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Laois woman to compete for Ireland's Best Young Entrepreneur National title
Dr Diane Cooper with Honor Deevy, Seamus Doran and Evelyn Reddin
Competing for Ireland's Best Young Entrepreneur in the upcoming National final will be Dr. Diane Cooper from Portarlington.
Dr. Cooper is a founding director of True Fitness, based in Portarlington, and has developed a new business idea – "Know Your Insulin' point-of-care testing device which will allow for the global measurement of insulin resistance.
The other two Laois finalists - Aisling Kirwan and Amie Colgan
The Laois, Offaly Kildare and Westmeath Region 'Best Young Entrepreneurs' were announced at an awards ceremony hosted by the four Local Enterprise Offices on Wednesday, June 12 at Bloomfield House Hotel, Mullingar. The winners were chosen from 12 finalists, shortlisted from 218 applicants in the region which was launched earlier this year by the LEO's as part of a nationwide search to find 'Ireland's Best Young Entrepreneur (IBYE).'
Now in its fifth year, IBYE is a nationwide campaign to celebrate Ireland's young entrepreneurs and is open to individuals aged 18 to 35 who have an innovative business idea, new start-up or established business.
Eight regional finals are taking place across the country over the next few weeks in the search for Ireland's Best Young Entrepreneur 2019. The previous LEO Laois National finalist was Kelly Ging of Kelly Lou Cakes.
The Laois, Offaly, Kildare & Westmeath Regional final was hosted by Ronan Berry, Midlands 103 and Councillor Paddy Hill, An Cathaoirleach of Westmeath County Council was also in attendance to present the awards to the winning entrepreneurs.
The Winner of the 'Best Business Idea' category was won by Dr. Diane Cooper of True Fitness representing #TeamLaois and Local Enterprise Office Laois.
The winner of the 'Best Start-Up Business' category was Pierce Dargan, founder of Equine Medirecord, representing #TeamKildare and Local Enterprise Office Kildare.
The winner of 'Best Established Business' went to Dr. Emma Rose Conroy, founder of Eurostallions, representing #TeamOffaly and Local Enterprise Office Offaly.
Twenty-four regional winners will now proceed to compete for the national title of Ireland's Best Young Entrepreneur in Google Headquarters on Sunday, September 15. A further €100,000 investment fund will be available to invest in the winners of the three categories at the national final - one of which will also be named as 'Ireland's Best Young Entrepreneur.'
Speaking at the Regional final, Evelyn Reddin, Head of Enterprise, Local Enterprise Office Laois said, "We are delighted to have had such a positive response from so many strong candidates from the Laois, Kildare, Offaly, Westmeath region this year - it is fantastic to see so many young entrepreneurs with innovative ideas and businesses.
"The skills and knowledge gained by all involved in the competition we hope will stay with each participant and help grow their businesses even further. We are excited to see what will be in-store for our regional winners and we wish them every success in the upcoming national finals! IBYE is a remarkable platform that we hope will encourage and grow further young entrepreneurship and job creation in the region."


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University of Kansas Health System Receives $2 Million Gift
The University of Kansas Health System in Kansas City has announced a $2 million gift from Cloud L. "Bud" Cray, Jr., and his late wife, Sally Cray, in support of its cardiac health programs.
Given in recognition of the care the Cray family received from cardiologist Charles Porter and the staff of the system's heart program, the gift will support the cardiomyopathy/heart failure and cardio-oncology programs.
Bud Cray is chairman emeritus of MGP Ingredients in Atchison. The Cray family have been longtime supporters of the health system and provided the resources to open the Cray Diabetes Center in 1979.
"We are so grateful to have Bud Cray and his late wife, Sally, as supporters and friends of the University of Kansas Health System," said University of Kansas Health System president and CEO Bob Page. "Because of their belief in our heart program, their gift will help future patients who are the sickest of the sick receive the most advanced care."


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Immunization of metastatic breast cancer patients with a fully synthetic globo H conjugate: A phase I trial
Contributed by Samuel J. Danishefsky
The carbohydrate antigen globo H commonly found on breast cancer cells is a potential target for vaccine therapy. The objectives of this trial were to determine the toxicity and immunogenicity of three synthetic globo H-keyhole limpet hemocyanin conjugates plus the immunologic adjuvant QS-21. Twenty-seven metastatic breast cancer patients received five vaccinations each. The vaccine was well tolerated, and no definite differences were observed among the three formulations. Serologic analyses demonstrated the generation of IgM antibody titers in most patients, with minimal IgG antibody stimulation. There was significant binding of IgM antibodies to MCF-7 tumor cells in 16 patients, whereas IgG antibody reactivity was observed in a few patients. There was evidence of complement-dependent cytotoxicity in several patients. Affinity column purification supported the specificity of IgM antibodies for globo H. On the basis of these data, globo H will constitute one component of a polyvalent vaccine for evaluation in high-risk breast cancer patients.
On the basis of promising clinical results, there has been renewed interest in the investigation of an immunotherapeutic approach with either monoclonal antibodies (1, 2, †) or vaccines (3–8) for the treatment of breast cancer. In particular, tumor-associated carbohydrate antigens, expressed as protein or lipid conjugates, are commonly found on breast cancer cells and may serve as potential targets for vaccine therapy. Among these, we have been particularly interested in the immunomodulatory potential of the hexasaccharide portion of the glycoceramide globo H. This antigen was identified on the human breast cancer cell line MCF-7 (9) as well as on a variety of epithelial cell tumors of ovarian, gastric, pancreatic, endometrial, prostate, and lung (small cell and nonsmall cell) origin (10). It is also expressed on the luminal surfaces of normal epithelial cells in the breast, pancreas, uterus, lung, ovary, stomach, and prostate (10). The structure of globo H was assigned by Hakomori and colleagues as Fucα1→ 2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1→1Cer, (1, Fig. 1) (11) and was subsequently synthesized by Bilodeau et al. (12).
We have developed an approach for augmenting the immunogenicity of synthetic antigens by conjugation to the immunogenic protein carrier keyhole limpet hemocyanin (KLH) combined with the potent immunological adjuvant QS-21 (13–16). There is a variety of methods for conjugation of KLH to an antigen, including direct conjugation and conjugation with a bifunctional linker group such as 4-(4-N-maleimidomethyl) cyclohexane-1-carboxyl hydrazide (MMCCH) (17). This latter method can result in higher antigen/KLH ratios, greater yields of the antigen/KLH conjugate, and improved immunogenicity.
Mouse studies have confirmed the generation of antibodies against globo H after vaccination with KLH or CRM197 (diptheria toxoid) conjugates, prepared by a direct conjugation protocol (18, 19). There was evidence of a polyclonal antibody response, mediation of complement cytotoxicity, and binding of IgM antibodies with MCF-7 breast cancer cells (18). In patients with recurrent prostate cancer, vaccination with a globo H-KLH conjugate plus QS-21 resulted in the production of significant IgG and IgM antibody titers, predominantly IgM (20–22). Of 18 evaluable patients, 10 were found to develop IgM antibodies reactive with MCF-7 cells with no significant IgG reactivity (20). An increase in complement-dependent cytotoxicity (CDC) was observed in nine patients. Immune response did not appear dose related among the three higher doses of globo H, including 10 μg, 30 μg, and 100 μg, although the 3-μg dose yielded lower antibody titers.
On the basis of these encouraging results, we initiated a clinical trial in patients with metastatic breast cancer without evidence of disease or with stable disease on hormone therapy. The first objective of this trial was to determine the toxicity of this fully synthetic vaccine in pretreated breast cancer patients. The second objective was to determine whether immunization with a globo H-KLH conjugate plus QS-21 would generate an antibody response against globo H and breast cancer cells expressing globo H, and in particular to assess whether these antibodies could mediate CDC and antibody-dependent cell-mediated cytotoxicity (ADCC). The third objective was to evaluate whether the method of conjugation between globo H and KLH (direct or crosslinked) or the type of formulation of the vaccine (stored in saline or lyophilized) would affect the immune response. In addition to the well established "direct conjugation" strategy, we also examined the "crosslinked conjugation method" by using the bifunctional linker MMCCH (17). Finally, although clinical response was not a primary endpoint, the patient's disease status was monitored.
Patients and Methods
Patients with a history of metastatic breast cancer without evidence of disease after therapy or those with active disease who were on hormonal therapy were eligible. Four weeks had to have elapsed since prior surgery, chemotherapy, or radiation therapy, and 6 weeks since prior immunotherapy. Exclusion criteria included: a seafood allergy, a known autoimmune or immunodeficiency disorder, active steroid therapy, clinically significant New York Heart Association Class 3 or 4 disease, other active cancers (excluding basal cell or squamous carcinomas of the skin), and Karnofsky performance status ≤80. Premenopausal women were required to have a normal β human chorionic gonadotrophin level, as pregnant women were ineligible. Patients were required to have the following laboratory parameters: total lymphocyte count of ≥0.5 × 106/ml, total white blood cell count of ≥3,000 cells/mm3, serum creatinine ≤1.5 × upper limit of normal, serum aspartate aminotransferase ≤1.5 × upper limit of normal, and serum alkaline phosphatase ≤1.5 × upper limit of normal.
Pretreatment evaluation included the following within 3 weeks of protocol treatment: history and physical examination, rectal examination with hemoccult, chest x-ray, complete blood count with differential, chemistry profile, serum amylase, carcinoembryonic antigen, and CA15–3 or BR2729 level. The following studies were required within 4 weeks of treatment: computerized tomography scan of the chest, abdomen and pelvis, bone scan, and pelvic examination. All patients signed an informed consent approved by the Institutional Review Board and the Food and Drug Administration.
Treatment Plan and On-Study Evaluation.
The globo H-KLH conjugate plus QS-21 was administered s.c. during weeks 1, 2, 3, 7, and 19 for a total of 5 doses for each patient. The vaccine was usually injected into the upper arm or thigh by nurses in the Immunology Outpatient Unit. Each vaccine contained 10 μg of globo H in a globo H-KLH conjugate and 100 μg of QS-21. This dose of QS-21 had previously been confirmed as effective with minimal toxicity (23). Three versions of the globo H-KLH conjugate were evaluated: Group 1, direct conjugation of globo H and KLH plus QS-21 in saline; Group 2, crosslinked conjugation of globo H and KLH plus QS-21 in saline; Group 3, crosslinked conjugation of globo H and KLH plus QS-21 lyophilized and reconstituted with saline at the time of injection. Each version of the vaccine was evaluated in 9 patients for a total of 27 patients. Patients were sequentially assigned to a specific vaccine beginning with Group 1.
During the trial, patients were monitored for clinical toxicity and response. Laboratory studies, including complete blood count, chemistry profile, amylase level, carcinoembryonic antigen and CA15–3 or BR2729 levels, and stool hemoccult were performed intermittently as outlined in Table 1. Most patients also had repeat computerized tomography scans and bone scans during weeks 21–24.
Vaccine Preparation.
The globo H antigen was prepared by total synthesis (see Fig. 1) (12, 17, 22, 24). The synthetic globo H construct was then conjugated to KLH (PerImmune, Rockville, MD) by two different methods. The direct method involved reductive linkage of the aldehyde group derived from 2 (Fig. 1) to the NH2 groups on KLH by using sodium cyanoborohydride. The conjugation ratio of globo H molecules conjugated to each KLH molecule was 373:1 in 7% yield, based on 2. The crosslinked method attached the aldehyde group derived from 2 (Fig. 1) to the NH2 groups on the crosslinker MMCCH (Pierce, Rockford, IL) with sodium cyanoborohydride, as previously described (17). Sulfhydryl groups on thiolated KLH were then attached to the maleimide group on the MMCCH and incubated for 2 h at room temperature. The globo H/KLH conjugation ratio was 732:1 in 29% yield, based on 2 (Fig. 1). After conjugation, the globo H-KLH conjugates were washed, filtered, and placed in individual vials containing 10 μg of conjugated globo H in saline or lyophilized and stored, to be reconstituted in saline at time of injection. In Groups 1 and 2, the globo H-KLH conjugate was mixed with 100 μg of QS-21 (Aquila Biopharmaceutical, Framingham, MA) and stored in saline. In Group 3, the lyophilized globo H-KLH conjugate was mixed with 100 μg of QS-21 immediately before vaccination. All vaccines underwent testing for sterility and immunogenicity.
Serologic Assays.
Peripheral blood was sampled at various time points (see Table 1) to determine whether IgM and IgG antibodies against synthetic globo H and tumor cells expressing globo H were generated. If feasible, patients returned every 3 months for further antibody testing.
Blood samples were evaluated by ELISA assays according to the following procedure (22). NUNC 96-well ELISA plates were coated with 0.1 μg of globo H-ceramide per well in ethanol and dried overnight at room temperature. Unreactive sites were blocked by incubation with 3% human serum albumin for 2 h. Serial dilutions of the patient's sera were added to the wells, left at room temperature for 1 h, and washed. Secondary antibodies, either alkaline phosphatase-labeled goat anti-human IgM or unlabeled mouse anti-human IgG, were added. For IgG detection, a tertiary antibody, alkaline phosphatase-labeled goat anti-mouse IgG (Southern Biotechnology Associates) was then added. After a 45-minute incubation, the plates were washed, developed, and read at 414 nm on the ELISA reader. The highest serum dilution with an absorbance of ≥0.100 was recorded as the antibody titer.
Fluorescence-Activated Cell Sorter (FACS).
FACS analyses were performed on pretreatment and posttreatment sera to determine whether IgM or IgG antibodies were able to bind to MCF-7 tumor cells that express globo H (22). Dilutions (1:10) of patient sera were added to the tumor cells, which were washed and mixed with 20 μl of a 1:25 dilution of goat anti-human IgM or IgG antibody (Southern Biotechnology). These antibodies were FITC-labeled. After a 30-minute incubation on ice, the cells were washed, and the percentage of positive cells and mean fluorescence was detected by a flow cytometer (FACScan, Becton Dickinson).
Chromium release assays to assess complement-mediated cytotoxicity were performed for each patient at various time points (25). MCF-7 tumor cells were washed in FCS-free media two times, resuspended in 500 μl of media, and incubated with 100 μCi 51Cr per 10 million cells for 2 h at 37°C. The cells were then shaken every 15 min for 2 h, washed 3 times in media to achieve a concentration of approximately 20,000 cells/well, and then plated in round-bottom plates. The plates contained either 50 μl cells plus 50 μl monoclonal antibody, 50 μl cells plus serum (pre- and posttherapy), or 50 μl cells plus mouse serum as a control. The plates were incubated in a cold room on a shaker for 45 min. Human complement of a 1:5 dilution (resuspended in 1 ml of ice-cold water and diluted with 3% human serum albumin) was added to each well at a volume of 100 μl. Control wells included those for maximum release of isotope in 10% Triton X-100 (Sigma) and for spontaneous release in the absence of complement with medium alone. The plates were incubated for 2 h at 37°C, centrifuged for 3 min, and then 100 μl of supernatant was removed for radioactivity counting. The percentage of specific lysis was calculated as follows: % cytotoxicity = [(experimental release–spontaneous release)/(maximum release–spontaneous release)] × 100. A doubling of the CDC to >20% was considered significant.
MCF-7 tumor cells, cultured in DME plus 10% FBS, were labeled with 100 μCi 51Cr for 1 h (26). After being washed three times with culture medium, cells were resuspended at 105/ml, and 100 μl/well were plated onto 96-well round-bottom plates. Donor peripheral blood mononuclear cells were plated at a 100:1 and 50:1 ratio; 20 μl/well of pre- and postimmune patient sera or commercially available pooled human AB serum (Gemini Biological Products, Calabasas, CA) were added. After an 18-h incubation at 37°C, supernatant (30 μl/well) was harvested and transferred onto Lumaplate 96 (Packard), dried, and read in a Packard Top-Count NXT γ counter. Each measurement was carried out in triplicate. Spontaneous release was determined by cpm of tumor cells incubated with medium and maximum release by cpm of tumor cells plus 1% Triton X-100 (Sigma). Specific lysis was defined as: % specific lysis = [(experimental release–spontaneous release)/(maximum release–spontaneous release)] × 100. The percent ADCC is expressed as peak specific lysis postimmune subtracted by preimmune percent specific lysis. A doubling of the ADCC to >20% was considered significant.
Affinity Column Purification of Globo H Antibodies.
Pre- and postvaccination sera for five patients (patients nos. 11, 14, 15, 16, and 17) were selected to evaluate the specificity and to quantify the vaccine-induced antibodies. To this end, the antibodies were isolated from serum and purified through affinity chromatography. The affinity columns were designed, synthesized, and used for isolation purposes, as described (21). Briefly, the antigen was prepared by total synthesis and conjugated to the amino agarose gel (0.6 μmol globo H/ml of gel). By using 3 ml of column material, 1 ml of patient sera was added and incubated at 4°C for 1 h with gentle agitation. Column elution, collected in 1-ml fractions, was performed as described (21). Proteins were detected by using the Pharmacia LKB Ultrapsec III at 280 nm. ELISA assays by using the previously described technique were performed, with 0.2 μg globo H ceramide, and read at an absorbance of 414 nm. Purified antibodies were pooled, centrifuged in Centricon 30 tubes at 4°C for an average of 25 min, and then redissolved in 1 ml PBS. ELISA assays and protein quantification were performed on these samples, by using globo H ceramide coated plates or Ley-coated plates.
Criteria for Cessation of Treatment and Dose Reduction.
Patients with evidence of disease progression while on study requiring chemotherapy or radiation therapy were removed from the trial. Grade III or greater local or systemic toxicity according to the Common Toxicity Criteria resulted in a 50% reduction in the components of future vaccines for the individual patient. Grade III lymphopenia was excluded, because a grade 3 value was acceptable as a pretreatment value.
Biostatistical Considerations.
A total of 27 patients were entered into this pilot trial to evaluate the immunogenicity of the globo H-KLH plus QS-21 vaccine. After vaccination, a serologic response included an antibody titer of ≥1:40 with a baseline titer of 0 or a ≥2-fold increase with a baseline titer of greater than 0. On the basis of prior statistical analyses (27), if more than four of nine patients achieve a serologic response, the vaccine would be considered promising.
Twenty-seven patients with metastatic breast cancer were treated during this trial between September 1997 and August 1999. Patient characteristics were comparable between the three groups, as outlined in Table 2. The median age was 46 years (range 35–63 years). Of these, 15 had a history of metastatic disease, but at the time of protocol entry had no definite evidence of disease, and 12 patients had metastatic disease that was relatively stable on hormone therapy. The number of patients with the following dominant sites of disease before protocol entry included: bone (8), lung (2), chest wall (11), liver (1), and lymph nodes (5). Metastatic disease was found in 4 patients within 6 weeks of the original diagnosis of breast cancer. For all patients, the median interval between breast cancer diagnosis and diagnosis of metastatic disease was 141 weeks (range 0–1,386 weeks); the median interval from diagnosis of metastatic disease to entry into this study was 96 weeks (range 11–446 weeks). During the trial, 22 patients were on hormone therapy, either tamoxifen, anastrazole, or megestrol acetate.
Twenty-six patients received five vaccinations each, and one patient (no. 12) was removed from the trial because of disease progression in the liver after the fourth vaccine. However, all patients were considered evaluable for toxicity and serologic response. Of the 26 patients treated with 5 vaccinations each, 24 patients were treated according to schedule. Two patients experienced treatment delays. One patient (no. 17) developed an elevated amylase level, which is further described below. Another patient (no. 13) developed an infection of a breast implant requiring surgical removal and prolonged antibiotic therapy after the third vaccine. She received the fourth and fifth vaccinations during weeks 35 and 47, respectively, at the full doses.
In general, the vaccine was well tolerated; local skin reactions and mild flu-like symptoms were the predominant side effects. The common toxicities observed during the trial are noted in Table 3. Local reactions at the vaccine site, including discomfort, erythema, and induration, usually ranged from 1–7 days in duration, although most resolved within 3–4 days. Flu-like symptoms, including myalgias, arthralgias, fever, and fatigue, were transient, ranging from 1–7 days duration, but often resolved within 2–3 days. Serial hemoccult stool samples revealed no evidence of gastrointestinal bleeding. Five patients noted a recall reaction at the first vaccine site after the second vaccination. Several patients complained of transient pruritis at the vaccine site, and one patient complained of grade 2 pruritis of the scalp, palms, and soles of the feet for 3 days on one occasion. Two patients experienced enlarged inguinal nodes after vaccinations on the thigh.
One patient developed erythematous papules on the face approximately 6 days after the second vaccine, after sun exposure. The rash resolved after 1 day of treatment with triamcinolone cream. She subsequently complained of scalp sensitivity after the fourth vaccine without further rashes. During week 19, two patients (nos. 10 and 11) complained of subjective heaviness or fatigue in the lower extremities. Neurologic and radiographic evaluations were normal; these symptoms were likely not related to the vaccine.
During week 18, one patient (no. 17), who had a normal amylase level prevaccine and during week 7, developed a grade 3 elevation in the amylase level of 281 units/liter (normal 25–125 units/liter). She was without significant symptoms, and an upper abdominal ultrasound and chemistry profile were normal. A lipase level was 37 units/liter (7–60 units/liter). Fractionation of the amylase level included: total 186 units/liter (30–70 units/liter), salivary isoamylase 138 units/liter (12–137 units/liter), pancreatic isoamylase 48 units/liter (7–54 units/liter); macroamylase, none detected. By week 20, the amylase level had normalized to 102 units/liter (25–125 units/liter), and the patient was asymptomatic at week 21. She received the fifth vaccination during week 26 with a 50% reduction of all components because of the grade 3 toxicity. On that day, the amylase level was 106 units/liter and subsequently increased to 129 units/liter (25–125 units/liter) at week 28 with a normal lipase level. By week 30, the amylase level was normal and remained normal 4 and 7 months later. The etiology of the hyperamylasemia is unclear, although possible etiologies include infection, drugs, or the vaccine. Three other patients also had elevated amylase levels. These included two patients with grade 1 pretreatment amylase levels; in one patient, the value normalized by week 3, and in the other patient the grade 1 value persisted. A third patient developed a grade 1 value at week 19 that normalized by week 31.
Several patients developed grade 1 toxicity laboratory values for glucose, alkaline phosphatase, serum aspartate aminotransferase, calcium, albumin, or potassium. One patient had a pretreatment grade 3 total bilirubin level (1.6 mg/dl with a normal direct bilirubin level) that did not increase during the trial; no dose reduction was made. Another patient had a pretreatment grade 3 glucose value that was present occasionally during the trial; no dose reduction was made. One patient began the trial with a grade 1 creatinine level that transiently increased to a grade 2 value during week 2 and then returned to baseline, which was likely because of medication for a viral infection. Several patients had transient decreases in various hematologic values as outlined in Table 3. It is unclear whether these variations were directly related to the vaccine or to normal biologic fluctuations. One patient had a pretreatment grade 3 hemoglobin that continued intermittently during the trial. There was no evidence of hemolysis, and the anemia was felt to be secondary to prior high-dose chemotherapy and mild renal insufficiency. No dose reduction was made as it predated the vaccine.
Serologic Response.
Evaluation of IgM antibody titers in patient sera was performed by ELISA (Fig. 2). Although median antibody titers were slightly higher in the first group of patients, serologic assays demonstrated no distinct differences among the three groups. Low IgG antibody titers were consistently observed (data not shown) with the following range of values: group 1 (0–40), group 2 (0–10), group 3 (0–160). The globo H vaccines generated a strong IgM response independent of formulation or linker. Flow cytometric assays to assess the percentage of MCF-7 tumor cells reactive with the patient's IgM antibodies pre- and posttherapy are presented in Table 4. Over half of the patients in this trial exhibited at least a 3-fold increase in IgM reactivity, by FACS analysis, including 4 patients in Group 1, 5 patients in Group 2, and 7 patients in Group 3. There was little reactivity of IgG antibodies with tumor cells in these assays, although 3 patients (2 in Group 1 and 1 in Group 3) demonstrated a significant increase in IgG reactivity (data not shown). CDC was analyzed by using chromium release assays. A significant increase in activity was observed in 9/27 patients (Table 4). A significant increase in ADCC was also observed in 8/27 patients including 5 patients in Group 3 (data not shown).
To further evaluate response to vaccination, posttherapy antibodies detected in sera from five patients were isolated and purified by using affinity columns bearing the synthetic globo H antigen. All anti-globo H activity was removed from the sera, and the presence of IgM antibodies was confirmed. The IgM antibodies induced by vaccination demonstrated reactivity with globo H, whereas they proved unreactive with the tumor-associated carbohydrate antigen Ley, as assessed by ELISA (data not shown). To further demonstrate this specificity, an affinity column bearing the Ley antigen was incubated with sera from patient no. 11. No significant antibody binding was observed.
Clinical Response.
Although clinical response was not a primary endpoint of this trial, the following observations were made. Of the 15 patients without evidence of disease (NED) at the beginning of this trial, all remained free of disease at the conclusion of the protocol (weeks 21–24) except for patient no. 8, who developed progression of disease in the chest wall. Of the remaining 14 patients, 10 remain NED, and 4 had progression of disease, with a median followup (interval from date on study to date of most recent evaluation) of 107.5 weeks (range 85–153 weeks).
Of the 12 patients who began this trial with stable disease, 9 remained with stable disease, and 3 had disease progression at the conclusion of the protocol (weeks 21–24). One patient (no. 12) progressed in the liver and received only 4 vaccinations. The other two patients (nos. 21 and 22) had progression of disease in lymph nodes and increasing CA15–3 levels at the conclusion of the protocol. Of the remaining 9 patients, 5 remain with stable disease and 4 had progression, with a median followup (interval from date on study to date of most recent evaluation) of 111 weeks (range 61–152 weeks).
Of the 27 patients, 3 have subsequently died of disease (nos. 5, 8, and 21).
Overall, this study demonstrates that vaccination of metastatic breast cancer patients with a globo H-KLH plus QS-21 vaccine can generate an immunogenic response with minimal toxicity. Several conclusions can be drawn. First, the most common toxicities were transient local skin reactions at the vaccine site and mild flu-like symptoms. The amylase level was monitored closely, because globo H is expressed on normal pancreatic cells. One patient exhibited a significant grade 3 amylase level that resolved within 2 weeks and did not require medical therapy. Whether this episode was directly related to the vaccine, other medications, or an infection cannot be definitively determined, but it did not recur with an additional immunization. Another patient developed a transient grade 1 amylase level and was also asymptomatic. The two patients with pretreatment grade 1 levels did not exhibit any significant increase in these values. Pancreatitis was not observed in a trial after vaccination of 18 prostate cancer patients with a globo H vaccine (20). Therefore, it is unlikely that this vaccine would stimulate episodes of clinically significant pancreatitis. Two patients exhibited vague neurologic symptoms without clinically significant findings. Neither patient has exhibited evidence of a connective tissue disease to suggest an autoimmune reaction related to the vaccine. We observed no significant changes in hematologic, renal, metabolic, or hepatic function. Transient alterations in these values are unlikely related to the vaccine and may be because of normal biologic fluctuations. The toxicities we observed in this trial are similar to those observed in a previous breast cancer vaccine trial and are likely due to the immunological adjuvant QS-21 (28).
Second, vaccination of breast cancer patients with this vaccine was able to stimulate moderate IgM antibody titers in the majority of participants. IgG reactivity was stimulated to a lesser extent with lower peak titers. In most patients, the peak antibody titers seemed to occur between weeks 5 and 13, with a subsequent decrease despite a fifth vaccination at week 19. This pattern was also observed in the prostate cancer globo H vaccine trial (20). The peak antibody titers and duration of antibody detection were greater in a previous breast cancer vaccine trial with a MUC1-KLH conjugate plus QS-21 (28). In that trial, although the same vaccination schedule was used, the antibody titers in the 9 patients were higher and remained elevated for a minimum of 106 weeks following the last vaccination. This difference probably reflects the relative immunogenicity of the synthetic MUC1 peptide and globo H glycolipid antigens. It is unclear at this time whether the level of the antibody titers has a significant impact on clinical outcome. Intuitively, it would seem that a prolonged duration of detectable antibody levels would be optimal in terms of clinical outcome.
Significant binding of the patients' IgM antibodies to MCF-7 tumor cells (a tripling of the values between pre- and posttherapy samples) was observed in 16 of the 27 patients by FACS analysis. IgG antibody reactivity was observed by FACS analysis in only three patients. Nine patients also demonstrated increased CDC, which is encouraging because potential antitumor mechanisms of antibodies involve binding to the tumor cell surface and induction of complement-mediated lysis. In comparison to a previous MUC1 vaccine trial, the frequency of induction of significant antibody reactivity against MCF-7 cells was similar (28). Evidence of ADCC was observed in 8/27 patients including 5 patients in Group 3.
Third, no significant differences were observed in antibody titers by ELISA assays, flow cytometric analyses, CDC, or ADCC between the three formulations of globo H vaccine in this trial. Further analysis by using affinity column purification supports the observation that the IgM antibodies induced by vaccination in this trial seemed to be specific for globo H, in that reactivity against a second fucose containing pentasaccharide, Ley, was not detected. The use of the MMCCH bifunctional linker group, which greatly improved the conjugation yield, did not appear to decrease the globo H specificity or tumor cell reactivity of the antibodies induced.
Fourth, although clinical response was not a primary endpoint of this trial, several observations can be made. During or at the conclusion of the trial, 4 of the 27 patients developed progression of disease. With a median followup of approximately 2 years, of the other 23 patients, 10 remain without evidence of disease, and 5 have stable disease. It is not possible to correlate immunologic response with clinical response from this trial because of patient heterogeneity, small numbers of patients, and use of hormone therapy during this study.
In summary, vaccination with the globo H-KLH plus QS-21 vaccine can induce antibodies reactive with globo H-positive tumor cells that mediate CDC and ADCC. As we observed no significant differences in immunologic response among the three different versions of the vaccine, we plan to use the crosslinked method of conjugation because of the higher antigen/KLH yields. We are currently exploring additional approaches to augmenting the titer and duration of the antibody response, including various vaccination schedules, use of a second carrier protein, and additional immune adjuvants. It is important to consider that not all breast tumor cells may display the globo H antigen. Thus, targeting globo H antigen alone may result in limited clinical impact. Therefore, we plan to incorporate the globo H antigen into a polyvalent vaccine containing several other antigens (Ley, TF, sTn, etc.). With a full complement of antigen-based vaccines and a set of affinity columns to complement serological analyses, the simultaneous targeting of multiple antigens may result in the most significant clinical impact.
We are grateful for the motivation and compliance of the participants in this trial. We thank Dr. George Sukenick of the Sloan Kettering Institute NMR Core Facility (CA-08748) for mass spectral and NMR analyses. We also thank the members of the Breast Cancer Service, Department of Medicine, at Memorial Sloan-Kettering Cancer Center (MSKCC) and other physicians for patient referrals, and the nurses on the Outpatient Immunology Unit at MSKCC. This work was supported by the National Institutes of Health [Grant CA28824 (S.J.D.)], Spore in Breast Cancer (2P50CA68425–06), and the Breast Cancer Research Foundation. Postdoctoral fellowship support from the Selma and Lawrence Ruben Foundation is gratefully acknowledged by L.J.W.
- keyhole limpet hemocyanin;
- complement-dependent cytotoxicity;
- antibody-dependent cell mediated cytotoxicity;
- 4-(4-N-maleimidomethyl) cyclohexane-1-carboxyl hydrazide;
- fluorescence-activated cell sorter
- Accepted December 28, 2000.
- Copyright © 2001, The National Academy of Sciences
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text:
Offering exhilaration and relaxation in equal measures, the 5-star Sandals Ochi Beach Resort, on the stunning island of Jamaica, is a divine tropical sanctuary where you can do as little or as much as you like. Whether your plans involve unwinding by the pool or water-skiing in the azure waters of the Caribbean Sea, this is a place where holiday dreams become a reality. Set beside its own private stretch of pristine beach, the all-inclusive Sandals Ochi Beach Resort is a uniquely-spectacular paradise retreat that offers you the perfect Jamaican experience.
Sandals Ochi Beach Resort boasts its own private beach.
A handful of shops, bars and restaurants can be found a short walk away from Sandals Ochi Beach Resort.
Sandals Ochi Beach Resort is approximately 100km away from Sangster International Airport.
The Sandals Montego Bay all-inclusive programme includes the following:
Details, including times and benefits, may be subject to change. You will be provided with full details of the all-inclusive programme on arrival at the hotel.
Vista Sky
Soy Sushi Bar
The Reef Terrace
The Southern Table
Manor House
Kelly's Dockside
Great House Café
Tapas on the Riviera
The Mariner Seaside Bar and Grill
Dino's Pizzeria Italiana
Le Gourmand
Bella Napoli Pizzeria
The Jerk Shack


text:
Online in full
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Search results for: cia in all categories
696 results found.
70 pages of results.
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511. The view from the bridge [Lobster #57 (Summer 2009)]
... the next two days. Jo Ackermann, head of Deutsche Bank, will be travelling somewhere in Europe. Jean-Claude Trichet, head of the European Central Bank, will not be around until the end of the week..... ' Defence against which missiles?There is one section of the John Diamond book on the CIA, reviewed below, which deserves picking out. Diamond points out that the missile defence system which the US is deploying, apparently against 'rogue states', is not to defend the US against nuclear attack by 'rogue states' but to enable the US to intervene in smaller states, free from the fear of nuclear attack. Its purpose ...
Terms matched: 1 - Score: 14 - 01 Jun 2009 - URL: http://www.lobster-magazine.co.uk/online/issue57/lob57-24.htm
512. International Labour and the Origins of the Cold War (Book review) [Lobster #24 (Dec 1992)]
... .S . sphere of economic influence (or: their informal empire). Cue, notably, the Marshall Plan: Europe rebuilds with American money, buying American goods, employing the American urban masses. But the loans have American strings. Cue the 'regulators' -- good old Irving Brown et al -- - a regiment of CIA agents and Labour Attachés to fund and steer the anti socialist wing of the European labour movement in the name of 'the communist threat'. This left revisionist thesis, specifically the wide-spread belief on the European Left that the shape of post-war unionism in Europe was largely down to the machinations of American agents like Irving Brown ...
Terms matched: 1 - Score: 14 - 01 Dec 1992 - URL: http://www.lobster-magazine.co.uk/online/issue24/lob24-12.htm
513. The 'Wilson plots' and related parapolitics (Book review) [Lobster #27 (Jun 1994)]
... another and from one minister to another. One of the failures of the government at the time of the Falklands episode was that information of actions taken by my noble friend Lord Callaghan with regard to the Argentine were not passed on until it was far too late.... ' (col 1052) 'It was a member of the CIA, a man called Angleton, who did great harm in this country under the "dirty tricks" campaign. ' (col 1053) Rinka RIP Curious piece in the Daily Telegraph, 26 November, 1993, reporting that Andrew Newton, now known as Hann Redwin, one of the people at the centre of the Jeremy Thorpe scandal ...
Terms matched: 1 - Score: 14 - 01 Jun 1994 - URL: http://www.lobster-magazine.co.uk/online/issue27/lob27-11.htm
514. The Trouble With Harry: A memoire of Harry Newton, MI5 agent [Lobster #28 (Dec 1994)]
... , such as the house journal of the Economic League. I never saw any of these articles. East-West Digest A couple of months later I received in the post from Professor John Vincent, a copy of the September issue of East-West Digest. This had the reputation in left-wing circles of being funded by the CIA. Vincent appended a note saying, 'I thought this would interest you' to an unsigned article, 'Strategy of Destruction: the ILP Re-Assessed' - By a Special Correspondent', pp. 701-705. The article was critical but reasonably accurate. It listed all the National Administrative Committee (NAC) members and nationally ...
Terms matched: 1 - Score: 14 - 01 Dec 1994 - URL: http://www.lobster-magazine.co.uk/online/issue28/lob28-09.htm
515. On the Trail of the JFK Assassins [Lobster #57 (Summer 2009)]
... when the assassination returned to the stage, some of them generated by the Garrison inquiry, none of which ultim-ately amount to much. Russell reports on the inquiry by Senator Schweiker and the House Investigation; interviews Gerry Hemmings; and the first HSCA director, Richard Sprague, on the politics of the HSCA; discusses the death of CIA big-wig Paisley; accumulates a fair bit of Garrisonia; gives us more about Nagell; discusses Oswald qua Manchurian candi-date; and interviews MK Ultra's Sydney Gottleib. Russell is a journalist, and a good one to judge by the evidence presented here. It is easy to understand how Nagell's style of offering tantalising fragments, ...
Terms matched: 1 - Score: 14 - 01 Jun 2009 - URL: http://www.lobster-magazine.co.uk/online/issue57/lob57-43.htm
516. Historical Notes: Anglo-American Conflict? UK becomes a US intelligence target [Lobster #38 (Winter 1999)]
... There is an interesting snippet in the July 1999 Monthly Review. It comes from the highly distinguished American Marxist scholar Paul Sweezy. Interviewed on the 50th anniversary of the Monthly Review, which he has co-edited since its foundation, Sweezy spoke a little about his wartime work for the OSS (Office of Strategic Services, precursor of the CIA). Sweezy revealed that he worked from 1942-45 in London, then Paris, then Germany, on 'research and analysis', evaluating intelligence and British policy. He said - and this is the interesting admission -'...the fact that they would want somebody in OSS who was keeping track of British post- ...
Terms matched: 1 - Score: 14 - 01 Dec 1999 - URL: http://www.lobster-magazine.co.uk/online/issue38/lob38-02.htm
517. British History and the British Right: Britannia's Burden: the Political Evolution of Modern Britain 1951-1990 (Book review) [Lobster #28 (Dec 1994)]
... -pictures of the politicians who have dominated the period. The author is one of the first historians to acknowledge the parapolitical dimension in modern British history, from the formation of the Special Branch to the construction of the new MI6 headquarters over a century later. This is allied to a perception that covert forces, including in the 1970s the CIA, have generally worked to protect the interests of property and capital when these have been (or are imagined to have been) under threat from the Left. Notable examples are the anti-Bolshevik panics of the 1920s, the attempted destabilisation of Labour governments in the 1960s and 1970s, and the surveillance of trade unionists (notably the ...
Terms matched: 1 - Score: 14 - 01 Dec 1994 - URL: http://www.lobster-magazine.co.uk/online/issue28/lob28-12.htm
518. The View from the Bridge [Lobster #30 (Dec 1995)]
... murder of WPC Yvonne Fletcher Joe Vialls' exploration of this murder - which he thinks he committed, while under some kind of mind control - has taken a significant lurch forward. In the Australian magazine New Dawn number 27 (GPO Box 3126FF, Melbourne, 3001), Vialls has a long analysis of the event, 'The 'Perfect" CIA Assassination'. In this Vialls analyses the event - shots, angles, newsreel coverage - and tries to show that the available evidence proves that the Libyans did not shoot Fletcher, and that the shots came from a then unknown office of the Hughes Tool Company in the same street. (Vialls does not name Hughes in the piece ...
Terms matched: 1 - Score: 14 - 01 Dec 1995 - URL: http://www.lobster-magazine.co.uk/online/issue30/lob30-07.htm
519. Lobster Issue 32: Contents [Lobster #32 (Dec 1996)]
... (Summer 2009) Clandestine Caucus (1996) About Lobster Subscribe See also... © 2001 Lobster Contents | Cover Image The Bilderberg Group and the project of European unification SAS: the Stiff Memoir Operation Julie revisited: the strange career of Ron Stark, parapolitical alchemist From Parapolitics to Deep Politics Plot elements in the Colosio Murder Mystery The CIA and radiation experiments on humans UFOs and the governments of the USA and UK Is Libya still the prime suspect for the murder of WPC Fletcher? The state in politics: Wallace, Holroyd and Lobster The view from the bridge Obituaries Books Export or Die: Britain's Defence Trade with Iran and Iraq UK Eyes Alpha the Inside Story of British ...
Terms matched: 1 - Score: 14 - 01 Dec 1996 - URL: http://www.lobster-magazine.co.uk/online/issue32/index.htm
520. NASA, Nazis and JFK: the Torbitt Document and the JFK Assassination (Book review) [Lobster #32 (Dec 1996)]
... check it out you find that the allegations are mostly unsubstantiated and uncheckable; and much of the purported documentation is a fraud. That is, if you check the source given it doesn't actually substantiate the claim made by 'Torbitt' for which it is offered as evidence. I'm reasonably certain that 'Torbitt' is disinformation, probably produced by the CIA in the wake of the Garrison inquiry. It may even have been a response to the French disinformation production, Farewell America, a couple of years before. For 'Torbitt' lays the blame not at the CIA's door, but jointly on the FBI and something called the Defence Industries Security Command. (On the latter I have never ...
Terms matched: 1 - Score: 14 - 01 Dec 1996 - URL: http://www.lobster-magazine.co.uk/online/issue32/lob32-18.htm
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Posted on Sat, Apr 28, 2018
OUR SERMON SERIES FOR MAY "Unwrapping the Presence and Power of the Holy Spirit" Our Lord Jesus knew that His disciples could not change the world in their own strength. The task was too great. Prior to His ascension, He said to them, "wait for the promise of the Father…you will be clothed with power from on high." (Luke 24:49) He was referring to the coming of the Holy Spirit on the day of Pentecost. They waited. They prayed. And when Pentecost came they received the Holy Spirit. They then preached Christ and lived the life of the Spirit and history tells the rest of the story. The story of the Church meandered through the centuries with victories and defeats, but all the while Spirit-filled Christians powerfully made a difference. 2,000 years later 2.2 billion believers cover the earth and give testimony to the presence and power of the Holy Spirit. Bring your friends to hear this new series…the story is compelling! In May we are going to rediscover the Holy Spirit for today. Let's unwrap the Gift of the Father. The Holy Spirit is for you and through you for the world. Our new sermon series "Unwrapping the Presence and Power of the Holy Spirit" will enfold with the following messages:
Sunday, May 6th – "The Holy Spirit and You" John 14 & 16 (Celebrating The Lord's Supper)
Sunday, May 13th – "I Believe in the Holy Spirit" Biblical Women Telling Their Stories (Mother's Day and Prayers for Healing and Wholeness)
Sunday, May 20th – "WIND & FIRE: Living Out the Book of Acts" Acts 2:1-13, 41-47 (Pentecost Sunday and People's Pantry Sunday)
Sunday, May 27th – "The Holy Spirit in Today's World" 1 Corinthians 12 & 13 (Memorial Day Sunday and Reception of New Members
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The Pet Head Life's an Itch Skin Soothing Shampoo has an amazing formula effectively relieves skin irritations caused by insect bites and dry skin. It contains no harsh chemicals, coal tar or drugs such as cortisteriods. Scented like Passion Fruit.
Oatmeal and Aloe Vera: Work together to soothe the skin
Tea Tree Oil: Helps purify, fortify and moisturize hair follicles
Wheat protein, vitamins and chamomile extract: nourish the skin and leave the coat silky and conditioned
TO USE: Wet the coat completely with warm water. Apply shampoo gently, work back to the tail. Lather well into coat. Avoid eyes and ears. Rinse thoroughly and towel dry.
Comes in a 16 fl. oz bottle (473ml)
All Pet Head formulas are pH adjusted and free of paraben, petroleum derivatives, sulphate and DEA


text:
Cleveland, Ohio, and the surrounding communities on Lake Erie host dozens of festive New Year's Eve events, from family-friendly gatherings to classical concerts, from restaurant seatings to dinner cruises. More traditional late-night party venues turn up the tunes with DJs or live bands and live feeds to the ball drop in New York City. If you live in the area or are visiting for the holidays, make sure to plan ahead for the best New Year's Eve festivities.
The Lodge at Geneva On-The-Lake
The celebration carries over to the next day when you book a New Year's Eve package at the Lodge at Geneva State Park.
The ballroom package includes tickets to the New Year's Eve gala on December 31 from 7 p.m. to 1 a.m. It also includes a one-night stay, a full buffet dinner, live entertainment, a five-hour open bar, champagne toast at midnight with a ball drop, breakfast on New Year's Day, and a late checkout at noon—especially nice for those nursing hangovers! To ring in 2020, this year's gala theme is Hawaiian Luau.
Lago Custom Events NYE Soirée
Usher in the new year at a black-tie-optional event with lavish dining, endless cocktails, and non-stop dancing at the annual Lago Custom Events NYE Soirée in Cleveland. The theme for New Year's Eve 2020 is Cirque du Soirée: The Greatest Show. Tickets are available for purchase online, but VIP packages must be requested by e-mail.
Hollywood Glam Party
The 9 is a stylish hotspot in downtown Cleveland. For this club's 2020 celebration, it will have a Roaring Twenties theme with complimentary beer, wine, and craft cocktails as well as hors d'oeuvres. An all-night dance party and DJ will keep the evening upbeat as will the champagne toast when the clock strikes twelve. The venue sets the mood for that iconic speakeasy vibe, so don't forget your flapper dresses and fedoras.
Happy New Year's EV
Ring in 2020 at the Barley House with legendary Cleveland-based DJ EV. This late-night party starts at 10 p.m. and admission includes open bar, finger-food buffet, Champagne toast, party favors, a light show, and confetti drop. Plus, there will be a complimentary New Year's Day brunch with your New Year's Eve ticket. For groups of 10 or more there will be a $10 discount pr ticket.
NYE 2020 Hollywood Nights
At Magnolia, one of Cleveland's top entertainment venues, you can celebrate the new decade with a glitzy Hollywood-themed party. There will even be an appearance by reality TV-star Mike Johnson, who is well-known for being on the showThe Bachelorette and Bachelor in Paradise. Admission includes an open bar from 9 p.m. until midnight, hors d'oeuvres, and a champagne toast.


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Dr Eddie Murphy: Give yourself the New Year's gift of endless energy
Advice from Operation Transformation psychologist Dr Eddie Murphy
File photo via Pixabay
Do you wake up every morning feeling in need of a good night's sleep? Do you struggle through your morning's business, yawn through lunch meetings and drag yourself home in the evening to collapse, exhausted in front of the TV?
Hectic lifestyles can leave us with a constant feeling of fatigue, even if we sleep eight hours a night.
Longer work hours and lack of separation between work and play means there is no way to escape work stress or find time to take care of ourselves.
This causes tiredness which makes us even more stressed, so we start drinking and smoking, which saps our energy level even further.
Lifestyle Changes
If there is no obvious reason for your fatigue, like insomnia or illness, it's time to make some simple lifestyle changes. Just improving your diet or increasing your exercise can make your energy levels soar.
To start with, are you too tired for the gym? All the more reason to go: exercise is the best re-energiser around. However low you feel before a workout, you're guaranteed to feel better afterwards.
Exercise kick-starts your metabolism, It triggers the release of feel-good endorphins, which lift your mood and give you an extra burst to stay on form.
A fit body deals better with the daily stresses and strains. Exercising also helps you sleep better and boosts your immune system. Inject more activity into your daily life. Try walking or cycling to work; get off the bus a few stops earlier. Research shows a brisk post-lunch walk prevents mid-afternoon slump.
Progress to a regular exercise routine, scheduling workouts for the time of day you need a boost. You may find morning workouts prepare you for the day ahead or that exercising after work re-energises you for the evening. Never overdo it: over-exercising leads to exhaustion and stress.
Never miss breakfast
I see this every year with applicants for Operation Transformation.
Research shows people who eat breakfasts stay more physically and mentally alert through the day. Kick off that metabolism!
Having a healthier office and home environment helps counteract long hours and stress. Open windows for fresh air and maximise natural daylight.
Ensure your furniture allows you to sit up straight and avoid eye strain and take regular breaks to stretch and boost your circulation. Practice breathing deeply from your diaphragm, four five-minute sessions of deep breathing a day calms and re-energises you.
Save coffee for emergencies, caffeine raises your heart rate, heightening stress and fatigue. Instead drink two litres of water a day to prevent dehydration.
Relaxation is essential, especially for people who are always in work mode. Coming into this Christmas period, it's OK to come down a gear and take stock.
Reduce or become aware of alcohol intake as it's an energy leaker.
Planning time for yourself every day is as important as a regular holiday. It is like topping up your car with fuel — the more often you do it the less time it takes.
Just 20 minutes a day in a peaceful spot will help. Turn your mobile phone off, read a book, listen to music or try relaxation exercises like yoga, meditation or Tai Chi which soothe your mind while revitalising your body.
The power of sleep
Lastly, sleep soundly. Half of us don't get enough sleep to remain active and alert. The hours before midnight are the most refreshing, but quality is as important as quantity if you want to feel refreshed in the morning.
Unless you wind down before bedtime, work problems and worries disrupt your sleep leaving you groggy.
Take time to relax. Avoid caffeine, late-night eating and alcohol, all of which reduce sleep quality.
Make Three Christmas Wishes
* Eat breakfast
* Reducealcohol
* Prioritise rest and sleep
Dr Eddie Murphy runs a psychological and counselling service in Portarlington, Co Laois. If you are organising a speaker or training for school, community, voluntary, sporting or work groups, call Dr Eddie on 087 1302899 or go to www.facebook.com/ dr.eddie.murphy.psychologist


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Decision making is an important function of management and an integral part of the business management. In any organization, many decisions have to be taken by the top level management and the other employees working in the organization.
In the last article of mine, I have discussed what is decision making and the other things related to it like features and definitions. And if you wish to read that then you can do that by following the link provided below.
In this article of mine, I will be telling you about the decision making process. I will tell you about all the steps which are involved in making decisions in business management.
Before we begin I would like to tell you one thing and that is if you are a student then I recommend you reading my previous article before you read this one.
Because it will be easy for you to understand the things which are mentioned in this article.
The Steps in Decision Making Process
A decision can be a direction to something to do or not to do something. Effective decision making is required for the smooth functioning of the management.
The success of any organization depends upon the quality of the decision taken by the top level management and other important employees.
The steps involved in decision making are as mentioned below.
- Identification of the Problem.
- Collecting and Analysing Relevant Information.
- Discovery of Alternative Course of Actions.
- Analysis of Alternative Course of Actions.
- Selection of Best Alternative Course of Action.
- Implication.
- Verifying the Decision.
I will explain you all the 7 steps one by one in the further part of this article.
1) Identification of the Problem
Before taking any kind of decision in business management the manager has to identify the problem. The problem which his organization is facing from which they want to get rid off.
Without identifying the problem no manager can take the decision and that is the reason why identification of the problem is the first step involved in the process of decision making.
2) Collecting and Analysing Relevant Information
The first step was to identify the problem which is being faced by the organization. The next thing which the manager has to do is collect and analyze the information which is relevant to the problem.
But here the manager has to make sure that he is collecting only the information which is relevant to his organization and the problem.
3) Discovery of Alternative Course of Actions
After collecting and analyzing the relevant information now the manager has a good amount of information about the problem.
The next thing which comes to the picture is the course of action which they can use to solve the problem. But any problem can be solved in a number of ways so it is important to discover all those ways.
4) Analysis of Alternative Course of Actions
As soon as the alternative course of actions are discovered the next step is to analyze all the course of actions. Analyzing also includes the screening of them.
5) Selection of Best Alternative Course of Action
There is no doubt that every problem can be solved in many ways. But all the ways may not be suitable for the organization and that is the reason why the best alternative course of action has to be selected.
In this step, the manager has to be very careful about his selection because the effectiveness of the decision depends on this step.
6) Implication
Now the best alternative course of action has been selected so it is time for action. That course of action has to be implicated now. This is the step from where the effect of the decision making starts.
7) Verifying the Decision
The last step in the decision making process is to verify that the decision taken by the manager and the organization is correct. It can be done by analyzing the performance of the course of action.
If you want to know about the types of decision making then you can follow this link. There are 10 types of decision making which are taken in every organization.
So these are the 7 steps which are involved in the process of decision making. I hope you are clear with all the 7 steps, but if you have any kind of doubts then you can comment down below.


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The webmaster is aware of the fact that this web site doesn't look as intended on mobile devices (most cell phones, some tablets). It is recommended that you visit this site using a desktop or laptop computer only. When the site was redesigned last, HTML 5 and CSS 3 were not available or not yet implemented in all popular browsers. However, they are now becoming the standard. These two technologies provide browser-level support to deal with the small screens that mobile devices have. However, from ongoing testing, it is now clear that a substantial amount of re-work of this site will be required to (hopefully) maintain the same look. It currently is the webmaster's plan to try to roll out a small-screen-device-compatible version of this web site some time in 2020.
My name is Peter Vanvliet. I live in Houston, Texas. I have been maintaining web sites since January 1994.
I own my own software products company, called Fourth Ray Software. This is my main activity. I maintain web sites for several select clients as my secondary activity.
When there is some time and energy left over at the end of the day or on the weekends, I am building a 4ft by 8ft, multiple-section, exact-scale replica diorama of the Hazel Mine complex in southwestern Canonsburg, Pennsylvania as it was in the summer of 1924. This industry was served by the Pennsylvania Railroad's Chartiers Branch.
I started model railroading in the 1970s, in N-scale (1:160). In mid-1999, I switched my main hobby from woodworking to model railroading. In mid-2008 I switched from N-scale to S-scale. I became the NASG's webmaster in late 2011.
Please use any of the methods below to contact me.
There are many file-sharing services available, and they may make your life easier. However, from this webmaster's perspective, they tend to have and create a bunch of extra overhead. So, I will not accept any submissions of files on a file-share service that requires any kind of log-in, account-creation, or other such efforts. If the file that you want to submit for my consideration for use on this web site can be directly accessed on a third-party's site, then I will take a look. However, please, consider using any of these methods below for submitting files for consideration.
You can contact the webmaster via e-mail using the firstname.lastname@example.com address (click the link to start a new e-mail message). All e-mail is read and (if necessary) responded to, as soon as possible. If you are expecting a reply and you haven't heard back within 24 hours, it could be that the message did not make it across. Try the form below instead. All e-mail correspondence with the NASG webmaster is considered private. Your e-mail address will not be used for any other purpose other than to try to respond to your question. If your topic includes information that one or more of the NASG officials (e.g. the Membership Secretary or Dispatch Editor) should be made aware of, the webmaster may forward some or all of your e-mail's message to them.
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ALL of this.
The new single "Distance" is available via all digital outlets everywhere.
Shoutout to Mark Chappelle.
I want the full song!😁😉😊 Love this song ; round applause 👏
I love this theme song I want it so bad on my phone but can't seem to find it anywhere!


text: This evening seminar deals with the challenging task of creating, managing and promoting yourself as an expert witness.Professionals, although being specialists in their own area of practice, are often unsure of the principles of running what is essentially a micro business. You've provided a high quality service, delivering everything your instructing solicitor required on time, and yet you have to battle to get paid. You're not alone. Research shows as many as 50 percent of experts do not get paid on time but what can you do about it?This panel discussion will explore ways you can significantly improve your chances of being paid on time, and provide remedies for those times that you do not. This seminar will help any expert witness to fully capitalise on their expert knowledge and create a successful practice.BOOK NOWEWI Member Rate: £40 Non-member Rate: £60Email: email@example.com Call: 020 7936 2213


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The 2019 GAS Conference, themed Charting a Course: Visions in Glass will explore the new energy of St. Petersburg and the Florida Gulf Coast, from Sarasota to Tampa, offering a new perspective on future directions in glass for the GAS Conference March 28-31, 2019. Sun – Sand – Sea – St. Pete!
This is a huge accolade for the St. Pete arts community. "St. Petersburg is a city of youthful, vibrant arts communities and dynamic change, as well as famous fine white sandy beaches. With an average citizen age of 39, the city has benefited from the migration of forward-thinking entrepreneurs, artists, and businesses attracted by its livability. It's a glass-loving town as attested by the Chihuly Collection, the Morean Arts Center and hot shop, Imagine Museum, Duncan McClellan Gallery and hot shop, and the Zen Glass Studio, all within 2 miles of each other," says the Glass Arts Society (GAS).in their release.
The GAS conference is an opportunity to meet and review the past and approach the future in the spirit of the glass art pioneers from whose intention, innovation and momentum we benefit every day.Artists will benefit both from the creative and business insights this conference provides including.
• Charting career skills and new routes of success
• New relationships with the science and technology of glass
• New creative directions in the work of emerging glass artists
• Changes in market conditions and developing responsive strategies
• Exploring new directions in collecting
SUBMIT A PROPOSAL by Jan. 19th: Individuals and groups to submit proposals for demonstrations, lectures, lec-mos, and panels in kiln casting/forming, hot glass, flameworking, and coldworking. Proposals with content that highlight the theme may be submitted for consideration from now through Friday, January 19, 2018 by 11:59 pm PST. Click here to learn more.
About The Glass Art Society: The Glass Art Society is an international non-profit organization founded in 1971 whose purpose is to encourage excellence, to advance education, to promote the appreciation and development of the glass arts, and to support the worldwide community of artists who work with glass. The membership of the Glass Art Society (GAS) is over 2,200 from 47 countries around the world.
GAS holds an annual conference (in 2018 – Murano, Italy), publishes the Glass Art Society Journal and provides online versions of GASnews and the Glass Art Society online Member Directory featuring member profiles with image galleries, bios and more. GAS strives to stimulate communication among artists, educators, students, collectors, gallery and museum personnel, art critics, manufacturers, and all others interested in and involved with the production, technology and aesthetics of glass.
(Photos courtesy of GAS)


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Read Transcript
Hi, I'm Dr. Vonda Wright with advice to help you stay on your feet. Seven out of ten people say foot pain keeps them from walking, and that may lead to weight gain. The solution? Prevent the three most common foot problems, avoid athlete's foot, there are 250, 000 sweat glands in your feet so it's no wonder itchy smelly fungal infections grow there.
If you're prone to athletes foot, change your shoes and socks twice a day, buy socks that wick away moisture and always wear flip flops in locker rooms and pool showers. Don't cover off nasty nails. Hiding thick discolored nails inside shoes or under nail polish makes them worse. See your doctor to be sure there is no underlying medical condition under the nail.
The cause is often fungal. So use the same tips to prevent athletes foot. Keep your feet dry. Soothe foot pain. Problems in the heel or balls of your feet can result from weight gain, pounding the pavement or poor arch support, so stretch your leg muscles. Icing your feet can help too, and see a podiatrist for possible inserts.
For more ways to stay pain-free, watch all our smart tips right here.


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Gun Dog
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Acme Dog Whistle 211.5
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Acme Dog Whistle 211.5
Cork Screw Tether
£7.00Tethers are used in conjunction with a slip lead. Helps to control the dogs obedience when temptation arises. Superior quality forged steel. Pla...
Cork Screw Tether
Danish Design - Tweed Dog Coat
£15.00This Danish Design Tweed Dog Coat is a stylish coat featuring full chest protection, showerproof tweed fabric and a warm padded lining, making this...
Danish Design - Tweed Dog Coat
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£18.00Blending tan and country green tweed colours, the Hunter Tweed Snuggle bed provides a warm and cosy sleeping spot. The high sides of the bed provid...
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Deerhunter Dog Bed
£30.00Warm and robust dog bed made of fibre pelt from Deerhunter. The dog bed is machine washable. Measurements are 100x 70cm. Material 100% Polyester.
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Sold OutSize 56cm across by 42cm deep. Will easily hold 10 1lb training dummies with room for more! 2 large front pockets Mesh front Washable and removab...
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£29.50An ideal training aid, promoting the correct handling and retrieval of game. Lifelike body made from a soft foam, with free swinging head, and natu...
Turner Richards Teal Launcher dummy
£35.00The spare teal dummy is soft and correctly weighted to simulate a dead birdIts feet and head are hard plastic and swing, helping train your dog not...


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Note from the Editor-in-Chief
Hi there! First off, thank you so much as always for your time to read CIVILIAN. Now, we are about to welcome the fall season. I was actually wondering whether I should discuss fashion or feast, or something else that can be associated with the season we absolutely love. However, considering a wide range of topics and conversations we cover in this Fall I issue, scratch that – I think I should really use this page to, once again, thank all the talents we have been able to work with thus far for opening up so candidly to us in hopes of reaching so many lives of young people through stories accompanied by incredible photographs.
Recently, I went to see an X Ambassadors show in NYC, and the lead singer Sam Nelson Harris (who we featured in our 2019 Summer issue) was encouraging us, the audience, to celebrate our individuality and diversity, and to have such pride in ourselves for who we are. But when he said the band would make sure to continue to offer a safe space for everyone, that actually hit me.
As you can see, we have way too much going on everywhere in society, and sometimes, it's a massive struggle especially for the youth to maintain a sense of belonging and self-esteem. Technology is so advanced that it's easy for us to connect online but it would be so heartbreaking to see ourselves disconnected offline. That is why CIVILIAN is a digital and print publication, that is why we are always focused on individuals and their stories, and that is why we would like to be everyone's ally so that we can take one step together instead of having one person take 1,000 steps on their own.
I should probably note that we regularly receive emails and DMs from our readers suggesting who we should feature. They usually get forwarded to me, and I read every single one of them. Thank you so much again for all your tremendous support.
Thank you,
Eiko Watanabe


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- Home
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- Men jackets
- Biker jacketsAvengers Age Of Ultron Elizabeth Olsen (Wanda Maximoff) Red Jacket
Avengers Age Of Ultron Elizabeth Olsen (Wanda Maximoff) Red Jacket
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Product Code: Age Of Ultron Elizabeth Olsen£74 .00Price: £74
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Avengers Age Of Ultron Wanda Maximoff Red Leather Jacket
This Wanda Maximoff jacket is the ultimate outer wear for ladies who are daring and want t look stylish. It is made from 100% genuine leather and it is designed to rejuvenate the personality of a girl. The interiors of this slim fit jacket are lined with wool and polyester to keep you warm and comfortable. The Avengers Age Of Ultron Wanda Maximoff jacket is full sleeved and has a stand up collar. It has a front zipper and two side pockets. This is a very versatile Wanda Maximoff jacket that can be worn over any long or short dress to complement it. You can have all heads rolling when you wear this beautiful Wanda Maximoff red jacket in a party.
- Made from genuine leather
- Stand up collar
- Full sleeved
- Inner viscose lining
- Twin waist pockets
- Inspired from: Avengers Age Of Ultron
- Worn by: Elizabeth Olsen as Wanda Maximoff
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Washable Book
|Agency Network
|McCann Worldgroup
|Advertiser Brand
|Entrant Company
|McCann Health Japan
|Group Creative Director, Planner
|Shunsuke Kakinami
|Senior Art Director
|Hisashi Matsui
|Illustrator, Art Director
|Noriaki Tanimura
|Senior Copywriter
|Mai Kaneda
|Hideki Kanishi
|Account Director
|Shinichiro Oku
|Executive Creative Director
|Sean Riley
|Head of Client
|Manami Sakamura
|Production Manager
|Kyoichi Hara
|Production Manager
|Misa Shoyouiriki
|Production Manager
|Go Watanabe
|Production Manager
|Sayaka Nanamiya
|Film Producer
|Yasushi Ono
|Film Director
|Makoto Imamura
This 2018 Clio Health Shortlisted entry titled 'Washable Book' was entered for ANGFA by McCann Health Japan, Tokyo, part of agency network: McCann Worldgroup. The piece was submitted to the medium: Direct (Health & Wellness) within the entry type: Lifestyle and the category: Print/Mail. It consists of 1 video and 1 image.


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I'm new to qgis and I want to find the length of some roads in a map. So I used the following code,
from shapely.wkb import loads
def getLength():
layer = qgis.utils.iface.mapCanvas().currentLayer()
total = 0
for feature in layer.selectedFeatures():
geom = feature.geometry()
wkb = geom.asWkb()
line = loads(wkb)
total = total + line.length
return total
print getLength()
It shows the length in degrees I think. Is there any way to convert the result I got to meters, without changing the CRS of project. I want to do it programatically(without adding new field using field calculator).


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Set Up A Property Management Notification Solution
Sign Up For A Free Trial Today!Request Information
Part of owning property is knowing that an emergency can arise at any moment. As a landlord or HOA leader you have the responsibility of alerting your tenants and communities as quickly as possible, no matter what time of day or night.
To ensure that you can meet that responsibility, you need to have a mass notification system like DialMyCalls in place.
Maximize your ability to protect your tenants and minimize property damage by having plans in place for any property emergency scenario. This should include fires, flooding, gas leaks, and natural issues relevant to your area such as hurricanes, earthquakes and tornadoes.
Sign Up For A Free Trial Today!Request Information
There should not just be a clear evacuation plan in place, but a way to communicate with tenants and residents when they should remain indoors.
Here's a step by step to putting mass SMS and call broadcasting to good use in a property emergency.
With a solid plan in place and clear means of communicating, you can avert any disaster that may strike your property. Know that property emergencies are going to arise, and be proactive to ensure that all of your residents are taken care of.
Below are just a few of the groups that are using us to keep everyone informed.


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Legislative Committee
The Legislative Committee works in tandem with the Legislative Advocate to establish, monitor and advocate legislative issues on behalf of CAJPA and its members. The Legislative Committee keeps CAJPA members apprised of key bills and regulatory issues, and mobilizes support as needed. To ensure that all issues with potential to impact CAJPA members are reviewed, the committee is divided into subcommittees based on subject areas of interest: health care, joint powers authorities, loss control, tort liability and workers' compensation. The committee is comprised of 15 volunteer members who are subject matter experts in their respective areas. The Legislative Committee meets five times per year and is responsible for:
- Reviewing pertinent legislation and regulations and taking appropriate positions
- Prioritizing and directing CAJPA resources toward lobbying efforts
- Meeting with legislators and their staff to advocate for CAJPA and its members
- Working with government agencies on regulatory matters of importance to CAJPA
- Reviewing ideas for CAJPA-sponsored legislation and making recommendations to the Board
- Keeping the Board and membership informed on important legislative and regulatory issues
- Working with other employer and public sector groups as part of a coalition
Legislative Committee
If you need contact information, please login
- Norman Lefmann, Chair, California Joint Powers Insurance Authority (CJPIA)
- Jackie Miller, Vice Chair, Bickmore
- Rose Burcina, Redwood Empire Schools Insurance Group (RESIG)
- Robin Flint, ACWA JPIA
- Robert Greenfield, ACWA JPIA
- Lois Gormley, Schools Excess Liability Fund (SELF)
- Robin Johnson, Law Office of Robin Johnson
- Beth Lyons, Risk Pool Administrators
- Jeanette Mason, Athens Administrators
- David McGhee, BETA Healthcare Group
- Terrie Norris, York Risk
- Brooks Rice, Shasta-Trinity SIG
- Jeff Rush, California JPIA
- Debra Russell, Schools Insurance Authority
- Dan Sanger, Alliance of Schools for Cooperative Insurance Programs (ASCIP)
- Craig Schweikhard, SMCSIG
- Janet Selby, NBSIA
- John Stenerson, Self-Insured Schools of California (SISC)
- Cindy Wilkerson, Schools Insurance Group
- Faith Lane
If you're interested in CAJPA's legislative activities or joining the CAJPA Legislative Committee, please contact the Committee Chair Norman Lefmann.


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Inside this kit you will find everything you need to train your Small Group Leaders in your church, your way and with your style! Each Leader Training 1 and 2 resource includes:
• Audio File
• Instructor Guide
• Student Guide
• Powerpoint
• Transcripts File
Plus, included in this kit are the Spiritual Health Assessment and Spiritual Health Planner used in previous leadership training courses. These electronic files will help you tailor fit our Leadership Development Pathway to your Small Group System.
To add to shopping basket, enter quantity required:
Please note: Our web based order facility is available for UK and Eire
customers only.
Please call the PDM UK office on (+44) 208 8570 3351 for orders from outside of
the UK or Eire. Thank you.


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Only 2 Remaining
All furniture deliveries will go via our White Glove Delivery service:
While we want you to love every piece as much as we do, we understand that sometimes things just aren't quite right. As such, we're happy to offer you 30 days to make up your mind. Click here to find out more.
The foundation of Sue's design was the walls which were painted to create a plastered effect, adding texture and depth as well as making the rooms feel cooler during the scorching Californian summers.
Round Callanish Dining Table - Dry Pebble Gray
Callanish Dining Table - Brown
Round Callanish Dining Table - Brown
Product has low stock and therefore we were only able to add to your Cart.


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In this series, we'll be hiking the burger trail to find the latest, greatest and most delicious burgers in Milwaukee. Click here for an explanation of the criteria used to rate each burger. Where have we been? Check out the complete catalog of burger reviews here.
Lagniappe Brasserie
17001 W. Greenfield Ave., New Berlin
(262) 782-7530
Looking for cozy? You can't get much cozier than Lagniappe Brasserie, a former residence-turned-restaurant that retains that possesses gallons of homey, welcoming charm.
The menu, which changes daily, is a seasonal feast of French inspired fare, often served up with a global twist. Dishes are moderately priced, and you'll find a good number of French staples, like escargot, fricassee and frangipane tart for dessert.
It's a brasserie. So it's the sort of place where steak frites might be common; but it's not necessarily the sort of place you'd expect to find a burger. And yet, there it is on the lunch menu, listed under "Fine Dining Sandwiches."
The Kobe Burger is comprised of a half-pound Australian wagyu patty with a choice of Hook's Maahentery Jack or cheddar; 13-year aged cheddar is also available for an additional $2 (I went with that). The burger is served with a choice of sides: Italian pasta salad, cottage cheese or gaufrette chips ($12).
Note: The Kobe burger is only available on the lunch menu, which is served Tuesday through Friday from 11:30 a.m. to 2 p.m.
Presentation: 8
There's not a ton of pomp and circumstance surrounding this burger. In fact, it's as simple as can be, served with its majestic patty front and center and its accompanying bun in sort of a hat-tip of sorts, almost as if it's paying homage to the beef, the true star of the show.
Bread/bun: 10
The burger is served on a housemade petit pain au lait topped with black sesame seeds. It's a lovely little milk bun with a soft dense interior that's not quite as sweet as brioche, but very tender. It's exterior is nicely crisp, as are the cut sides of the bun, which came nicely toasted. The burger was juicy, but the bun was up to the task, soaking up the juices from the burger patty with ease.
Burger: 10
The half-pound burger patty is thick and well shaped. It's almost too perfect in its shape. But, based on the attention to detail granted to other dishes at Lagniappe, I'm suspecting it's been hand-pattied with the help of a mold, giving it a uniform shape and thickness. The patty is chargrilled to order; in my case, it came to the table a perfect mid-rare. The meat was very well seasoned and plenty juicy with a meaty texture that offered just the right amount of resistance when bitten.
Toppings: 8
This is the sort of burger that doesn't need much in the way of embellishments to shine. But the 13-year cheddar – with its salty tang – offered an intense flavor boost that you'd be unlikely to get from another type of cheese. It was beautifully melted and coated the whole of the burger, so each bite was augmented with its flavor. The burger was also accompanied a small mound of fresh spring mix, sliced red onion and a skewer of cherry tomatoes and cornichons, all of which one might choose to add to the burger, though in my estimation they weren't needed.
Value: 9
The menu calls the kobe burger a "fine dining sandwich" … and the moniker isn't inappropriate. That's thanks to the little details from the fine housemade roll, to the ultra-beefy patty and the exceptional aged cheese. Based on the quality alone, it's a $14 burger worth eating.
Total: 45/50
The burger at Lagniappe is deceptively simple, but quite wonderful.
Lagniappe Brasserie is open for lunch Tuesday through Friday from 11:30 a.m. to 2 p.m. and for dinner Tuesday through Saturday from 5 to 9 p.m.
Lori Fredrich (Lo) is an eater, writer, wonderer, bon vivante, traveler, cook, gardener and girlwonder. Born and raised in the Milwaukee area, she has tried to leave many times, but seems to be drawn to this quirky city that smells of beer and alewives.
Some might say that she is a little obsessed with food. Lo would say she is A LOT obsessed with food. After all, she has been cooking, eating and enjoying food for decades and has no plans to retire anytime soon.
Lo's recipes and writing have been featured in a variety of publications including GO: Airtran Inflight Magazine, Cheese Connoisseur, Cooking Light, Edible Milwaukee, Milwaukee Magazine and the Milwaukee Journal Sentinel, as well as on the blog Go Bold with Butter, the web site Wisconsin Cheese Talk, and in the quarterly online magazine Grate. Pair. Share.