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Tibia fracture (BF) enhances stroke injury and post-stroke memory dysfunction in mouse. Reduction of neuroinflammation by activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced acute neuronal injury and sensorimotor dysfunction in mice with BF 1-day after stroke. We hypothesize that reduction of neuroinflammation by activation of α-7 nAchR improves long-term memory function of mice with BF 6-h before stroke. The mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and methyllycaconitine (antagonist) treatment groups. The sensorimotor function was tested by adhesive removal and corner tests at 3 days, the memory function was tested by Y-maze test weekly for 8 weeks and novel objective recognition test at 8 weeks post-injuries. We found PHA-568487 treatment reduced, methyllycaconitine increased the number of CD68+ cells in the peri-infarct and hippocampal regions, neuronal injury in the infarct region, sensorimotor and long-term memory dysfunctions. PHA-568487 treatment also reduced, while methyllycaconitine treatment increased atrophy of hippocampal granule cell layer and white matter damage in the striatum. In addition, PHA-568487 treatment increased neuron proliferation in granule cell layer. Our data indicated that reduction of neuroinflammation through activation of α-7 nAchR decreased neuronal damage, sensorimotor and long-term memory dysfunction of mice with BF shortly before stroke.

Introduction: Tibia fracture (BF) enhances stroke injury and when occurring 6 hrs before stroke (BF6+Stroke) causes long-lasting cognitive dysfunction in mouse. Activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced neuroinflammation, neuronal injury and sensorimotor dysfunction in mice with BF one day after stroke (Stroke+1BF). Hypothesis: Activation of α-7 nAchR improves long-term cognitive function of BF6+Stroke mice. Methods: BF6+Stroke mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and MLA (α-7 nAchR antagonist) treatment groups. The sensorimotor function were tested by adhesive removal and corner tests at 3 days, the cognitive function was tested by Y-maze weekly for 8 weeks and Novel Objective Recognition (NOR) at 8 weeks post-injuries. The neuronal damage, neuroinflammaiton, neurogenesis were analyzed 3 and/or 8 weeks post-injuries. Results: Similar to Stroke+1BF mice, PHA reduced and MLA enhanced neuronal injury, neuroinflammation, and sensorimotor dysfunction of BF6+Stroke mice. Further, PHA reduced and MLA enhanced their long-term cognitive dysfunction. In Y maze test, all mice made fewer alternations 1-week post-surgeries than baseline; PHA group recovered to baseline at week 5 post-surgeries; saline and MLA groups continuously made fewer alternations throughout the 8-weeks. In NOR test, PHA group spent more time, MLA group spent less time than saline group on novel objects. Injection of BrdU in the 2 nd week post-surgeries labeled more neurons in the contralateral than in the ipsilateral dentate gyrus in all groups; PHA group had the most, MLA group had the least BrdU + neurons. Injection BrdU in the 7th week post-surgeries did not labeled any neuron. Conclusion: Activation of α-7 nAchR decreased neuronal damage and neuroinflammation, increased neurogenesis at the dentate gyrus of BF6+Stroke mice; and improved their sensorimotor and long-term cognitive function.

Background and Purpose: Tibia fracture (BF) causes long-lasting memory dysfunction in stroke mice, which is associated with microglia accumulation in the hippocampus ipsilateral to the stroke injury. The underlying mechanism is unclear. Hypothesis: BF exacerbates blood brain barrier (BBB) breakdown and fibrin extravasation in the hippocampus enhancing white matter damage of stroke mice. Method: C57 mice (8-weeks) were randomly assigned to BF, stroke (pMCAO), BF+stroke (BF 6h before stroke) and sham groups. The integrity of BBB, fibrin deposition and CD68 + cells infiltration in the hippocampus were analyzed 3 days and the white matter injury in the basal ganglia was analyzed 8 weeks after the surgeries. Results: Compared to BF group, stroke and BF+stroke groups had lower level of claudin-5, fewer pericytes, more extravascular fibrin and CD68 + cells in the ipsilateral side of stroke 3 days after the injuries. BF+stroke group had the lowest level of claudin-5, fewest pericytes, highest extravascular fibrin and most CD68 + cells among the three groups. BF+stroke group also had a lower level of claudin-5 and fewer CD13 + pericytes in the contralateral side than the other two groups. Compared to sham group, the white matter bundle areas in the basal ganglia were reduced in stroke and BF+stroke groups in both contralateral and ipsilateral sides 8 weeks after the injuries. Stroke and BF+stroke groups also has smaller white matter bundle areas in the ipsilateral than contralateral side, and the white matter bundle areas in the contralateral side of BF+stroke group were also smaller than stroke group. Conclusion: BF shortly before stroke causes long-lasting memory dysfunction in mice through enhancing BBB breakdown and fibrin extravasation in the hippocampus, which exacerbates neuroinflammation and white matter damage.

Background: Tibia fracture (BF) before stroke shortly causes long-term post-stroke memory dysfunction in mice. The mechanism is unclear. We hypothesize that BF enhances neuroinflammation and blood brain barrier (BBB) breakdown in the hippocampus and white matter (WM) damage. Methods: Mice were assigned to groups: BF, stroke, BF+stroke (BF 6 h before stroke) and sham. BBB integrity was analyzed 3 days after the surgeries and WM injury was analyzed 3 days and 8 weeks after the surgeries. Results: Stroke and BF+stroke groups had more activated microglia/macrophages and lower levels of claudin-5 in the ipsilateral hippocampi than the BF group. BF+stroke group had the highest number microglia/macrophages and the lowest level of claudin-5 among all groups and had fewer pericytes than BF group. Stroke and BF+stroke groups had smaller WM areas in the ipsilateral basal ganglia than the sham group 8 weeks after the injuries. The BF+stroke group also had smaller WM areas in the ipsilateral than sham and BF groups 3 days after the injuries and in the contralateral basal ganglia than stroke and BF groups 8 weeks after the injuries. Conclusions: BF exacerbates neuroinflammation and BBB leakage in the hippocampus and WM damage in basal ganglia, which could contribute to the long-lasting memory dysfunction in BF+stroke mice.

Importance The use of a radiotherapy (RT) boost to the tumor bed after whole-breast RT (WBRT) for ductal carcinoma in situ (DCIS) is largely extrapolated from invasive cancer data, but robust evidence specific to DCIS is lacking. Objective To compare ipsilateral breast tumor recurrence (IBTR) in women with DCIS treated with vs without the RT boost after breast-conserving surgery and WBRT. Design, Setting, and Participants This retrospective analysis pooled deidentified patient-level data from 10 academic institutions in the United States, Canada, and France from January 1, 1980, through December 31, 2010. All patients had newly diagnosed pure DCIS (no microinvasion), underwent breast-conserving surgery, and received WBRT with or without the boost with a minimum of 5 years of follow-up required for inclusion in the analysis. Given the limited events after WBRT, an a priori power analysis was conducted to estimate the DCIS sample size needed to detect the anticipated benefit of the boost. Data were uniformly recoded at the host institution and underwent primary and secondary reviews before analysis. Sample size calculations (ratio of patients who received the boost dose to those who did not, 2:1; α = .05; power = 80%) estimated that 2982 cases were needed to detect a difference of at least 3%. The final analysis included 4131 patients (2661 in the boost group and 1470 in the no-boost group) with a median follow-up of 9 years and media boost dose of 14 Gy. Data were collected from July 2011 through February 2014 and analyzed from March 2014 through August 2015. Interventions Radiotherapy boost vs no boost. Main Outcomes and Measures Ipsilateral breast tumor recurrence. Results The analysis included 4131 patients (median [SD] age, 56.1 [10.9] years; range, 24-88 years). Patients with positive margins, unknown estrogen receptor status, and comedo necrosis were more likely to have received an RT boost. For the entire cohort, the boost was significantly associated with lower IBTR (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) and with IBTR-free survival (boost vs no-boost groups) of 97.1% (95% CI, 0.96-0.98) vs 96.3% (95% CI, 0.95-0.97) at 5 years, 94.1% (95% CI, 0.93-0.95) vs 92.5% (95% CI, 0.91-0.94) at 10 years, and 91.6% (95% CI, 0.90-0.93) vs 88.0% (95% CI, 0.85-0.91) at 15 years. On multivariable analysis accounting for confounding factors, the boost remained significantly associated with reduced IBTR (HR compared with no boost, 0.68; 95% CI, 0.50-0.91; P = .01) independent of age and tamoxifen citrate use. Conclusions and Relevance This patient-level analysis suggests that the RT boost confers a statistically significant benefit in decreasing IBTR across all DCIS age groups, similar to that seen in patients with invasive breast cancer. These findings suggest that a DCIS RT boost to the tumor bed could be considered to provide an added incremental benefit in decreasing IBTR after a shared discussion between the patient and her radiation oncologist.

Background: Hypophosphatemia (HP) is frequent following liver resection, and thought to represent use of phosphate during liver regeneration. We sought to evaluate the association of post-hepatectomy HP with liver insufficiency and recovery. Methods: Liver resections were retrospectively reviewed from 2009 to 2012 at a single institution. We explored the relationship between HP (defined as serum phosphate ≤0.65 mmol/L), occurrence of initial liver insufficiency (ILI) [bilirubin >50 μmol/L, international normalized ratio (INR) >1.7 within 72 hours of surgery] and in-hospital recovery of ILI. Secondary outcomes included 30-day post-operative major morbidity (Clavien grade 3 and 4 complications), mortality, and re-admission. Results: Among 402 patients, 223 (55.5%) experienced HP and 64 (15.9%) met our definition of ILI, of which 53 (82.8%) recovered. Length of stay, 30-day post-operative major morbidity, mortality, and re-admission were similar between patients with and without HP. Among patients with ILI, 44 (68.8%) experienced HP. Following ILI, patients with HP recovered more often than those with NP (90.9% vs. 65.0%; P=0.03). Conclusions: In patients who experience post-hepatectomy ILI, HP is associated with improved recovery, potentially indicating more efficient liver regeneration. Further studies should explore the usefulness of post-hepatectomy HP as an early prognostic factor of recovery from ILI.

Gli3 is a major regulator of Hedgehog signaling during limb development. In the anterior mesenchyme, GLI3 is proteolytically processed into GLI3R, a truncated repressor form that inhibits Hedgehog signaling. Although numerous studies have identified mechanisms that regulate Gli3 function in vitro, it is not completely understood how Gli3 function is regulated in vivo. In this study, we show a novel mechanism of regulation of GLI3R activities in limb buds by Gata6, a member of the GATA transcription factor family. We show that conditional inactivation of Gata6 prior to limb outgrowth by the Tcre deleter causes preaxial polydactyly, the formation of an anterior extra digit, in hindlimbs. A recent study suggested that Gata6 represses Shh transcription in hindlimb buds. However, we found that ectopic Hedgehog signaling precedes ectopic Shh expression. In conjunction, we observed Gata6 and Gli3 genetically interact, and compound heterozygous mutants develop preaxial polydactyly without ectopic Shh expression, indicating an additional prior mechanism to prevent polydactyly. These results support the idea that Gata6 possesses dual roles during limb development: enhancement of Gli3 repressor function to repress Hedgehog signaling in the anterior limb bud, and negative regulation of Shh expression. Our in vitro and in vivo studies identified that GATA6 physically interacts with GLI3R to facilitate nuclear localization of GLI3R and repressor activities of GLI3R. Both the genetic and biochemical data elucidates a novel mechanism by Gata6 to regulate GLI3R activities in the anterior limb progenitor cells to prevent polydactyly and attain proper development of the mammalian autopod., Author Summary Gli3 is a major regulator of Hedgehog signaling in the limb, where Gli3 counteracts Sonic hedgehog (Shh) for patterning and proliferative expansion of limb progenitor cells. In the anterior limb mesenchyme, GLI3 is proteolytically processed into GLI3R, a truncated repressor form that inhibits Hedgehog signaling. In this study, we show a novel mechanism of regulation of GLI3R activities in limb buds by Gata6, a member of GATA transcription factor family. Conditional inactivation of Gata6 in mice caused formation of an extra digit in the anterior hindlimbs, a common congenital limb malformation. This phenotype was associated with ectopic Hedgehog signaling activation, and later ectopic Shh expression, in the anterior of hindlimb buds. We show that Gata6; Gli3 compound heterozygous mutants developed anterior extradigit without ectopic Shh expression, indicating there to be an additional and prior mechanism before ectopic Shh activation that induces extradigit formation. We identified that GATA6 physically interacts with GLI3R and that the interaction facilitates nuclear localization of GLI3R and repressor activities of GLI3R. Therefore, our study identified a novel mechanism by Gata6 to regulate GLI3R activities in the anterior limb mesenchyme to prevent extra digit formation and proper development of the mammalian autopod.

Axillary node dissection (ALND) is the standard of care for patients who have a positive sentinel lymph node (SLN) on sentinel lymph node biopsy (SLNB). We sought to identify a low-risk patient population with positive SLN that may not need cALND. We analyzed SLNB for breast cancer at our institutions between 1999 and 2007. We identified 130 patients who had a positive SLN but did not undergo completion ALND. We evaluated clinical data, adjuvant treatment patterns and intermediate locoregional and distant events. The median patient age was 50; 19% had N0(i+) disease, 53% had micrometastatic (N1mi) disease, and 28% had macrometastasis. Eighty-eight percent of patients underwent radiation therapy; 66 patients (51%) had documented nodal radiation (of these 50 were treated with three fields and 14 with high tangents. Local recurrence in the breast occurred in two patients (2%) and nine patients (7%) developed distant metastases; there were no axillary/nodal recurrences. In this highly selected group of patients who had a positive SLNB but did not undergo cALND, we observed no axillary recurrences.

Purpose: To evaluate the safety and feasibility of concurrent radiation therapy and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide (AC). Methods and Materials: After definitive breast surgery and AC chemotherapy, 40 patients with operable Stage II or III breast cancer received protocol-based treatment with concurrent paclitaxel and radiation therapy. Paclitaxel was evaluated on 2 schedules, with treatment given either weekly × 12 weeks (60 mg/m 2 ), or every 3 weeks × 4 cycles (135–175 mg/m 2 ). Radiation fields and schedules were determined by the patient's surgery and pathology. The tolerability of concurrent therapy was evaluated in cohorts of 8 patients as a phase I study. Results: Weekly paclitaxel treatment at 60 mg/m 2 per week with concurrent radiation led to dose-limiting toxicity in 4 of 16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and CT-based radiotherapy simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135–175 mg/m 2 . However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2 of 24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule. Conclusions: Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible after adjuvant AC chemotherapy for early-stage breast cancer. Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury.

This paper reviews the epidemiology, pathophysiology and clinical significance of isolated systolic hypertension (ISH) in the elderly. Aging is associated with structural and functional changes in the arterial tree. Intimal thickening, migration of small muscle cells to the intima, medial fibrosis, and elastic fiber degeneration result in increased arterial stiffness and ISH. The augmented systemic vascular resistance in the elderly is mediated by increased arterial stiffness. Aging is correlated with overactivity of the sympathetic nervous system, reduced neuronal plasma norepinephrine uptake, and baroreceptor dysfunction. These functional changes all contribute to the development of ISH in elderly persons. Prospective and epidemiological studies have demonstrated that ISH is associated with coronary and cerebrovascular morbidity and mortality. There is good evidence indicating that lifestyle modifications such as weight reduction, increased physical activity, moderation of dietary sodium, and decreased alcohol intake, in combination with pharmacological therapy can effectively reduce blood pressure in elderly individuals with ISH. Primary health care providers can make significant contributions to the care of elderly persons with ISH. These contributions involve educating elderly people to control hypertension through lifestyle modification, monitoring the efficacy of antihypertensive therapy, and preventing complications associated with non-compliance with therapeutic regimens.

Observational and interventional studies that evaluate the impact of hormone replacement therapy (HRT) on cardiovascular changes have produced inconsistent and inconclusive results. The present study sought to elucidate the influence of HRT on aortic distensibility, left ventricular mass (LVM) and 24-h blood pressure (BP) profile in 38 menopausal women who were either HRT users or non-users. The two groups were similar for age, ambulatory BP, aortic distensibility, cardiac mass, lipid profile and body mass index but differed in clinic diastolic BP (DBP). HRT non-dippers had significantly lower clinic and daytime DBP and a smaller nocturnal BP reduction than dippers. Daytime DBP was significantly and inversely related to duration of HRT use. The present study demonstrates that hormonal therapy after menopause lowers DBP, but shows no significant influence on aortic distensibility, cardiac mass or 24-h BP profile. HRT users who were dippers demonstrated a significantly greater nocturnal BP reduction. Long-term controlled trails are needed to better define the effects of estrogen and progestin on the aorta, the heart and 24-h BP profile in normotensive and hypertensive menopausal women.

The aim of this study was to: (i) separately estimate the effects of secular trends and senescence from the blood pressure (BP) data of a cohort follow-up study, and (ii) compare cohort and population stroke mortality trends with systolic blood pressure (SBP) senescence (aging) and secular trends. The data for this work came from a Japanese (n = 508 men) and a Yugoslavian cohort (n = 552 men) of the Seven Countries Study. This report is restricted to one cohort of each country for reason of data availability. Our analysis showed that BP rose with age even after correcting for the secular trends. A significant difference in SBP rise with age was found between Yugoslavian and Japanese cohorts (0.8 vs 1.4 mmHg/year, p = 0.0001). The secular and aging trends in SBP were significantly associated with the cohort and population stroke mortality in both cohorts. In conclusion, our results suggest that BP change with age does not result exclusively from biological aging; other factors also participate in the process. The rate of BP rise with age differs in two ethnically different populations. Difference in arterial stiffness and/or dietary salt intake between these populations may account for this observation.

Postoperative acute confusion (ACS) is a significant problem among older surgical patients; its incidence is greater in orthopaedic than in general surgery. This descriptive prospective study described the hospital recovery pattern of older confused and non-confused patients after hip surgery. The study sample included 54 patients aged 60 years or older consecutively admitted to a teaching hospital for emergency or elective hip surgery. Their cognitive status assessed by the Confusion Assessment Method (CAM), physiological status, functional ability, sleep satisfaction, and perceived discomfort were evaluated at baseline. These assessments were repeated on the first 4 postoperative days. The incidence of ACS over 4 postoperative days was 35%, 37%, 28% and 12%, respectively. Confused and non-confused patients differed significantly in age, admission diagnosis, and length of hospital stay ( P

Coronary heart disease (CHD) is known as a disease of postmenopausal women. While hormone replacement therapy is recommended increasingly to postmenopausal women for the prevention of CHD, the potential impact of non-pharmacologic interventions on cardiovascular disease reduction has been largely unexplored. The purpose of this article is to develop the understanding of the research literature on three risk factors by which estrogen and physical activity, a non-pharmacologic intervention, may confer cardiovascular protection in postmenopausal women. Three risk factors are lipoproteins, systolic pressure, and changes in the vascular endothelial functions. Effects of estrogen and physical activity on these biological factors are compared.

Transforming growth factor-β (TGF-β) has been implicated in the in vivo resistance of the EMT-6/CTX and EMT-6/CDDP murine mammary tumors. Both of these tumors have a higher number of intratumoral vessels than the EMT-6/parent tumor. Animals bearing the resistant tumors have higher plasma levels of TGF-β than animals bearing the parent tumors; however, upon treatment with cytotoxic therapies there is a greater rise in plasma TGF-β levels in animals bearing the parent tumor than in animals bearing the resistant tumor. In situ hybridization for TGF-β mRNA and immunohistochemical staining for TGF-β protein showed that the resistant tumor levels of this growth factor are higher than those of the parent tumor prior to treatment; however, after cytotoxic therapy the increase in TGF-β is greater in the parent tumor than in the resistant tumors. Treatment of tumor-bearing animals with the naturally occurring TGF-β inhibitor decorin did not alter the sensitivity of the parent tumor to cyclophosphamide or to CDDP as determined by tumor cell survival assay. However, administration of decorin increased the sensitivity of the EMT-6/CTX tumor to cyclophosphamide and of the EMT-6/CDDP tumor to CDDP so that the drug resistance of these tumors was nearly ablated. A similar pattern was observed in the drug response of the bone marrow granulocyte-macrophage colony-stimulating factor of animals bearing each of the 3 tumors. Int. J. Cancer, 71:49–58, 1997. © 1997 Wiley-Liss, Inc.