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The invention relates to the treatment of kintoplastid infections by administering a pharmaceutical composition containing an extract from the plant Artemisia annua. The invention also relates to isolated, semi-synthetic and synthetic artemisinins that show improved efficacy in treating kinetoplastid infections. This invention also relates to a method of treating kintoplastid infections with artelinic acid and artemisinins and where Artelinic acid is administered orally.
1. A method of treating kinetoplastid infections in a mammal comprising: orally administering synthetic artelinic acid to said mammal until said kinetoplastid infection is reduced or cured.
2. A method of treating a kinetoplastid infection in a mammal, comprising orally administering an effective amount of a pharmaceutical dosage form of artelinic acid to said mammal.
3. The method of
4. The method of
5. The method of
6. The method of
The invention described herein may be manufactured, used and licensed by or for the U.S. Government.
1. Field of the Invention
This invention relates to methods of treating and managing kinetoplastid infections by administering artemisimins and artelinic acid.
2. Brief Description of Related Art
Trypanosomiasis is a re-emerging [1-3] tropical infectious disease that poses a real challenge to public health countermeasures. According to the World Health Organization (WHO) [4], about 36 sub-Saharan countries in West, Central, and East Africa and some 22 Latin countries in Central and South America delimit its geographic prevalence zone, thus, leading to the establishment of two distinct manifestations of the disease: African trypanosomiasis and American trypanosomiasis.
Trypanosoma species pathogenic to human beings and domestic animals in Africa, cause one of the world's most neglected tropical infections�African trypanosomiasis [3]. Nearly eliminated in the 1960s, African trypanosomiasis has been making an alarming comeback due to civil wars, population displacements, and the collapse of public health systems mainly due to political instability (www.accessmed-msf.org/documents/ssfactsheet.pdf) [1]. Human African trypanosomiasis (HAT) threatens 60 million [1,3-6] men, women, and children among, principally, the rural populations, but actually even the citadin populations, in countries of high endemicity such as Angola, southern Sudan, the Democratic Republic of Congo, and northern Uganda. The incidence rate in HAT is estimated between 300,000-500,000 cases annually [3-6] and only 3 to 4 million people at risk are under regular medical surveillance (http://www.who.int/inf-fs/en/fact259.htlm). In animal African trypanosomiasis (AAT), the infection threatens about 50 million head of cattle with an estimation of 3 million deaths per year in livestock (http://www.fao.org/ag/againfo/programmes/en/paat/disease.htlm).
American trypanosomiasis (�Chagas disease�) occurs mainly in countries such as Brazil, Chile, Mexico, Uruguay, Paraguay, Bolivia, and Argentina [10, 11]. Over 13 million persons in the Southern American region are at risk of infection and the annual incidence rates of the disease reaches 200,000 cases in 15 endemic countries [10]. The bloodstream protozoan Trypanosoma cruzi [10-12] is the etiologic agent of Chagas disease.
Host-to-host transmission is mediated by blood-sucking triatomine bugs such as Triatoma infestans [11]. Moreover, blood transfusion and congenital transmission have been encountered, particularly, in humans [10]. These pathogens are all cyclically transmitted to mammalian hosts through the bite of haematophagus tsetse flies (Glossina morsitans, Glossina palpalis) [9] serving as vectors of the disease.
The consistent decimation of human populations and cattle by African trypanosomiasis has reached dramatic proportions and represents a social and economical obstacle for development [6,7]. In AAT, breeding animal losses are estimated to cost African farmers US$4.5 billion per year [8]. Bloodstream flagellated protozoan, members of the taxonomic genus Trypanosoma, are incriminated as the causative agents [1-7]. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense provoke human African trypanosomiasis (�sleeping sickness�) while Trypanosoma congolense, Trypanosoma simiae, Trypanosoma vivax and Trypanosoma brucei brucei cause animal African trypanosomiasis (�nagana�) [http://www.vet.uga.edu/vpp/gray_book/FAD/AAT.htm].
In the particular case of human African trypanosomiasis, the trypanosomes multiply in the blood and lymph glands of the infected persons, therefore, defining the first-stage of sleeping sickness [5,13]. The symptoms in this early stage are characterized by bouts of fever, headaches, skin itching, pain in the joints, gradual loss of weight, nausea and vomiting [6,9]. Later, in the second stage, the trypanosomes cross the blood-brain barrier and invade the central nervous system to cause sleeping sickness. Sleeping sickness is characterized by neurological disorders such as mental confusion, sensory disturbances and poor muscular coordination, and reversal of the circadian sleep/wake cycle (insomnia in the night, drowsiness in the daytime) [5,9,13,14] hence, the nickname �sleeping sickness�. In the absence of effective treatment, sleeping sickness invariably leads to death [3,6].
Control measures for African trypanosomiasis are directed either against the transmission vector through eradication of the tsetse fly, or against the causative pathogen, trypanosomes. Although vector control strategies had been effective in the past, they have been virtually abandoned because of their harmful effects on the environment [7]. Treatment of infected persons with the few available synthetic trypanocidal agents have shown significant drawbacks [15-17] related to high cost, host toxicity, limited oral bioavailability, and a requirement for hospitalization during the entire course of treatment. The emergence of drug resistance has also limited the choice and effectiveness of affordable agents in clinical use. Moreover, the type of treatment depends on the stage of the disease: hemolymphatic (first stage) or cerebral (second stage). Effectiveness in the second stage relies on the ability of the drug to cross the blood-brain barrier and reach concentrations high enough to kill the infective trypanosome. The four trypanocidal drugs, shown below [5,6,13] that have been clinically used up-to-date against sleeping sickness are, in chronological order�: Suramin (developed in 1921 against T. b. rhodesiense in the first-stage infection), Pentamidine (discovered in 1941 against first-stage T. b. gambiense infection), Melarsoprol (developed in 1949 against both human-infective Trypanosoma subspecies in cerebral infection), and Difluoromethyl ornithine (developed in 1981 as an alternative to Melarsoprol treatment failure in cerebral sleeping sickness).
In the absence of prospective vaccine candidates for the disease, the limitations and drawbacks of these drugs emphasize the crucial need to develop new safe, effective and affordable drugs (trypanocides) against all forms of human and veterinary trypanosomiasis.
The Chinese plant Artemesia annua has been used to treat malaria for centuries. Research in the past three decades have uncovered artemisinin derivatives like artemisinin, dihydroartemisinin, artemether, artesunate that have played a critical role in the management of infectios caused by the multi-drug resistant malaria parasite, Plasmodium falciparum. Artemisinin has also been reported to be selectively active against cancer cells in vitro [39]. Utzinger et al. have demonstrated the use of artemisinin derivatives against tropical parasite species Schistosoma, responsible for schistosomiasis [40]. The effect of artemisinin and its derivatives on Leishmania major, another tropical parasite provoking leishmaniasis has also been reported [41]. However, the widespread use of this class of semi-synthetic artemisinin derivatives have been limited by the high cost of production, low bioavailability and long treatment regimens.
African, Asian and Amerindian societies have a rich tradition [17] in the use of plants for medical care. However, only few reports exist on the phytochemical treatment of sleeping sickness [17] and other kinetoplastid infections. Artemisinins have never before been used to treat human and veterinary trypanosomiasis. Until now, no experimental study has been carried out to establish the effectiveness of artemisinin or its derivatives on any Trypanosoma species.
The inventors are the first report on the trypanocidal potency of artemisinin and by extension, artemisinin-derived compounds, including artelinic acid.
Therefore, an object of the invention is to prepare a pharmaceutical composition containing artemisinin lead compounds from natural resources for the treatment of trypanosomiasis. Medicinal plants such as Artemesia annua have secondary metabolites of diverse molecular structures, physico-chemical properties, and pharmacological activities and offer an invaluable reservoir for new remedies.
Another object of the invention is to provide a cost effective treatment for kinetoplastid infections.
Another object of the present invention is to provide a method of treating humans and other mammals with kinetoplastid infections with artemisimin compounds such as artemisinin and artelinic acid.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
The invention relates to the treatment of kintoplastid infections by administering a pharmaceutical composition containing an extract from the plant Artemisia annua. The invention also relates to synthetic artemisinins that show improved efficacy in treating kinetoplastid infections. This invention also relates to a method of treating kintoplastid infections with artelinic acid and artemisinins.
The accompanying drawings show illustrative embodiments of the invention from which these and other of the objectives, novel features and advantages will be readily apparent.
The present invention relates to treatment of kinetoplasmid infections such as Leishmaniasis and Trypanosomaisis with artemisinins such as artelinic acid and/or trioxolane compounds.
The antimalarial activity of the artemisinins is believed to reside in the generation of toxic free oxygen radicals subsequent to the interaction with heme released from the metabolism of hemoglobin. The inventors have found that artemisinins and synthetic artemisinins, in particular, artelinic acid and trioxolane compounds, are effective in a method of treatment of kinetoplasmid infections, particularly against Leishmania and Trypanosoma.
The structural identity, and biological activity of compounds extracted from the medicinal plant Artemesia annua �Plant C-1 � was established. For these experiments, chromatographic techniques were used for total purification of the active principles. Various spectroscopic methods and conventional database analysis were also utilized for chemical structure elucidation. The identified candidates were subjected to standard bioassay protocols for in vitro characterization of their trypanocidal activity and also selective toxicity against trypanosomes versus mammalian host cells.
The extract of the plant Artemesia annua was shown to kill Leishmania parasited cultivated within mouse macrophages in vitro in a dose-dependant manner without significant toxicity to the mouse macrophages. The results were duplictated using commercially sourced artemisinin. The active compound in the compound was isolated and purified and chemically identified as artemisinin.
Materials and Methods
a. Plant Material
Artemesia annua can be obtained in countries where it is cultivated such as its native China and Kenya. Freshly cut leaves of Artemesia annua were collected in Kenya, sun-dried and then ground into powder that can be stored in a refrigerator prior to extraction.
In the case of artemisinin, the compound was extracted from Artemisia annua with 70% aqueous EtOH at room temperature for 48 h (first extraction) and then 24 h each for the second and third extraction. The extracts were combined and concentrated under reduced pressure to obtain the EtOH extract. The EtOH extracts were purified by organic solvent fractionation and a combination of chromatographic procedures such as ion exchange on a DIAION HP-20 column and hydrophobic interaction on an ODS column and gel filtration on a Sephadex column. The active fractions were then identified. The following experiment confirms that the compounds that were extracted are efficacious against kinetoplastid infection and are artemisinins.
b. General Experimental Procedures: (Plant C-1)
1H-NMR (500 MHz) spectra were measured on JEOL Lambda 500 spectrometer in CHCl3-d1 as well as MeOH-d4 with TMS as an internal standard. 13C-NMR (600 MHz) and 2D-NMR (600 MHz) data were recorded on Varian Inova 600 in CHCl3-d1. Fast-atom bombardment (FAB) and high-resolution fast-atom bombardment (HR-FAB) mass spectra were recorded in positive ion mode JMS SX-102 spectrometer. For column chromatography, silica gel (Fuji Sylisia BW-200, Merck), ODS (Cosmosil 75C18 OPN, Nacalai) were used. Thin-layer chromatography (TLC) analyses were performed over normal phase pre-coated plates (Kiesel gel 60F254, Merck) and reversed-phase high-performance thin-layer chromatography (HPTLC) plates (RP-18 WF254S, Merck). Spots on chromatograms were detected under UV light (254 and 365 nm) and by spraying with phosphomolybdic acid (5 g, EtOH 100 mL), vaniline/H2SO4 (vaniline 5 g, conc. H2SO4 95 mL), and p-anisaldehyde/H2SO4 (AcOH 5 mL, conc. H2SO4 25 mL, EtOH 425 mL, p-anisaldehyde 25 mL) followed by heating. For high-performance liquid chromatography (HPLC), detection of analytes was carried out with a refractive index detector (Shodex RI-71). For in vitro trypanocidal assay, stock solutions of samples were prepared in DMSO (Wako, for biochemical assay) which concentration in culture medium never exceeded 1%. Pentamidine (Sigma) was used as a positive control. For cytotoxic evaluation in vitro, mitomycin C was used as the positive control.
c. Trypanosome Stocks
Culture suspension of Trypanosoma brucei brucei (T. b. brucei) was obtained from Research Institute for Microbial Diseases (Osaka University, Japan). Trypanosomes were subcultured in appropriate medium (see 5.1.2) as frequently as needed to avoid overgrowth, and maintained in culture flasks at 37� C. in a humidified, 5% CO2 atmosphere incubator. In addition, parasite culture stabilates were prepared by suspending trypanosomes centrifugation (1500 rpm, room temperature, 3 min) pellet in 1 mL of a mixture of 77% (v/v) trypanosome dilution buffer [56] and 33% (v/v) glycerol. The whole volume was transferred into cryotubes and stored at −80� C. until further needed.
d. Culture Medium for Trypanosoma brucei brucei
The axenic cultivation of the bloodstream forms of T. b. brucei was performed in Iscove's Modified Dulbecco's Medium (Gibco) supplemented with L-glutamine and 25 mM HEPES buffer. Additionally, 15% heat-inactivated (56� C., 40 min) fetal bovine serum (FBS, MultiSer) and also 0.05 mM bathocuproine disulfonic acid disodium salt (Dojin), 1.5 mM L-cystein (Nacalai), 1.0 mM hypoxanthine (Nacalai), 0.16 mM thymidine (TCI), 0.2 mM 2-mercaptoethanol (Sigma), and 1.0 mM sodium pyruvate (Nacalai) were aseptically incorporated in the culture medium.
e. Trypanocidal Assay
All fractions obtained stepwise in the course of the separation process of the plant crude extracts were assessed for their in vitro activity against T. b. brucei. Various concentrations of test samples were prepared in neat dimethyl sulfoxide (DMSO, Wako-for biochemical assay) then diluted in the culture medium so that DMSO content decreased to 10% in the medium. Trypanosomes were harvested at late exponential growth level, counted with a hemocytometer (Erma Tokyo 7059), and resuspended by appropriate dilution in culture medium for achieving a final density of 1�104 cells/mL. Aliquots of 90 μL of T. b. brucei suspension (1�104 cells/mL) were transferred in wells of a Becton Dickinson 96-well microculture plate. Then, 10 μL of each sample preparation containing 10% DMSO were added to each inoculum well, achieving a final concentration of 1% DMSO. The microculture plate was incubated in a humidified, 5% CO2 atmosphere incubator at 37� C. After successively 24, 48, and 72 hr-incubations, parasites viability was determined by observing directly inside the wells of the microculture plate with an optical microscope (Injectoscope model IMT-YF/Olympus). The in vitro trypanocidal potency of each sample was then evaluated and translated into mathematic symbols [(−): <80% growth inhibition level, (�): ≧80% growth inhibition level, (+): 100% growth inhibition level]. Control wells with the commercial drug pentamidine (positive control) and the solvent DMSO only (negative control) were also achieved in the same conditions as the test samples. A blank (parasites only in culture medium) was also included for reference.
f. Culture Medium for HeLa S3 Cells
An axenic culture of human carcinoma HeLa S3 cell line was established in Dulbecco's Modified Eagle's Medium (D-MEM, Sigma) supplemented with 4500 mg glucose/L, L-glutamine, NaHCO3, and pyridoxine HCl, to which 10% heat-inactivated (56� C., 40 min) fetal bovine serum (FBS, MultiSer) was added.
g. Sample Preparation for Cytotoxic Evaluation In Vitro
Plant chromatographic fractions, which have shown potent trypanocidal activity in vitro, were selected for cytotoxicity assay. Previously dissolved in neat DMSO (Wako-for biochemical assay), an aliquot of 10 μL of each test sample was diluted in 490 μL of the cell culture mediumwith the intent of decreasing the DMSO concentration to 2% in the medium.
h. Cytotoxicity Assay In Vitro
HeLa S3 cells maintained in culture dish (Sumilon) were washed with Dulbecco's phosphate saline buffer (−) [DPBS (−), Nissui Pharmaceutical Co., Ltd] after syphonating the culture medium. Adherent cells were released from their dish bottom substrate by adding trypsin (Nacalai) and gently tapping with hand on the round lateral side of the dish. Thus, trypsinized cells were harvested, suspended in culture medium then centrifuged at 800�1000 rpm for 3 min at room temperature. After removing the supernatant, the remaining pellet was resuspended in the culture medium. Cells were counted with a hemocytometer (Erma Tokyo 7059), and then diluted appropriately to achieve a final density of 1�105 cells/mL in the culture medium. Later on, cells were seeded in a 96-well microtiter plate (Becton Dickinson), each well containing 100 μL (1�105 cells/mL) of cell suspension. Then, 100 μL of test samples preparation (see 5.2.2) were added in triplicate for each concentration into respective wells, thus achieving a final concentration of 1% DMSO. Respective triplicate wells for the positive control (mitomycin C) and the negative control (1% DMSO only in culture medium) were also included. After 72 hr-incubation at 37� C. in a humidified, 5% CO2 atmosphere incubator (Sanyo), 25 μL of MTT [3-(4,5-dimethylthazol-2-yl)-2,5-diphenyl tetrazolium bromide] [57-59] reagent were added to each well including controls. The microtiter plate was returned in the same incubator for an additional 3 hr-exposure at 37� C. to allow the formazan [57-59] crystals to accumulate. Then, supernatants were syphonated from the wells and 200 μL of DMSO were added to solubilize the formazan crystals. After shaking (MS1 Minishaker IKA) for 3-5 min, the absorbance in each well was measured at 540 nm in a microtiter plate reader (ImmunoMini NJ-2300). The percentage of cytotoxicity (growth inhibition level) was calculated as (A-B)/A�100, where A is the mean optical density of negative control wells and B is the mean optical density of test sample wells.
i. Bioassay-guided Isolation of Active Constituents of Artemisinin
Dried and pulverized powder from �plant C-1� (2.3 kg) were extracted three times with 80% ethanol after 24-hr maceration (first time) and 3-hr maceration (second and third time) at room temperature. The liquid extracts were combined, filtered, and concentrated under reduced pressure with a rotary evaporator below 30� C. The ethanolic residue (240 g) obtained exhibited a complete inhibition of trypanosomes growth at 30 μg/mL after 24-hr exposure and 100% growth inhibition in vitro against T. b. brucei at 100 μg/mL after 24-hr exposure. This residue was later on dissolved in double-distilled water, then subjected to solvent-solvent partition in EtOAc and n-BuOH to yield, after solvent evaporation, 72 g of EtOAc extract, 74 g of n-BuOH extract, and 94 g of H2O extract. The strongest trypanocidal activity in vitro was observed in the EtOAc extract exhibiting 100% and ≧80% growth inhibition against T. b. brucei, respectively, at the concentrations of 50 μg/mL and 5 μg/mL after 24 hr-exposure. This most potent EtOAc residue was applied to SiO2 gel column and eluted successively with binary solvent mixtures of hexane: EtOAc=4:1→1:1→1:1.5→1:2→100% MeOH. The eluted fractions were monitored by normal phase TLC and similar fractions were pooled into five main fractions named A (280 mg), B (341 mg), C (1.72 g), D (1.84 g), and E (690 mg). Among them, fraction C was the only one that showed trypanocidal activity until the low concentration value of 1 μg/mL, thus featuring ≧80% growth inhibition after 24-hr incubation. Further separation of fraction C carried out by reversed-phase ODS column chromatography and eluting gradually with 60% MeOH→80% MeOH→90% MeOH→100% MeOH yielded seven fractions named from C-1 to C-7. Fractions C-4 (629 mg), C-5 (16 mg), and C-6 (139 mg) showed the highest biological potency and an encouraging selectivity toward HeLa cell in vitro at 0.5 μg/mL with, respectively, 100% trypanocidal level and 5.5% cytotoxic level for C-4, ≧80% trypanocidal level and 10.5% cytotoxic level for C-5, and ≧80% trypanocidal level and 14.9% cytotoxic level for C-6.
Firstly, C-4 was subjected to final purification with HPLC (column: 5 SL-II type Waters, 10�250 mm i.d.; flow rate: 3.0 mL/min; detection: refractive index detector at range 512; eluent: hexane/EtOAC=8/1) leading to isolation of C-46 (7.1 mg) at a tR of 21.27 min (
j. Chemical Structure of C-46
Comparison of 1H- and 13C-NMR, 1H-1H COSY, HMBC, FAB-MS, and specific rotation data in our hands with those reported in the literature [34,35] led to conclusion that C-46 was (+)-artemisinin (
1H-NMR spectrum analysis for structure elucidation of C-46 indicated the presence of doublet peaks, respectively, at δ1.19 (3H, d, J=7.4 Hz) and δ0.98 (3H, d, J=6.0 Hz), and a singlet peak at δ1.43 (3H, s). This set of peaks was indicative of the three methyl groups at C-13, C-14, and C-15, respectively. The signal observed at δ5.84 was assignable to H-5, which corresponding carbon signal was displayed at δ93.9 on the 13C-NMR spectrum. The signal that appeared at δ172.2 was assignable to the carbonyl moiety of the lactone group at C-12. The signal that appeared at δ105.6 was due to the quartenary carbon C-4 activated by two geminal oxygen atoms. The peak observed at δ79.7 was due to the quartenary carbon C-6 connected to an oxygen atom. In addition, the positive ion mode FAB-MS displayed [M+Li]+ at m/z 289 (65%), [M+Na]+ at m/z 305 (100%), and [M+H]+ at m/z 283 (12%). Additionally, the optical rotation parameter revealed [α]D 24=+41.5 (c=0.2, CHCl3). Comparison between spectral data in our hands with those in the literature database led to conclusion that C-46 corresponded to (+)-artemisinin (C15H22O5, Mw=282).
k. Chemical Structure of C-53
Relevant 1H� and 13C-NMR, 1H-1H COSY, HMQC, HMBC, NOESY, FAB-MS, and HRFAB-MS data were recorded; the specific rotation value was calculated.
C-53 has trypanocidal potency in vitro but is slightly weaker than that of (+)-artemisinin. Nevertheless, from its chemical characterization, 1 D- and 2D-NMR, FAB- and HRFAB-MS, and specific rotation data that have been collected, spectral data analysis reveals that C-53 might be polyalicyclic; containing three characteristic methyl substituents and an unsaturated lactone ring; displaying a molecular weight of 234 associated to the chemical formula C15H22O2. Accordingly, C-53 is presumed to be a sesquiterpene lactone congenere of artemisinin, but obviously lacking the endoperoxide bridge. This activity is of more general interest because the mechanism of action of artemisinins, as an anti-plasmodial or anti-tumoricidal agent, is believed by some to be related to the presence of the endoperoxide bridge.
The information obtained by careful examination of C-53 and C46 as well as other eluted compounds in the above experiment verify that artemisinins are active ingredients in artemeseia annua that hinder the growth of kintoplastid infections.
Both compounds Artemisinin and Artelinic acid belong to the same class of compounds and both have been found by the inventors in testing to be effective against leishmaniasis and other kinteplastid infections.
Preliminary drug screening (in vitro amastigote/macrophage culture) of artemisinin and artelinic acid compounds.
Four compounds were obtained.
The four compounds were dissolved in the respective solvents as indicated in the table below (Table 1) and were tested against Leishmania major ATCC 50122 amastigotes in vitro in a mouse macrophage system. A positive (Pentostam) and negative (culture medium) controls were set for each plate. Compounds were tested at 2.0 μM in a total volume of 2-0 mls. Drug was added to well every 4 hours�1, 2 and 3, and results shown in (Table 2) below.
The results of the initial screen showed that Artelinic acid at 2 uM cleared all of the amastigates in macrophages. Observer also noted pinkish staining of the cytoplasm of the macrophages that was interpreted as cell toxicity. However, similar changes were also noted in the negative control that had no compound added. The effectiveness of the WRAIR compounds tested in the screen was judged to be:
Because of the high potency of Artelinic acid relative to the other compounds, the experiments were repeated with different doses of Artelinic acid alone. Additionally, the addition of drug to culture wells q4h did not seem to affect the results for this compound (Table 2). Hence, Artelinic acid was added once in the dose response experiments (Table 3).
The initial observation implicating Artemisinins was obtained with crude extracts from the plant (Artemesia annua. On the strength of these results Artemisinin-derived compounds that had been synthesized previously as potential anti-malarials were secured from the WRAIR inventory and tested (See U.S. Pat. No. 4,791,135, incorporated in its entirety by reference for the preparation of synthetic artemisinins, dihydroartemisinins, and artesunic acid.). The active principle in the plant extract was prepared into pharmaceutical compositions suitable for treating kinetoplastid infections.
Pharmaceutical compositions containing the active ingredients from the plant artemesia annua, including artemisinins and artelinic acid can be prepared using any known pharmaceutical carrier suitable for i.p. injection including but not limited to saline. Carriers for oral administration can be capsules or pills made by any known and accepted pharmaceutical composition used for carrying active ingredients to the digestive tract. Acceptable doses for oral administration are 4-8 ul/kg for i.p or oral administration. Concentrations for in vitro testing are 0.01 to 2.0 uM
Effects of Different Concentrations of Artelinic Acid (Dose Response) on Leishmania Amastigotes.
As shown in the results above (Table 3), killing of intracellular amastigotes was noted at concentrations as low as 0.1 μM of Artelinic acid and clearance was complete at doses as low as 0.25 μM of compound.
Because of the marked potency of Artelinic acid in the clearance of intracellular Leishmania amastigotes, an in vivo screen was undertaken using BALB/C mice. One foot pad was infected with infective Leishmania promastigotes while the other foot served as control. After the infected foot pads had developed lesions, mice with similar size lesions were selected and treated daily with test article for one week. The first doses were administered on 18 May. Lesions were measured with calipers prior to dosing and 9 days after commencement of treatment (27 May) and the difference in lesion size calculated. The thickness of the uninfected footpad was also measured. Only Artelinic acid and the crude methanol extract of the plant Artemesia annua, that had shown marked potency in the mouse macrophage/amastigote in vitro screen were tested in vivo. Test articles were administered orally and intra-peritoneally (ip).
Results (Table 4) show that Artelinic acid and plant extract of Artemesia annua, containing artemisinins, either given orally or ip to BALB/c mice for one week led to a decrease in the size of Leishmania major lesions induced in the footpad of the animals. Both Artelinic acid and plant extract were much more effective than Pentostam, the positive control, at the doses and route of administration tested.
The in vivo experiments, are remarkable in that Artelinic acid and the active ingredient in the plant extract, artemisinins, show potency against Leishmania when administered orally. Moreover the in vitro experiments demonstrate that these compounds do not require to be metabolized into an active moiety by the liver for them to show potency against intracellular Leishmania amastigotes.
The invention has been described herein with reference to certain preferred embodiments. However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto.
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New Delhi: State Bank of India today said it
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What do I have?
jodikayAugust 8, 2011
What a gorgeous butterfly, just hanging out on the butterfly weed. I don't care for the color orange but its definately worth having in my native garden! No accounting for color choice - LOL!
Check out the other one. What a pig! Also on the butterfly weed.
Sorry for the pictures. I was so excited I wasn't paying attention to what I was doing with my camera.
Thanks for the help,


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New York Breweries Open For Business Thanks to Kickstarter Campaigns
Kickstarter, the crowd-sourcing fundraising site, shared on its blog all the restaurants, breweries and distilleries that have been opened thanks to using Kickstarter to fund their operations. There are two New York breweries who went this route.
Toast A Green Beer On St. Patrick's Day [VIDEO]
Some of us may be interested in hoisting a green beer on St. Patrick's Day. There's no real mystery here how to make your own, but I do recall that when I worked as a tour Guide at the F.X. Matt Brewing Company, they refused to inject kegs of draft beer with green food coloring, and I respect that. So, if you want to make one of your own, watch this video.
Saranac at 'Utica on Tap' March 22nd
Utica's largest craft beer festival is just around the corner! Join us for the 1st Annual Utica on Tap on Saturday, March 22 at The Stanley. Enjoy unlimited sampling of over 60 beers from a variety of the country's best craft breweries, including Saranac from FX Matt Brewery.


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soda cards?
Does Princess have soda cards? And if so can you get juices and sports drinks such as powarade or gatorade with these cards?
you get COKE from the bar, not in a can
$49 and you can share one card as they don't seem to notice who has it.
You can set any tape type drink they have, like soda water, n canned anything
Princess do have the cards they only cover Diet/coke,lemonade,sodawater,dry ginger. Nothing more. But did prove to be good value to me.
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I am no expert at eye liner so I'm constantly trying new ones. My lines are always crooked or come out awful! This is the first eyeliner that I really enjoy. It is perfect for amateurs such as myself especially since it really does always stay sharp!
My one complaint and only reason I gave it one star less is cuz I've had it easily break off, even after just a couple issues. Then it's kind of annoying to attempt to get it full and sharp again.
I was very skeptical about ordering this waterproof mechanical pencil eyeliner. I was really banking on it being super waterproof. When it arrived, I actually tested it out on the day I ran the Warrior Dash. It held up to sweat, mud, and dirty water. I was really impressed. Perfect for every day wear. It is now my go-to liner for any occasion. Nothing else comes close. Love it!!!4


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Chevron Infinity Scarf: Free Pattern and Tutorial
This 15-Year-Old Babysitter Is Making $500,000 a Year
COACH OVERSTOCK CLEARANCE: New Coach Bags for $99 & Falling!
Why You Should Never Wash Your Jeans
THe Non-Diet Secret to Losing Weight for Good
6 Edgy Pieces to Instantly Update Your Style
5 Real Ways To Look Younger Overnight
10 Things to Never Buy at Target
Bloated? 6 Foods to Shrink Your Belly
5 Rules That Helped Me Become A Millionaire By 40
4 Easy, Unusual Ways to Make Extra Money
10 Engagement Photos That Will Make You Completely Jealous
18 of the Ugliest Leggings We Can't Believe People Actually Buy
The Hottest Spring Fashion Trends to Buy Now
6 Things You Should Know About Your Bra
8 Lesbian Chic Looks Every Girl Can Wear
5 Spring Styles You'll Love From Rihanna, Zendaya & More
How to Wear Spring 2015's Hottest Colors
8 Natural Weight Loss Supplements
How To Maintain Style Without Packing Your Whole Closet
Money-Saving Travel Hacks
Never Buy This Kind of Storageware Again
The Truth About Bamboo Clothing
9 Best Snacks For Weight Loss
Vacuum Seal These Items to Save
The Anti-Inflammatory Diet to Protect You From "Inflamaging"
Heart-Lovin' Hot Cocoa
1 Fruit That "Fights" Diabetes
How to Walk in Heels!
8 Ways to Game a Life Insurance Exam and Get a Better Rate


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Linda's Lake Powell Condos
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Antelope Canyon, Horseshoe Bend, Bucktank Draw
... Just as we were about to give up, turned around and back to our car, we spotted the "metal gate" leading to the wash. Hiked in the dry wash for 2+ miles, trying to find the "Birthday Arch" in Bucktank Draw trail, w/o success. We turned around and hiked back to our car before it's too dark.
Really would love to hike the short 1.5 miles round trip to "Toadstool", but will have to pass as the daylight is ...
Lottery Day
... see all these strange twisted rock formations. Really beautiful! It's worth the money. But don't be disappointed that the colours of the rocks you know from photos are not the same than in reality. For human eyes the rocks are just beige but your camera will take a colourful picture if you just change some simple settings. The Horseshoe Bend is located just outside of Page and it's a rock which (you guessed it) looks like a ...
Day 20 Flagstaff To Page
... years and left 500 foot mountains. Every cowboy and indian film ever made was filmed here. Also the mountain in "Close Encounters of the Third kind" and the "Eiger Sanction" were filmed here. By the way we, went into Utah today for 2 hours. We were going to stoop at Las Vegas tonight but we would have to drive for another 2 hours so we stopped at a place called Page ...
Whirls and Spirals
... Ember in air conditioned comfort. The tour guide was a native Navajo and was knowledgeable. Over time names have been given to various whirls and spirals. Too bad I couldn't always see the image and my pictures didn't find most of them either. So I just snapped away at the various walls and ceilings. For a brief period of time, when the sun is overhead shafts of sunlight filter down into the canyon. This ...
Natural Monuments - Monument Valley
... was it did not begin for another three hours. We managed to kill the three hours in the middle of nowhere.
The tour was in an open truck with bus like seats. The driver/guide was a Navajo woman who seemed quite knowledgeable. She pointed out the various buttes and monuments by name and I hope I have remembered them accurately.
On a side note, the Gouldings established a trading post on the reservation after WWI helping ...


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Since the move to CBSI, the GB crew has sat on the worst of chairs. Scrounging for furniture in the office and sitting uncomfortably, unbeknownst to them, making life hell for themselves.
I mean.. I know that the furniture stayed at the Whiskey Media Office, but COME ON. It pains me to see how uncomfortable they are on their current furniture. I say we help. I say... We get Ryan and Jeff & the rest a rightful throne again. I say... We find couches just like the ones above.
I remember watching The Big Live Live Show Live and seeing everyones smiling face, around the couch, laughing it up. Any comfortable couch brings the comfort and relaxivity you need to have a conversation, be yourself, and let go. And according to my science and tape review, that couch brought a whopping 62 RPUC (i.e. the change in relaxation rate per unit concentration).... SCIENCE! Let's do something awesome everyone. Let's get our heads together and figure out how we can get two couches, exactly as pictured above, to the crew. They looked so uncomfortable when TNT's happened! These classy guys deserve better!
Thoughts? Concerns? Hurdles? Impossible? What say you?


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Jim Harbaugh
Who's Down For The Harbaugh Breakfast Challenge? [VIDEO]
Click the link to donate and send us your video via Twitter with #ChadTough and we will post your videos as well.
Justice Hayes Announces He Will Transfer From Michigan For Final Year
"I truly appreciate the offer from Coach Harbaugh to allow me to return for my 5th year," Hayes wrote.
Jim Harbaugh Uses Gatorade As A Replacement For Milk With His Cereal [VIDEO]
Jim Harbaugh is one heck of a football coach. He is also one heck of a character in my opinion.
Harbaugh Adds 2 More Assistant Coaches To Michigan Staff
The Wolverines said Friday that Jedd Fisch will coordinate the passing game and John Baxter will be the special teams coordinator.
Harbaugh Hitting Recruiting Trail Hard, Showing Up At Metro Detroit High Schools
In the in-state recruiting war, Michigan got immeasurably more competitive when it hired alumnus and former 49ers head coach Jim Harbaugh.
Michigan Hires Jackson As Secondary Coach
Greg Jackson has been hired as the secondary coach at Michigan.
Michigan's Harbaugh Should Consider QB Braxton Miller [BLOG]
After all, it's win, and win now, right?
Michigan Hires Drevno As Harbaugh's Offensive Coordinator
Drevno was the running game coordinator and offensive line coach at Southern California last season, and he has worked with Harbaugh extensively in the past.
Jim Harbaugh Is Rooting For Ohio State To Win National Title
Eisen also asked Harbaugh who he will be rooting for in the national championship game between Oregon and Ohio State on Monday.
Report: Michigan To Hire D.J. Durkin As Defensive Coordinator
New Michigan head coach Jim Harbaugh has reportedly added another assistant coach to the fold.


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DU heddiw
Turning very windy with rain spreading east later.
A bright start for many, although wintry showers will continue across the far north with sunny spells too. Cloud, rain and strong winds will then spread eastwards through the afternoon, with gales developing around coasts, locally severe in the west.
Mae'r cynnwys hwn ar gael yn Saesneg yn unig.


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If you watched Sesame Street back in the day, prepare for a trip down Memory Lane. The lead single off Dunson's forthcoming street album finds the Phatboiz (producer of John Legend's Tonight [Best You Ever Had]) flipping the Pointer Sisters' iconic Pinball Number Count theme music as the DMV rhymesayer counts off the many qualities that set him apart from the competition. Feeling it? Then keep it locked for further fresh leaks leading up to the release of Dunson's as yet unscheduled mixtape, The Investment.
Written by richard on 02/15/12
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text: POPSUGAR Food Beer Happy Hour: Black and Tan by partysugar 3/12/10 0 Shares Like us on Facebook Previous Photo 1 of 11 View on One Page ADVERTISEMENT ( more slides) Next Share This Link Copy 1 Happy Hour: Black and Tan Previous Photo 1 of 11 View on One Page ADVERTISEMENT ( more slides) Next Read More Beer CocktailBlack And TanSt Patricks DayHappy HourBeer Beer Guinness — It Really Is Good For You! The Easiest Hack For Making Green Beer Homemade Bread the Fast-Fix Way Top 10 Highest-Calorie Beers (and the 10 Lowest!) Get inspired with our daily newsletter Enjoy gorgeous decor ideas, fast and easy recipes, and more in your inbox. Food DIY Love & Sex Vegetarian Tech Home Sign up with Link Love A new study shows another health benefit of coffee — Grub Street 7 ways to use (and misuse) Cadbury eggs — FWx Spring pasta recipes to serve up all season long — HuffPost Taste Scrumptious breakfast casseroles for brunch and beyond — Southern Living 37 absurd kitchen gadgets you definitely need — BuzzFeed Food Why you should drink hot water with lemon every morning — POPSUGAR Fitness Latest Food


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Atb Financial, Branches, South West, Westhills Branch
Financial Services Calgary
Financial Services Calgary
Atb Financial, Branches, South West, Westhills Branch can be found at 601 Stewart Green Southwest . The following is offered: Financial Services. The entry is present with us since Nov 27, 2008 and was last updated on Feb 5, 2015. In Calgary there are 116 other Financial Services. An overview can be found here.Published by: Opendi
Financial Services


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Compete for the opportunity to represent the United States in international competition. Read Article
MaxPreps' football rankings have been updated.
San Tan Foothills' national rank has moved +14. View Rankings
Sports360AZ Read Full Article Report Link
The football coaches in the Tucson area got together and voted on an All-City team. This was the result of that vote Read more


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The company plans to list on Nasdaq under ANTE
Boost your income with these fixes
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Humana Inc. (
) will begin trading ex-dividend on March 27, 2014. A cash dividend
payment of $0.27 per share is scheduled to be paid on April 25,
2014. Shareholders who purchased HUM stock prior to the ex-dividend
date are eligible for the cash dividend payment. This marks the 4th
quarter that HUM has paid the same dividend.
The previous trading day's last sale of HUM was $114.2,
representing a -4.78% decrease from the 52 week high of $119.93 and
a 71.88% increase over the 52 week low of $66.44.
HUM is a part of the Health Care sector, which includes
companies such as UnitedHealth Group Incorporated (
) and WellPoint Inc. (
). HUM's current earnings per share, an indicator of a company's
profitability, is $7.7. Zacks Investment Research reports HUM's
forecasted earnings growth in 2014 as -10.4%, compared to an
industry average of 2.6%.
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Kelly Preston
Kelly Preston News Feeds
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NBC's Natalie Morales & Thomas Roberts to Host 63RD ANNUAL MISS UNIVERSE PAGEANT, 1/25 (Dec 16, 2014)
John Travolta, John Gotti Jr. and Kelly Preston at Travolta Promotes GOTTI Film in New York City
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New Musicals CAKE OFF and GIRLSTAR Will Premiere at Signature Theatre; Full 2015-16 Season Announced!New Video Of Cut INTO THE WOODS Song 'She'll Be Back' Performed By Traci HinesSTAGE TUBE: Tony Winner Sutton Foster on How Theatre Educators Impacted Her CareerSTAGE TUBE: First Look at Highlights of Denver Center's World Premiere of THE 12 - Terence Archie, Mike Backes, Anthony Fedorov & More!Twitter Watch: Lin-Manuel Miranda Raps for Jimmy Fallon's Outgoing Voicemail Message!BWW TV Exclusive: BREAKING DOWN THE RIFFS w/ Natalie Weiss- Back in the Habit!STAGE TUBE: Lea Salonga Sings 'I Dreamed a Dream' on SETH SPEAKS!VIDEO: Neil Patrick Harris Appears in Two New TV Spots for Heineken Light!VIDEO: Watch Sutton Foster and YOUNGER Cast Attempt 'Millenial Vocab Quiz'STAGE TUBE: Watch Highlights from La Mirada's CARRIE THE MUSICAL!STAGE TUBE: Meet the Boys of FINDING NEVERLAND!BWW TV Exclusive: Backstage with Richard Ridge- SAG Foundation Conversations Series with Stockard Channing!BWW TV: Go INTO THE WOODS to Celebrate Stephen Sondheim's 85th Birthday!STAGE TUBE: Lin-Manuel Miranda Gives Jonathan Groff a Belated Birthday Present
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NBC Sets THE WIZ as 2015 Live Musical; Broadway Revival in the Works!
Craig Zadan Offers Update On Next NBC Live Musical; Announcement Monday?
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The Aloha Quilt (Elm Creek Quilts #16)by Jennifer Chiaverini
Another season of Elm Creek Quilt Camp has come to a close, and Bonnie Markham faces a bleak and lonely winter ahead, with her quilt shop out of business and her divorce looming. A welcome escape comes when Claire, a beloved college friend, unexpectedly invites her to Maui to help launch an exciting new business: a quilter's retreat set at a bed and breakfast amid the vibrant colors and balmy breezes of the Hawaiian Islands. Soon Bonnie finds herself looking out on sparkling waters and banyan trees, planning quilting courses, and learning the history and intricacies of Hawaiian quilting, all the while helping Claire run the inn.As Bonnie's adventure unfolds, it quickly becomes clear that Claire's new business isn't the only excitement in store for her. Her cheating, soon-to-be ex-husband decides he wants her stake in Elm Creek Quilts, which threatens not only her financial well-being but her dearest friendships as well. Luckily she has the artistic challenge of creating her own unique Hawaiian quilt pattern to distract her--and new friends like Hinano Paoa, owner of the Nä Mele Hawai'i Music Shop, who introduces Bonnie to the fascinating traditions of Hawaiian culture and reminds her that love can be found when and where you least expect it.
The Christmas Quilt (Elm Creek Quilts #8)by Jennifer Chiaverini
When Christmas Eve comes to Elm Creek Manor, the tenor of the holiday is far from certain. Sylvia Bergstrom Compson, the Master Quilter, has her own reasons for preferring a quiet, even subdued, Christmas. Her young friend Sarah McClure, however, takes the opposite view and decides to deck the halls brightly. As she explores the trunks packed with Bergstrom family decorations that haven't been touched in more than fifty years, Sarah discovers a curious Christmas quilt. Begun in seasonal fabrics and patterns, the quilt remains unfinished. Sylvia reveals that the handiwork spans several generations and a quartet of Bergstrom quilters -- her great aunt, her mother, her sister, and herself. As she examines the array of quilt blocks each family member contributed but never completed, memories of Christmases past emerge. At Elm Creek Manor, Christmas began as a celebration of simple virtues -- joy and hope buoyed by the spirit of giving. As each successive generation of Bergstroms lived through its unique trials -- the antebellum era, the Great Depression, World War II -- tradition offered sustenance even during the most difficult times. For Sylvia, who is coping with the modern problem of family dispersed, estranged, or even forgotten, reconciliation with her personal history may prove as elusive as piecing the Christmas Quilt. Elm Creek Manor is full of secrets, from a Christmas tree with unusual properties to the sublime Bergstrom strudel recipe. Sylvia's tales at first seem to inform her family legacy but ultimately illuminate far more, from the importance of women's art to its place in commemorating our shared experience, at Christmastime and in every season.
Circle of Quilters (Elm Creek Quilts #9)by Jennifer Chiaverini
When Elm Creek Quilts announces openings for two new teachers, quilters everywhere are vying to land the prestigious post. The impending departure of two founding members means untold changes for the Elm Creek Quilters. As they begin the interview process, a single question emerges: Who can possibly take the place of beloved colleagues and friends? "We must evaluate all of the applicants' qualities," advises Master Quilter Sylvia Compson. "Our choice will say as much about us as it says about who we decide to hire." Who merits a place among the circle of quilters? Will it be Maggie, whose love of history shines through in all her projects; Anna, whose food-themed quilts are wonderfully innovative; Russ, the male quilter with a completely original style; Karen, a novice teacher whose gifts for language complement her deep understanding of the quilters' mission; or Gretchen, the soulful veteran whose craft is inspired by quilting tradition?
The Cross-Country Quilters (Elm Creek Quilts #3)by Jennifer Chiaverini
Readers of The Quilter's Apprentice and Round Robin have been enchanted by Elm Creek Quilt Camp, where women gather each year for quilting, friendship, and fun. The third in the Elm Creek Quilts series introduces the Cross-Country Quilters, a group of far-flung friends who pledge to complete a "challenge quilt" -- symbolic of each woman's personal goals -- in one year's time. These five women arrive at Elm Creek Manor hoping to find in their quilt lessons an escape from the problems they left at home. Julia, an aging starlet, has pinned her hopes to a plum role in a historical epic whose director is under the mistaken impression that Julia already knows how to quilt. Megan is a successful engineer who has won prizes for her miniature quilt designs. The one challenge she has yet to master is single motherhood. Donna, a mother of two, must hasten to teach her daughter independence and self-esteem -- lessons she, too, must take to heart. Grace is a renowned curator of antique quilts, whose creative flair is waning for reasons she is unwilling to reveal -- even to her closest friends. Vinnie, the senior member of the group, is a sunny soul with a tragic past. Her overwhelming desire is to bring happiness into the lives of those she loves. Although the Cross-Country Quilters share a common creative goal, as the year goes by their bonds are tested by the demands of daily life. But despite differences in age, race, and background, the friends' love for quilting and affection for one another unite them in a patchwork of caring and acceptance. The quilt they make reminds them of an everlasting truth -- friends may be separated by great distance, yet the strength of their bond can transcend any obstacle.
An Elm Creek Quilts Companionby Jennifer Chiaverini
A beautiful keepsake volume to accompany the beloved New York Times bestselling series Over the course of the bestselling Elm Creek Quilts series, readers have expressed a longing to visit Elm Creek Manor, meet the quilters themselves, and admire their beautiful creations. Jennifer Chiaverini's An Elm Creek Quilts Companion is the next best thing to a guided tour. Inside, readers will discover a treasure trove of delights, including the Bergstrom family tree, character biographies, quilt block illustrations, full-color photographs of quilts featured in the novels, and "Behind the Scenes at Elm Creek Quilt Camp," an exclusive short story inspired by questions from real readers. No Elm Creek Quilts fan will want to be without this indispensable guide to the cherished series. .
The Giving Quilt (Elm Creek Quilts #20)by Jennifer Chiaverini
Every stitch makes a difference in New York Times bestselling author Jennifer Chiaverini's artful, inspiring novel that imagines what good would come from practicing the holiday spirit each and every day of the year. <P> At Elm Creek Manor, the week after Thanksgiving is "Quiltsgiving," a time to commence a season of generosity. From near and far, quilters and aspiring quilters--a librarian, a teacher, a college student, and a quilt-shop clerk among them--gather for a special winter session of quilt camp, to make quilts for Project Linus, a charitable organization dedicated to providing handmade quilts and blankets to children in need. Each quilter, ever mindful that many of her neighbors, friends, and family members are struggling through difficult times, pledges the strength of her creative gifts to alleviate their collective burden. So it happens that when the Quiltsgiving participants swap fabrics and trade techniques around the quilting circle, the warm, bright, beautiful quilts they piece are infused with love and comfort. So, too, are their personal stories, which collectively consider the strength of human connection and its rich rewards.
The Lost Quilter (Elm Creek Quilts #14)by Jennifer Chiaverini
Master Quilter Sylvia Bergstrom Compson treasures an antique quilt called by three names -- Birds in the Air, after its pattern; the Runaway Quilt, after the woman who sewed it; and the Elm Creek Quilt, after the place to which its maker longed to return. That quilter was Joanna, a fugitive slave who traveled by the Underground Railroad to reach safe haven in 1859 at Elm Creek Farm. Though Joanna's freedom proved short-lived -- she was forcibly returned by slave catchers to Josiah Chester's plantation in Virginia -- she left the Bergstrom family a most precious gift, her son. Hans and Anneke Bergstrom, along with maiden aunt Gerda, raised the boy as their own, and the secret of his identity died with their generation. Now it falls to Sylvia -- drawing upon Gerda's diary and Joanna's quilt -- to connect Joanna's past to present-day Elm Creek Manor. Just as Joanna could not have foreseen that, generations later, her quilt would become the subject of so much speculation and wonder, Sylvia and her friends never could have imagined the events Joanna witnessed in her lifetime. Punished for her escape by being sold off to her master's brother in Edisto Island, South Carolina, Joanna grieves over the loss of her son and resolves to run again, to reunite with him someday in the free North. Farther south than she has ever been, she nevertheless finds allies, friends, and even love in the slave quarter of Oak Grove, a cotton plantation where her skill with needle and thread soon becomes highly prized. Through hardship and deprivation, Joanna dreams of freedom and returning to Elm Creek Farm. Determined to remember each landmark on the route north, Joanna pieces a quilt of scraps left over from the household sewing, concealing clues within the meticulous stitches. Later, in service as a seamstress to the new bride of a Confederate officer, Joanna moves on to Charleston, where secrets she keeps will affect the fate of a nation, and her abilities and courage enable her to aid the country and the people she loves most. The knowledge that scraps can be pieced and sewn into simple lines -- beautiful both in and of themselves and also for what they represent and what they can accomplish -- carries Joanna through dark days. Sustaining herself and her family through ingenuity and art during the Civil War and into Reconstruction, Joanna leaves behind a remarkable artistic legacy that, at last, allows Sylvia to discover the fate of the long-lost quilter.
The Master Quilter (Elm Creek Quilts #6)by Jennifer Chiaverini
The Master Quilter opens with the sound of wedding bells ringing in the ears of the Elm Creek Quilters. The close-knit group can hardly believe that their own Sylvia Compson planned her holiday wedding to sweetheart Andrew in complete secrecy, without the help of even one of her friends. Eager to honor the newlyweds, the Elm Creek Quilters hasten to stitch a bridal quilt for their favorite Master Quilter. Until the time comes to unveil the surprise gift, they reason, Sylvia will be the one in the dark. Such little white lies seem harmless enough, especially in the service of future happiness. Yet Elm Creek Manor, and the quilting retreat established there by the Elm Creek Quilters, thrives on the strength of women sharing their creativity, their challenges, and their dreams. Somehow, in the race to commemorate in Sylvia's bridal quilt all that they hold dear about her wisdom, skill, and devotion, they forget to give honesty its pride of place. As the quilt blocks accumulate, the Elm Creek Quilters celebrate the joy of new beginnings and the ongoing success of their business -- until forces conspire to threaten their happiness and prosperity. Two among them falter in their personal relationships, yet they are too proud to share their pain. The financial problems of another leave the quilt project vulnerable to a malicious act that may prevent its completion. And as two others weigh the comfort of the present against dreams of a future far from Elm Creek Manor, closely guarded secrets strain the bonds of friendship with those who may be left behind. The Dallas Morning News has praised the Elm Creek Quilts series as "classics of their kind," and The Master Quilter is Chiaverini's latest gift to readers.
Mrs. Grant and Madame Juleby Jennifer Chiaverini
The New York Times bestselling author of Mrs. Lincoln's Dressmaker and Mrs. Lincoln's Rival imagines the inner life of Julia Grant, beloved as a Civil War general's wife and the First Lady, yet who grappled with a profound and complex relationship with the slave who was her namesake--until she forged a proud identity of her own.In 1844, Missouri belle Julia Dent met dazzling horseman Lieutenant Ulysses S Grant. Four years passed before their parents permitted them to wed, and the groom's abolitionist family refused to attend the ceremony.Since childhood, Julia owned as a slave another Julia, known as Jule. Jule guarded her mistress's closely held twin secrets: She had perilously poor vision but was gifted with prophetic sight. So it was that Jule became Julia's eyes to the world.And what a world it was, marked by gathering clouds of war. The Grants vowed never to be separated, but as Ulysses rose through the ranks--becoming general in chief of the Union Army--so did the stakes of their pact. During the war, Julia would travel, often in the company of Jule and the four Grant children, facing unreliable transportation and certain danger to be at her husband's side.Yet Julia and Jule saw two different wars. While Julia spoke out for women--Union and Confederate--she continued to hold Jule as a slave behind Union lines. Upon the signing of the Emancipation Proclamation, Jule claimed her freedom and rose to prominence as a businesswoman in her own right, taking the honorary title Madame. The two women's paths continued to cross throughout the Grants' White House years in Washington, DC, and later in New York City, the site of Grant's Tomb.Mrs. Grant and Madame Jule is the first novel to chronicle this singular relationship, bound by sight and shadow.
Mrs. Lincoln's Dressmakerby Jennifer Chiaverini
New York Times bestselling author Jennifer Chiaverini illuminates the extraordinary friendship between Mary Todd Lincoln and Elizabeth Hobbs Keckley, a former slave who won her freedom by the skill of her needle, and the friendship of the First Lady by her devotion. In Mrs. Lincoln's Dressmaker, novelist Jennifer Chiaverini presents a stunning account of the friendship that blossomed between Mary Todd Lincoln and her seamstress, Elizabeth "Lizzie" Keckley, a former slave who gained her professional reputation in Washington, D. C. by outfitting the city's elite. Keckley made history by sewing for First Lady Mary Todd Lincoln within the White House, a trusted witness to many private moments between the President and his wife, two of the most compelling figures in American history. In March 1861, Mrs. Lincoln chose Keckley from among a number of applicants to be her personal "modiste," responsible not only for creating the First Lady's gowns, but also for dressing Mrs. Lincoln in the beautiful attire Keckley had fashioned. The relationship between the two women quickly evolved, as Keckley was drawn into the intimate life of the Lincoln family, supporting Mary Todd Lincoln in the loss of first her son, and then her husband to the assassination that stunned the nation and the world. Keckley saved scraps from the dozens of gowns she made for Mrs. Lincoln, eventually piecing together a tribute known as the Mary Todd Lincoln Quilt. She also saved memories, which she fashioned into a book, Behind the Scenes: Thirty Years a Slave and Four Years in the White House. Upon its publication, Keckley's memoir created a scandal that compelled Mary Todd Lincoln to sever all ties with her, but in the decades since, Keckley's story has languished in the archives. In this impeccably researched, engrossing novel, Chiaverini brings history to life in rich, moving style. .
Mrs. Lincoln's Rivalby Jennifer Chiaverini
The New York Times bestselling author of Mrs. Lincoln's Dressmaker Jennifer Chiaverini's astute and lively novel of the politics of state--set against the backdrop of Civil War Era Washington Beautiful, intelligent, regal, and entrancing, young Kate Chase Sprague stepped into the role of establishing her thrice-widowed father, Salmon P. Chase, in Washington society as a Lincoln cabinet member and as a future presidential candidate. For her efforts, The Washington Star declared her "the most brilliant woman of her day. None outshone her."None, that is, but Mary Todd Lincoln. Though Mrs. Lincoln and her young rival held much in common--political acumen, love of country, and a resolute determination to help the men they loved achieve greatness--they could never be friends, for the success of one could come only at the expense of the other.common--political acumen, love of country, and a resolute determination to help the men they loved achieve greatness--they could never be friends, for the success of one could come only at the expense of the other. When Kate Chase married William Sprague, the wealthy young governor of Rhode Island, it was widely regarded as the pinnacle of Washington society weddings. President Lincoln was in attendance. The First Lady was not. Jennifer Chiaverini excels at chronicling the lives of extraordinary yet littleknown women through historical fiction. What she did for Elizabeth Keckley in Mrs. Lincoln's Dressmaker and for Elizabeth Van Lew in The Spymistress she does for Kate Chase Sprague in Mrs. Lincoln's Rival.
Mrs. Lincoln's Rivalby Jennifer Chiaverini
The New York Times bestselling author of Mrs. Lincoln's Dressmaker, Jennifer Chiaverini, reveals the famous First Lady's very public social and political contest with Kate Chase Sprague, memorialized as "one of the most remarkable women ever known to Washington society." (Providence Journal) Kate Chase Sprague was born in 1840 in Cincinnati, Ohio, the second daughter to the second wife of a devout but ambitious lawyer. Her father, Salmon P. Chase, rose to prominence in the antebellum years and was appointed secretary of the treasury in Abraham Lincoln's cabinet, while aspiring to even greater heights. Beautiful, intelligent, regal, and entrancing, young Kate Chase stepped into the role of establishing her thrice-widowed father in Washington society and as a future presidential candidate. Her efforts were successful enough that The Washington Star declared her "the most brilliant woman of her day. None outshone her." None, that is, but Mary Todd Lincoln. Though Mrs. Lincoln and her young rival held much in common--political acumen, love of country, and a resolute determination to help the men they loved achieve greatness--they could never be friends, for the success of one could come only at the expense of the other. When Kate Chase married William Sprague, the wealthy young governor of Rhode Island, it was widely regarded as the pinnacle of Washington society weddings. President Lincoln was in attendance. The First Lady was not. Jennifer Chiaverini excels at chronicling the lives of extraordinary yet littleknown women through historical fiction. What she did for Elizabeth Keckley in Mrs. Lincoln's Dressmaker and for Elizabeth Van Lew in The Spymistress she does for Kate Chase Sprague in Mrs. Lincoln's Rival.
The New Year's Quilt (Elm Creek Quilts #11)by Jennifer Chiaverini
As each holiday season approaches, some revel in welcoming the New Year ahead; others quietly mourn the passing of time gone by. "We can't hold on to the past," says Master Quilter Sylvia Compson, "but we can keep the best part of 'Auld Lang Syne' in our hearts and in our memories, and we can look forward to the future with hope and resolve." As Sylvia, a late-in-life newlywed, has discovered, love can enter our lives at any age. Yet before she can truly delight in her present happiness, she must face the sorrow hidden in her past -- her own role in the tragic circumstances that left her estranged from her sister, Claudia, until it was too late to make amends. Vowing not to repeat the mistake with her new daughter-in-law, Amy, who opposed Sylvia's marriage to her father, Andrew, Sylvia must convince Amy that family is more precious than pride. As Sylvia takes up a quilt for the season, begun and abandoned over six years, she recalls the New Year's Eve festivities of her youth at Elm Creek Manor as a member of the Bergstrom family. She titles the quilt "New Year's Reflections," after her belief that year-end reflections precede resolutions. The quilt blocks she chooses commemorate the wisdom that no one can ever be truly alone if she keeps the memory of those she loved and those who loved her alive in her heart. The New Year's Quilt is a novel to enjoy today and to treasure anew each holiday season.
The Quilter's Apprentice (Elm Creek Quilts #1)by Jennifer Chiaverini
Tangled, anxious thoughts relaxed when she felt the fabric beneath her fingers and remembered that she was creating something beautiful enough to delight the eyes as well as the heart, something strong enough to defeat the cold of a Pennsylvania winter night. She could do these things. She, Sarah, had the power to do these things. From debut novelist Jennifer Chiaverini comes The Quilter's Apprentice, a delightful, timeless story of loyalty and friendship. When Sarah McClure and her husband, Matt, move to the small town of Waterford, Pennsylvania, to get a fresh start, Sarah struggles to find a fulfilling job. Disheartened by failed interviews, she reluctantly accepts a temporary position at Elm Creek Manor helping seventy-five-year-old Sylvia Compson prepare her family estate for sale after the recent death of Sylvia's estranged sister. As part of her compensation, Sarah is taught how to quilt by this reclusive, cantankerous master quilter. During their lessons, Mrs. Compson slowly opens up to Sarah, sharing powerful, devastating stories of her life as a young woman on the World War II home front. Hearing tales of how Mrs. Compson's family was torn apart by tragedy, jealousy, and betrayal, Sarah is forced to confront uncomfortable truths about her own family -- truths that she has denied for far too long. As the friendship between the two women deepens, Mrs. Compson confides that although she would love to remain at her beloved family estate, Elm Creek Manor exists as a constant, unbearable reminder of her role in her family's misfortune. For Sarah, there can be no greater reward than teaching Mrs. Compson to forgive herself for her past mistakes, restoring life and joy to her cherished home. Heartfelt and inspiring, The Quilter's Apprentice teaches deep lessons about family, friendship, and sisterhood -- and about creating a life as you would a quilt: with time, love, and patience, piecing the miscellaneous and mismatched scraps into a harmonious, beautiful whole.
A Quilter's Holiday (Elm Creek Quilts #15)by Jennifer Chiaverini
The Elm Creek Quilters are home for the holidays in this heartwarming Christmas story from New York Times bestselling author Jennifer Chiaverini. For the Elm Creek Quilters, the day after Thanksgiving marks the start of the quilting season, a time to gather at Elm Creek Manor and spend the day stitching holiday gifts for loved ones. This year, in keeping with the season's spirit of gratitude, Master Quilter Sylvia Bergstrom Compson Cooper is eager to revive a cherished family tradition. A recent remodeling of the manor's kitchen unearthed a cornucopia that once served as the centerpiece of the Bergstrom family's holiday table. Into it, each Bergstrom would place an object that symbolized something he or she was especially thankful for that year. On this quilter's holiday, Sylvia has invited her friends to continue the tradition by sewing quilt blocks that represent their thankfulness and gratitude. As each quilter explains the significance of her carefully chosen block, stories of love and longing for family and friends emerge--feelings that are also expressed in the gifts they work on throughout the day. An early winter storm blankets Elm Creek Manor in heavy snow as the quilters find new meanings in their best-loved traditions and new reasons to be thankful. A Quilter's Holiday is a story of holiday spirit, in its truest, most generous sense.day is a story of holiday spirit, in its truest, most generous sense.
The Quilter's Homecoming (Elm Creek Quilts #10)by Jennifer Chiaverini
A Roaring Twenties adventure unfolds in Jennifer Chiaverini's latest bestselling Elm Creek Quilts novel, another in "a series that neatly stitches together social drama and the art of quilting" (Library Journal). Newly wed in a festive yet poignant ceremony at Elm Creek Manor, bride Elizabeth Nelson takes leave of her ancestral Pennsylvania home. Setting off with her husband, Henry, on the adventure of a lifetime, Elizabeth packs the couple's trunk with more than the wedding quilts she envisions them dreaming beneath every night of their married lives. They are landowners who hold the deed to Triumph Ranch, 120 acres of prime California soil located in the Arboles Valley, north of Los Angeles. "Triumph Ranch," says Mae, a traveling companion whom Elizabeth has let in on the promise of the Nelsons' bright future. "That sounds like a sure thing." But in a cruel reversal of fortune, the Nelsons arrive to the news that they've been had, and they are left suddenly, irrevocably penniless. They are hired as hands at the farm they thought they owned, and Henry struggles mightily with his pride. Yet clever, feisty Elizabeth -- drawing on her share of the Bergstrom women's inherent economy and resilience -- vows to defy fate through sheer force of will. As her life intertwines with Rosa Diaz Barclay, native to the Arboles Valley and a fellow quilter, their blossoming friendship sheds light on many secrets that have kept each of them and their families from their rightful homes. In the cabin where Henry and Elizabeth are living on Triumph Ranch, Elizabeth discovers quilts belonging to Rosa's mother, and in their exquisite patterns recognizes a misplaced legacy of love, land, and family. But her newfound understanding of the burden of loss that Rosa shares with the mysterious Lars Jorgensen places her in mortal danger. Only by stitching the rift between the past and the future can the inhabitants of Triumph Ranch hope to live in peace alongside history.
The Quilter's Kitchenby Jennifer Chiaverini
Anna Del Maso had known that she wanted to be a chef since she was in the seventh grade. "Somehow everything in my life ends up being about food," she realizes, as she begins the latest of her food-themed quilts. Her twin passions have converged in a brand-new position as head chef for Elm Creek Quilts, Waterford, Pennsylvania's popular quilting retreat. As she joins the circle of quilters at historic Elm Creek Manor, Anna is eager to preserve the manor's culinary heritage, dating to 1858, while also celebrating the new favorites of their many guests. Yet as Master Quilter Sylvia Bergstrom Compson well knows, the manor's kitchen, last updated in the 1940s, can't create food that compares to the state-of-the-art quilting instruction for which Elm Creek Quilts is renowned. A full renovation of the kitchen must be completed by the start of the new camp season. Though the task is daunting, Anna is assured in her belief that "A kitchen is the heart of a home." As she and Sylvia begin to dismantle the old to make way for the new, Sylvia's reminiscences remind them both of just how many of the manor's traditions have involved food and celebrations. Whether the feast is one of the holiday menus prepared and enjoyed by generations of Bergstroms, or one of the Welcome Banquets and Farewell Breakfasts that have become hallmarks of Elm Creek Quilt Camp, there is a story for every recipe, and a recipe for every story. The Quilter's Kitchen follows Anna's flavorful explorations of the kitchens of Elm Creek Manor, past and present. As she records beloved recipes and creates original dishes seasoned with love, she discovers anew how the gifts of the table gather friends and family ever closer.
The Quilter's Kitchen (Elm Creek Quilts #13)by Jennifer Chiaverini
Anna Del Maso had known that she wanted to be a chef since she was in the seventh grade. "Somehow everything in my life ends up being about food," she realizes, as she begins the latest of her food-themed quilts. Her twin passions have converged in a brand-new position as head chef for Elm Creek Quilts, Waterford, Pennsylvania's popular quilting retreat. As she joins the circle of quilters at historic Elm Creek Manor, Anna is eager to preserve the manor's culinary heritage, dating to 1858, while also celebrating the new favorites of their many guests. Yet as Master Quilter Sylvia Bergstrom Compson well knows, the manor's kitchen, last updated in the 1940s, can't create food that compares to the state-of-the-art quilting instruction for which Elm Creek Quilts is renowned. A full renovation of the kitchen must be completed by the start of the new camp season. Though the task is daunting, Anna is assured in her belief that "A kitchen is the heart of a home." As she and Sylvia begin to dismantle the old to make way for the new, Sylvia's reminiscences remind them both of just how many of the manor's traditions have involved food and celebrations. Whether the feast is one of the holiday menus prepared and enjoyed by generations of Bergstroms, or one of the Welcome Banquets and Farewell Breakfasts that have become hallmarks of Elm Creek Quilt Camp, there is a story for every recipe, and a recipe for every story. The Quilter's Kitchen follows Anna's flavorful explorations of the kitchens of Elm Creek Manor, past and present. As she records beloved recipes and creates original dishes seasoned with love, she discovers anew how the gifts of the table gather friends and family ever closer.
The Quilter's Legacy (Elm Creek Quilts #5)by Jennifer Chiaverini
When precious heirloom quilts hand-stitched by her mother turn up missing from the attic of Elm Creek Manor, Sylvia Bergstrom Compson resolves to find them. From scant resources-journal entries, receipts, and her own fading memories-she pieces together clues, then queries quilting friends from around the world. When dozens of leads arrive via the Internet, Sylvia and her fiance, Andrew, embark on a nationwide investigation of antique shops and quilt museums. Sylvia's quest leads her to unexpected places, where offers of assistance are not always what they seem. As the search continues, revelations surface about her mother, who died when Sylvia was only a child. Burdened with poor health and distant parents, Eleanor Lockwood defies her family by marrying for love. Far from her Manhattan home, she embraces her new life among the Bergstroms-but although warmth and affection surround Eleanor at last, the Bergstroms cannot escape the tragedies of their times. As Sylvia recovers some of the missing quilts and accepts others as lost forever, she reflects on the woman her mother was, and mourns the woman she never knew. For every woman who has yearned to know the untold story of her mother's life, and for every mother who has longed to be heard, THE QUILTER'S LEGACY will resonate with heartfelt honesty as it reveals what tenuous connections bind the generations, and celebrates the love that sustains them.
Round Robin (Elm Creek Quilts #2)by Jennifer Chiaverini
The sequel to her acclaimed debut novel, Jennifer Chiaverini's Round Robin is a poignant tale of friendship and loyalty. The Elm Creek Quilters have begun a Round Robin quilt, created by sewing concentric patchwork borders to a central block, as a gift for their beloved fellow quilter Sylvia Compson. But even as the quilt is passed from friend to friend, its eloquent beauty increasing with every stitch, the threads of their happiness begin to unravel. As each woman confronts a personal crisis, a painful truth, or a life-changing choice, the quilt serves as a symbol of the complex and enduring bonds between mothers and daughters, sisters and friends.
The Runaway Quilt (Elm Creek Quilts #4)by Jennifer Chiaverini
After learning of her family's ties to the slaveholding South, Sylvia Compson scours her attic for clues and discovers a window into the world of her ancestors: the memoir of her great-grandfather's spinster sister, Gerda Bergstrom. Gerda's memoir chronicles the founding of Elm Creek Manor and the tumultuous years when Hans, Anneke, and Gerda Bergstrom sheltered fugitive slaves within its walls, using quilts as a signal of sanctuary. But little did the staunchly abolitionist Gerda know that a traitor was among them, placing the Bergstroms in grave danger and leading to family discord, betrayal, and a secret held for generations. With the help of the Elm Creek Quilters and clues hidden within antique quilts discovered in the manor's attic, Sylvia stitches together the pieces of her past and decodes the true nature of the Bergstrom legacy.
Sonoma Roseby Jennifer Chiaverini
New York Times bestselling author Jennifer Chiaverini returns with a Prohibition-era novel about one woman's journey to save her family--and herself With the nation in the throes of Prohibition, Rosa Diaz Barclay unwittingly discovers that her husband, John, has given over the duties of their Southern California rye farm in favor of armed bootlegging. Fearing the safety of her four beloved children, Rosa flees, with little more than a suitcase filled with John's ill-gotten gains and her heirloom quilts. Accompanying her is Lars, a good but flawed man who is the mother of two of her children. Under assumed names, Lars and Rosa hire on at a Sonoma County vineyard, seeking not only refuge from danger, but convalescence for two of the children, who suffer from a mysterious wasting disease. The devotion of the Italian-American community to the craft of viticulture inspires Rosa to acquire a vineyard of her own, even as she discovers firsthand its inherent hardships and dangers winemakers face in such turbulent times.
The Spymistressby Jennifer Chiaverini
New York Times bestselling author Jennifer Chiaverini is back with another enthralling historical novel set during the Civil War era, this time inspired by the life of "a true Union woman as true as steel" who risked everything by caring for Union prisoners of war -- and stealing Confederate secrets. Born to slave-holding aristocracy in Richmond, Virginia, and educated by Northern Quakers, Elizabeth Van Lew was a paradox of her time. When her native state seceded in April 1861, Van Lew's convictions compelled her to defy the new Confederate regime. Pledging her loyalty to the Lincoln White House, her courage would never waver, even as her wartime actions threatened not only her reputation, but also her life. Van Lew's skills in gathering military intelligence were unparalleled. She helped to construct the Richmond Underground and orchestrated escapes from the infamous Confederate Libby Prison under the guise of humanitarian aid. Her spy ring's reach was vast, from clerks in the Confederate War and Navy Departments to the very home of Confederate President Jefferson Davis. Although Van Lew was inducted posthumously into the Military Intelligence Hall of Fame, the astonishing scope of her achievements has never been widely known. In Chiaverini's riveting tale of high-stakes espionage, a great heroine of the Civil War finally gets her due.
The Sugar Camp Quilt (Elm Creek Quilts #7)by Jennifer Chiaverini
A week after Uncle Jacob's death, Abel Wright came to pay his respects. Dorothea Granger took him to the grave and stood some distance away while he bowed his head in silent prayer. Then he looked up and said, "I have something to tell you and your folks." History is thick with secrets in The Sugar Camp Quilt, seventh in the beloved Elm Creek Quilts series from bestselling author Jennifer Chiaverini. Set in Creek's Crossing, Pennsylvania, in the years leading up to the Civil War, the story begins with friends and neighbors taking sides in the abolitionist debate, and as events unfold, an ex-traordinary young heroine passes from innocence to wisdom against the harrowing backdrop of the American struggle over slavery. A dutiful daughter and niece, Dorothea Granger finds her dreams of furthering her education thwarted by the needs of home. A gifted quilter, she tragically loses her hope chest in a flood. A superior student, she is promoted from pupil to teacher -- only to lose her position to the privileged son of a town benefactor. But the ultimate test of her courage and convictions comes with the death of her stern uncle Jacob, who inexplicably had asked Dorothea to stitch him a quilt with four unusual patterns of his own design. After he meets with a violent end, Dorothea discovers that the quilt contains hidden clues to guide runaway slaves along the Underground Railroad. Emboldened by the revelations about her uncle's bravery, Dorothea resolves to continue his dangerous work. Armed with the Sugar Camp Quilt and its mysterious symbols, she must evade slavecatchers and outwit unscrupulous neighbors, embarking upon a heroic journey that allows her to discover her own courage and resourcefulness -- unsuspected qualities that may win her the heart of the best man she has ever known. Told with Jennifer Chiaverini's trademark historical suspense, The Sugar Camp Quilt blends danger, moral courage, romance, and hope into a novel of antebellum America whose lessons resonate with timeless honesty.
The Union Quilters (Elm Creek Quilts #17)by Jennifer Chiaverini
The New York Times bestselling author of the Elm Creek Quilts series joins the Dutton list with a Civil War-era tale of love and sacrifice behind Union lines. With The Union Quilters, Chiaverini delivers a powerful story of a remarkable group of women coping with changing roles and the extraordinary experiences of the Civil War. In 1862 Water's Ford, Pennsylvania, abolitionism is prevalent, even passionate, so the local men rally to answer Mr. Lincoln's call to arms. Thus the women of Elm Creek Valley's quilting bee are propelled into the unknown. Constance Wright, married to Abel, a skilled sharpshooter courageous enough to have ventured south to buy his wife's freedom from a Virginia plantation, knows well her husband's certainty that all people, enslaved and free, North and South, need colored men like him to fight for a greater purpose. Sisters-in-law Dorothea Nelson and Charlotte Granger wish safe passage for their learned husbands. Schoolmaster turned farmer Thomas carries Dorothea's Dove in the Window quilt with him. Charlotte's husband, Dr. Jonathan Granger, takes more than a doctor's bag to his post at a field hospital. Alongside the devotion of his wife, pregnant with their second child, Jonathan brings the promise he made to his unrequited love, Gerda Bergstrom: "My first letter will be to you." Together with the other members of the circle, the women support one another through loneliness and fear, and devise an ingenious business plan to keep Water's Ford functioning. That plan may forever alter the patchwork of town life in ways that transcend even the ultimate sacrifices of war.
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text:
Pasco County Sheriff Chris Nocco says they still don't know what led to a fight between a group of brothers that ended with two of them dead and another one in the hospital.
At a press conference Thursday morning, Nocco released the names of the brothers; Trevor Pimentel, 16, Kevin Pimentel, 12, Brady Pimentel, 6. He said Kevin would've turned 13 at the end of this month.
Nocco said initially they believed the fight was over food but now say Trevor and Kevin were preparing food at the time an argument broke out.
Deputies received the call at 6:19 p.m. from a mobile home in the 16000 block of Bachmann Avenue in Hudson.
"Sixteen-year-old Trevor called 911, telling the dispatcher his brother, Kevin, 12 years old, had just shot Brady, 6, then shot himself," Nocco said.
A deputy arriving on scene heard a boy screaming and he charged into the house, Nocco said.
Trevor was transported to a local hospital with a non-life threatening gunshot wound, according to deputies. Nocco said Trevor has been cooperative but he is emotional.
"Trevor's heart rate would go up during interview process with detectives," Nocco said. "He is grieving."
The boys' mother, Helen Campochiaro, was at work. Nocco described her as hard-working, noting she has two jobs and was recently in a car accident but chose to keep working.
An 18-year-old brother that also lives at the home also was not at the residence at the time of the shooting.
Brady attended Hudson Elementary School, Kevin went to Hudson Middle School and Trevor attended Hudson High School in the mornings through virtual education classes, according to Superintendent Kurt Browning.
Crisis teams will be at the elementary and middle schools "as long as we need to," Browning said. "It's very tragic but we are working to heal families and students."
Browning said Trevor attended Marchmen Technical College's culinary program in the afternoons.
Nocco said there are no signs child protection investigators or law enforcement has ever been to the home before.


text:
Plow & Hearth Exclusive
Made up of a savory blend of Virginia peanuts, cashews and roasted almonds with pepita seeds and sesame sticks tossed in a salty seasoning, they're the perfect treat for game day or anytime.
• Tailgate Snack Mix
• Virginia peanuts, cashews, roasted almonds, pepita seeds and sesame sticks
• Zesty flavor with a savory, salty seasoning
• A great treat for game day or anytime
• Also available as part of our Nuts of the Month Club (September selection)
18 oz.
Cannot ship to a PO Box.
Ships within the 48 contiguous states only.
Tell your friends what you really want this year!
Dear _______:
Want to step in for Santa? We happen to know this is high on _______'s Christmas list!
Olla (Spanish, pronounced "oh-ya") jars have been around since ancient times. Made of unglazed ceramic, ollas traditionally have short, narrow necks with wider bodies, and are made in a variety of shapes. They have been used for thousands of years for cooking, storage, and plant irrigation.
When used to irrigate plants, an olla is buried neck-deep in the ground near a plant's roots, with the opening of the olla extended above the soil so that it can be filled with water periodically. The porous walls of the unglazed pottery allow the water to seep through gradually, constantly and consistently hydrating the plants without overwatering them – and without wasting precious water to evaporation or runoff.
The use of ollas for irrigation was introduced to the American Southwest by Spanish conquistadors during Colonial times, becoming very common among Native American tribes and Hispanic settlers. Though the technique gave way to more modern methods of irrigation some time ago, its superior efficiency, coupled with its simplicity, has caused it to make a comeback. Though the technique has changed little since its introduction, today's ollas are usually capped off, making them even more water-efficient.
Perfect for home gardens, Ollas are a super-easy, eco-friendly, less time-consuming way to water annuals, perennials, herbs, vegetables and plants of all kinds in dry, sandy soil, very hot or drought-prone areas, raised beds, and even pots, planters and hanging baskets. Fill the olla before you leave on a short vacation to enjoy worry-free watering – and a smaller water bill!
Water is pulled directly through the terra-cotta!
Read more about Ollas on our blog.


text: Hi there! I'm Dietrich, a chillax, whimsical, witty, and persnickety passionate foodie. With over 30 years of experience in local Hong Kong, China, and Macao gastro scenes, I can guide you to the most interesting and eluding haunts to rustle up some grub and bacchanalian venues to quench a gargantuan thirst. A way off the beaten path gastronomist mixologist drinkologist maximus supremus; aka "DaiPaiDong D". Welcome to Hong Kong, my friends!!!