deficient and pharmacological blockaded mice, social behavioral impairment was not observed in the social interaction test through regulation of ERK1/2 phosphorylation. These findings suggest that memantine ameliorates social behavioral impairment in mice exposed to a single social defeat stress as juveniles by regulating the NMDA receptor and subsequent ERK1/2 signaling activation. Memantine may constitute a novel therapeutic drug for stress-related psychiatric disorders in juveniles with adverse juvenile experiences.

Health care worker burnout after the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Japan.

OBJECTIVES: To determine the prevalence of burnout according to job category after the first wave of COVID-19 in Japan and to explore its association with certain factors. METHODS: An online cross-sectional survey of health care workers (HCWs) from June 15 to July 6, 2020, was conducted at a tertiary hospital in Tokyo, Japan. Demographic characteristics, results of the Japanese version of the Maslach Burnout Inventory-General Survey, types of anxiety and stress, changes in life and work after the peak of the pandemic, and types of support aimed at reducing the physical or mental burden, were determined. RESULTS: Of 672 HCWs, 149 (22.6%) met the overall burnout criteria. Burnout was more prevalent in women (OR, 3.11; 95% CI, 1.45-6.67, P = .003), anxiety due to unfamiliarity with personal protective equipment (PPE) (OR, 1.98; 95% CI, 1.20-3.27, P = .007), and decreased sleep duration (OR, 1.96; 95% CI, 1.20-3.20, P = .008). Conversely, participants who felt that the delivery of COVID-19-related information (OR, .608; 95% CI, .371-.996, P = .048) and PPE education opportunities (OR, .484; 95% CI, .236-.993, P = .048) and messages of encouragement at the workplace (OR, .584; 95% CI, .352-.969; p = .037) was helpful experienced less burnout. CONCLUSIONS: There is a need to focus on the above factors to maintain the mental health of HCWs. The delivery of COVID-19-related information and educational interventions for PPE and messages of encouragement at the workplace may be needed to reduce the mental burden.

Sequential expression of neutrophil chemoattractants in cerebrospinal fluid after subarachnoid hemorrhage.

OBJECTIVE: Neutrophils induce inflammation through the exocytosis of cytotoxic granule proteins. Recently, neutrophils have been reported to be an independent parameter associated with unfavorable outcomes after subarachnoid hemorrhage (SAH). However, the mechanism by which neutrophils accumulate within the CSF after SAH remains undetermined. METHODS: Concentrations of C5a, epithelial neutrophil activating peptide 78 (ENA-78), interleukin-8 (IL-8), growth-regulated oncogene-α (GRO-α), neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase (MPO) were measured serially until day 14 in the CSF of 10 patients with SAH. CSF samples obtained from patients suffering from unruptured aneurysms were used as controls. RESULTS: The concentrations of C5a and ENA-78 were significantly increased on day 1, while those of IL-8 and GRO-α significantly increased during days 3-7 compared with those of the control samples. The levels of NGAL and MPO, components of neutrophil granules, significantly increased during days 1-5 and days 1-3, respectively, after SAH and gradually decreased thereafter. The correlations between ENA-78 and C5a on day 1, IL-8 and GRO-α on days 3-7, and NGAL and MPO on days 1-3 were significant. CONCLUSION: These neutrophil chemoattractants might be serially involved in the infiltration of neutrophils into the CSF after SAH. Migrated neutrophils play an important role in inflammatory reactions in the central nervous system after SAH.

Cardioprotection via Metabolism for Rat Heart Preservation Using the High-Pressure Gaseous Mixture of Carbon Monoxide and Oxygen.

The high-pressure gas (HPG) method with carbon monoxide (CO) and oxygen (O2) mixture maintains the preserved rat heart function. The metabolites of rat hearts preserved using the HPG method (HPG group) and cold storage (CS) method (CS group) by immersion in a stock solution for 24 h were assessed to confirm CO and O2 effects. Lactic acid was significantly lower and citric acid was significantly higher in the HPG group than in the CS group. Moreover, adenosine triphosphate (ATP) levels as well as some pentose phosphate pathway (PPP) metabolites and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were significantly higher in the HPG group than in the CS group. Additionally, reduced glutathione (GSH), which protects cells from oxidative stress, was also significantly higher in the HPG group than in the CS group. These results indicated that each gas, CO and O2, induced the shift from anaerobic to aerobic metabolism, maintaining the energy of ischemic preserved organs, shifting the glucose utilization from glycolysis toward PPP, and reducing oxidative stress. Both CO and O2 in the HPG method have important effects on the ATP supply and decrease oxidative stress for preventing ischemic injury. The HPG method may be useful for clinical application.

Arabidopsis GEX1 Is a Nuclear Membrane Protein of Gametes Required for Nuclear Fusion During Reproduction.

During the life cycle of flowering plants, nuclear fusion, or karyogamy, occurs three times: once during female gametogenesis, when the two polar nuclei fuse in the central cell, and twice during double fertilization. In Arabidopsis thaliana, nuclear fusion events during sexual reproduction proceed without the breakdown of the nuclear envelope, indicating that nuclear membrane fusion is essential for the completion of this process. Arabidopsis gamete expressed 1 (GEX1) is a membrane protein that is conserved among plant species. GEX1 shares homology with the yeast karyogamy protein Kar5, which is primarily expressed in the nuclear membrane. The GEX1 family represents a putative karyogamy factor. Herein, we show that GEX1 is required for the nuclear fusion events in Arabidopsis reproduction. GEX1-deficient mature female gametophytes were found to contain two unfused polar nuclei in close proximity within the central cell. Electron microscopy showed that the outer membrane of the polar nuclei was connected via the endoplasmic reticulum, whereas the inner membrane remained unfused. These results indicate that GEX1 is involved in polar nuclear membrane fusion following the fusion of the outer nuclear membrane. Furthermore, sperm nuclear fusion events were defective in the fertilized egg and central cell following plasmogamy in the fertilization of gex1-1 female gametophytes by gex1-1 pollen. An analysis of GEX1 localization in the female gametophyte using a transgenic line expressing GFP-tagged GEX1 driven by the GEX1 promoter showed that GEX1 is a nuclear membrane protein in the egg and central cell. Time-lapse live-cell imaging showed that in developing female gametophytes, the nuclear GFP-GEX1 signal was first detectable in the central cell shortly before the polar nuclei came in close contact, and then in the egg cell. Thus, we suggest that the GEX1-family proteins are nuclear membrane proteins involved in karyogamy in the reproduction of eukaryotes including flowering plants.

GC × GC-MS-Based Volatile Profiling of Male Domestic Cat Urine and the Olfactory Abilities of Cats to Discriminate Temporal Changes and Individual Differences in Urine.

Domestic cats (Felis silvestris catus) are solitary and territorial, and mark their territories by spraying urine, which emits a strong odor produced by volatile organic compounds (VOCs). Previous studies have focused on identifications of specific VOCs, such as 3-mercpto-3-methyl-1-butanol, a cat-specific VOCs. However, little is known about how whole volatile profiles of their sprayed urine change over time or how the profiles differ among individuals. This study investigated temporal changes and individual differences of volatile profiles produced by whole VOCs in cat urine, and the ability of cats to discriminate between these scent differences. Volatile profiles of fresh and aged cat urine were analyzed by using two-dimensional gas chromatography-mass spectrometry with a VOC preconcentrator comprehensively. Volatile profiles produced by hundreds of VOCs emitted from cat urine were influenced primarily by the age of the urine, and secondarily by individuality. During habituation-dishabituation tests, subjects discriminated between fresh and 24 h-old samples of same individuals, and between odor of different individuals from 0 h-, 3 h-old, and 24 h-old samples. These results strongly suggest that cats can recognize conspecific individuals via olfaction. Since most VOCs varied among individuals but were not stable over time, their urine may contain unknown VOCs that vary among individuals, are stable over time, and act as individual recognition signals.

In vivo and in vitro evaluation of novel µ-opioid receptor agonist compounds.

Opioids are the most effective and widely used drugs for pain treatment. Morphine is an archetypal opioid and is an opioid receptor agonist. Unfortunately, the clinical usefulness of morphine is limited by adverse effects such as analgesic tolerance and addiction. Therefore, it is important to study the development of novel opioid agonists as part of pain control. The analgesic effects of opioids are mediated by three opioid receptors, namely opioid µ-, δ-, and κ-receptors. They belong to the G protein-coupled receptor superfamily and are coupled to Gi proteins. In the present study, we developed a ligand screening system to identify novel opioid µ-receptor agonists that measures [(35)S]GTPγS binding to cell membrane fractions prepared from the fat body of transgenic silkworms expressing µ-receptor-Gi1α fusion protein. We screened the RIKEN Natural Products Depository (NPDepo) chemical library, which contains 5848 compounds, and analogs of hit compounds. We successfully identified a novel, structurally unique compound, that we named GUM1, with agonist activity for the opioid µ-receptor (EC50 of 1.2 µM). The Plantar Test (Hargreaves' Method) demonstrated that subcutaneous injection of 3mg/kg of GUM1 into wild-type rats significantly extended latency time. This extension was also observed in a rat model of morphine tolerance and was inhibited by pre-treatment of naloxone. The unique molecular skeleton of GUM1 makes it an attractive molecule for further ligand-opioid receptor binding studies.

Direct synthesis of N-H carbazoles via iridium(III)-catalyzed intramolecular C-H amination.

The iridium-catalyzed dehydrogenative cyclization of 2-aminobiphenyls proceeds smoothly in the presence of a copper cocatalyst under air as a terminal oxidant through intramolecular direct C-H amination to produce N-H carbazoles. A similar iridium/copper system can also catalyze the unprecedented dimerization reaction of 2-aminobiphenyl involving 2-fold C-H/N-H couplings.

Dorsal root ganglion pulsed radiofrequency for the management of intractable vertebral metastatic pain: a case series.

OBJECTIVE: Metastatic bone pain is characteristic of cancer pain and is a form of refractory cancer pain, as the pain includes not only nociceptive but also neuropathic pain. Although some drugs are effective in the management of painful bone metastases, pain while moving is one of the most refractory forms of pain. Although pulsed radiofrequency (RF) dramatically reduces neuropathic pain, chronic pain, and vertebral metastatic pain, the number of cases reported in these studies was very small (five or less). DESIGN: Case report. SETTING: Single pain center. PATIENTS: Fifteen patients suffering from intractable vertebral metastatic pain. INTERVENTIONS: Dorsal root ganglion (DRG) pulsed RF. OUTCOME MEASURES: A numerical rating scale (NRS) of pain at rest and while moving. RESULTS: Almost all patients experienced sound pain relief after the pulsed RF treatment. There were no severe side effects reported. CONCLUSION: DRG pulsed RF procedure provided sound pain relief for patients with intractable vertebral metastatic pain. Metastatic bone pain is characteristic of cancer pain and is a form of refractory cancer pain, as the pain includes not only nociceptive but also neuropathic pain. Although some drugs are effective in the management of painful bone metastases, pain while moving is one of the most refractory forms of pain. DRG pulsed RF procedure provided sound pain relief for patients with intractable vertebral metastatic pain.

Investigation of the teratogenic potential of VLA-4 antagonist derivatives in rats.

Very late antigen-4 (VLA-4), which is concerned with cell-cell adhesion, plays important roles in development of the heart, and some VLA-4 antagonists cause cardiac anomalies. In this study, we evaluated the teratogenic potential of VLA-4 antagonist derivatives as screening, and investigated the conditions that induce cardiac anomalies. Seventeen compounds were orally administered to pregnant rats throughout the organogenesis period, and fetal examinations were performed. In addition, drug concentrations in the embryos were assayed. As a result, the incidence of ventricular septal defect (VSD) ranged from 0 to 100% depending on the compound. Plasma drug concentrations in the dams were related to increased incidence of VSD; however, these incidences were not increased when the concentration of the compound in the embryos at 24h after dosing was low. It is considered that continuous pharmacological activity in the embryo for more than 24h might disrupt closure of the ventricular septum.

Ruthenium-catalyzed regioselective C-H alkenylation directed by a free amino group.

The ruthenium-catalyzed alkenylation reactions of 2-aminobiphenyls and cumylamine proceed smoothly to produce the corresponding regioselectively alkenylated products. These reactions involve a C-H bond cleavage directed by their free amino groups.

Neurolytic celiac plexus block reduces occurrence and duration of terminal delirium in patients with pancreatic cancer.

PURPOSE: WHO's three step ladder sometimes cannot provide adequate pain relief for pancreatic cancer. Some patients develop terminal delirium (TD). The aim of this study was to test if the addition of a celiac plexus block (CPB) to pharmacotherapy could reduce the incidence of TD. METHODS: Pancreatic cancer patients under the care of our palliative-care team were investigated with regard to the duration and occurrence of TD, pain scores [numerical rating score (NRS)] and daily opioid dose. Between August 2007 to September 2008, 17 patients received only pharmacotherapy (control group). Then, we modified our guideline for analgesia, performing CPB 7 days after the first intervention of our team. Between October 2008 to September 2009, 19 patients received CPB. RESULTS: The opioid doses in CPB group were significantly lower both at 10 days after the first intervention (3 days after CPB) (27 ± 11 vs. 66 ± 82 mg; p = 0.029) and 2 days before death (37 ± 25 vs. 124 ± 117 mg; p = 0.009). NRS in the CPB group were significantly lower both at 10 days after the first intervention (0 [0-2] vs. 3 [2-5], p < 0.0001) and 2 days before death (1 [0-2] vs. 3 [1-4.5], p = 0.018). The occurrence and duration of TD in CPB group were both reduced (42 vs. 94 %, p = 0.019; and 1.8 ± 2.9 vs. 10.4 ± 7.5 days, p = 0.0003). CONCLUSION: The duration and occurrence of TD and the pain severity were significantly less in pancreatic cancer patients who underwent neurolytic CPB.

Pulsed radiofrequency treatment within brachial plexus for the management of intractable neoplastic plexopathic pain.

We report on the use of pulsed radiofrequency (RF) within the plexus for the management of intractable pain in three patients with metastatic or invasive plexopathy. The patients were a 38-year-old woman with a history of breast cancer 6 years earlier whose computed tomography (CT) scans revealed a mass lesion at the infraclavicular part of the right brachial plexus, a 68-year-old man diagnosed with advanced lung cancer whose CT scans revealed a bone metastasis in the right humerus invading the axillary region of the right brachial plexus, and a 67-year-old woman diagnosed with advanced lung cancer whose CT scans revealed a bone metastasis in the left humerus invading the axillary region of the left brachial plexus. Ultrasound-guided pulsed RF was performed within the interscalene brachial plexus. During the follow-up period, their intractable pain was moderately controlled.

Low-dose gabapentin as useful adjuvant to opioids for neuropathic cancer pain when combined with low-dose imipramine.

PURPOSE: Painful neuropathic conditions of cancer pain often show little response to nonopioid and opioid analgesics but may be eased by antidepressants and anticonvulsants. Although gabapentin is effective in the treatment of neuropathic pain in patients with cancer, some patients experience intolerable side effects sufficient to warrant discontinuation. The aim of this study was to see whether low-dose gabapentin is effective in treating cancer-related neuropathic pain when combined with low-dose imipramine. METHODS: Fifty-two cancer patients diagnosed as having neuropathic pain were allocated into four groups: G400-I group took gabapentin 200 mg and imipramine 10 mg every 12 h orally; G400 group took gabapentin 200 mg every 12 h orally; G800 group took gabapentin 400 mg every 12 h orally; I group took imipramine 10 mg every 12 h orally. RESULTS: Low-dose gabapentin-imipramine significantly decreased the total pain score and daily paroxysmal pain episodes. Several patients developed mild adverse symptoms in the four groups, and three patients discontinued treatment due to severe adverse events in the G800 group. CONCLUSION: Low-dose gabapentin-antidepressant combination with opioids was effective in managing neuropathic cancer pain without severe adverse effects.

Diet-induced obesity disrupts ductal development in the mammary glands of nonpregnant mice.

Mammary glands develop postnatally in response to the hypothalamic-pituitary-gonadal axis. Obesity-induced changes in the local environment, however, retard mammary gland development during late pregnancy and lactation. To clarify the effects of obesity on fundamental duct development, we compared the mammary glands of nulliparous nonpregnant obese mice fed a high-fat diet with those of lean mice fed a normal diet. Obese mice had enlarged mammary glands, reflecting fat pad size, whereas the ducts in obese mice showed a less dense distribution with less frequent branching. Additionally, the ducts were surrounded by thick collagen layers, and were incompletely lined with myoepithelium. Because leptin receptors were localized in the epithelium region and leptin that was highly expressed in the obese glands suppressed mammary epithelial cell proliferation in vitro, the present results suggest that obesity disrupts mammary ductal development, possibly by remodeling the mammary microenvironment and promoting the expression of such paracrine factors as leptin.