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The purpose of the present study was to compare side-by-side the therapeutic efficacy of a 6-day infusion of carboplatin, followed by X-irradiation with either 6 MV photons or synchrotron X-rays, tuned above the K-edge of Pt, for treatment of F98 glioma bearing rats.
Carboplatin was administered intracerebrally (i.c.) to F98 glioma bearing rats over 6 days using AlzetTM osmotic pumps starting 7 days after tumor implantation. Radiotherapy was delivered in a single 15 Gy fraction on day 14 using a conventional 6 MV linear accelerator (LINAC) or 78.8 keV synchrotron X-rays.
Untreated control animals had a median survival time (MeST) of 33 days. Animals that received either carboplatin alone or irradiation alone with either 78.8 keV or 6 MV had a MeSTs 38 and 33 days, respectively. Animals that received carboplatin in combination with X-irradiation had a MeST of > 180 days with a 55% cure rate, irrespective of whether they were irradiated with either 78.8 KeV synchrotron X-rays or 6MV photons.
These studies have conclusively demonstrated the equivalency of i.c. delivery of carboplatin in combination with X-irradiation with either 6 MV photons or synchrotron X-rays.
F98 rat glioma; Carboplatin; Osmotic pumps; Intracerebral delivery; Radiotherapy with 6 MV photons or synchrotron X-raysBackground
High Z-enhanced synchrotron stereotactic radiotherapy relies on the dose-enhancement obtained when tumors, previously filled with a high-Z elements, are irradiated with medium energy x-rays (50–100 keV) in stereotactic conditions. The concept comes initially from the observation in the late 70's, of additional blood damages in pediatric diagnostic radiology, when using contrast agents [1]. The use of medium energy x-rays to treat cancer could appear surprising nowadays, specially for brain tumors, but as the photoelectric cross section increases proportionally to Z4/E3 (where Z is the atomic number of matter and E the energy of photons), there is a subsequent increase of the absorbing properties restricted to the target level, due to the release of secondary particles (photoelectrons, characteristic x-rays and Auger electrons), which deposit most of the initial photon energy in the close vicinity of the primary interaction. Photoelectric effect is the photon interaction that deposits locally the largest part of the photon initial energy (when compared to coherent or incoherent scattering events). This leads to improved dose distributions in comparison with conventional high energy treatments. Numerous studies have been performed for establishing that this method meets dosimetry criteria for patients [2-8]. From 50 to 80 keV, the brain half value layer increases from 2.93 to 3.64 cm. Although these values are relatively small, the dose is increased by (i) the irradiation geometry and (ii) by the presence of sufficient amount of high Z elements inside the tumor volume (≈ 3–10 mg/mL). LINAC spectra extend from MV to kV energies, however, the contribution of kV radiation in the dose-enhancement is negligible, as shown with Monte carlo simulations or experimentally using gel dosimetry [2-5,9]. The use of a modified conventional CT scanner, such as proposed by Norman and co-workers [10], appeared to be the main limitation of the technique due to (i) the beam shape (fan or cone-shaped beam with a high aperture) which broadens the isodoses as the beam goes through the patient; (ii) a low photon flux and a high thermal load which impose long irra-diation times and cooling phases; and (iii) a broad polychromatic spectrum of the beam which increases the dose to the skull and minimizes the dose enhancement effect. For these reasons, nearly parallel intense and tunable monochromatic beams provided by synchrotron source appear to be a must for this radiotherapy technique.
In a series of publications [11-14] we have reported on the therapeutic efficacy of short-term intracerebral (i.c.) convection enhanced delivery (CED) of either carboplatin or cisplatin or alternatively prolonged intratumoral (i.t.) infusion of carboplatin either alone or in combi-nation with X-irradiation for the treatment of the F98 rat glioma [11-13]. Irradiations were carried out at the European Synchrotron Radiation Facility (ESRF) using 78.8 keV synchrotron X-rays or 6 MV photons, by a medical linear accelerator (LINAC), at the University Hospital of Grenoble, France. Carboplatin was selected for these studies because we previously have shown that it was highly effective in treating F98 glioma bearing rats [11-14]. However, platinum containing drugs have their limitations [15-17] for the treatment of brain tumors. These include inadequate dose-limiting toxicity and reduced uptake by brain tumors following systemic administration due to the blood brain barrier (BBB) [18]. Delivery of carboplatin by CED was well tolerated when delivered i.c. to F98 glioma bearing rats [11,12,14,19-21] and non-human primates [22] and resulted in prolonged survival and cures of the former.
Cure rates of 20% to 55% were obtained in F98 glioma bearing rats treated with prolonged infusions of either carboplatin or cisplatin using Alzet osmotic pumps alone or in combination with synchrotron X-irradiation. In these studies, the beam energy was tuned at 78.8 keV, which was just above the K-edge of Pt [12,23]. The first study carried out at the ESRF with cisplatin [23], employed synchrotron X-rays and it was hypothesized that therapeutic efficacy was dependent upon the production of Auger electrons and photoelectrons following irradiation of Pt atoms with monochromatic X-rays. Above the Pt K-edge energy (78.4 keV), extraction of electrons from the K-shell by the photoelectric effect results in the creation of vacancies. The resulting gaps are filled successively by radiative (96%) and non-radiative (4%) transitions from outer shells, thereby resulting in the release of several low energy photons and electrons. If the Pt atoms are located near or within DNA, the emitted low energy electrons can be highly destructive for DNA and lethal to tumor cells [24], even with small concentrations of Pt. We further hypothesized that drugs such as cisplatin or carboplatin were ideal candidates for this approach, since they had two advantages: first, they were DNA alkylating agents [25] and second, they were efficient carriers of Pt, which has a high Z number. The photoelectric cross-section of Pt at 78.8 keV is 2860 barns/atom, 4.8 times greater than at 78.0 keV. Therefore, if therapeutic efficacy were related to the emission of Auger electrons and photoelectrons from the Pt atoms, a greater therapeutic gain should have been observed with X-irradiation above rather than below the Pt K-edge. Furthermore, and most impor-tantly, almost no enhancement should be observed with 6 MV photons. This is because the Pt photoelectric cross is < 1 barn/atom above 1 MeV (i.e. >2860 × less than the Pt cross section above its K-edge), which is not significantly different from that of water. The Compton interaction process is dominant in this energy range and does not induce local energy deposition, contrary to the photoelectric effect. However, our studies carried out over the past 4 years have called this interpretation into question. The best survival data and cure rate (55%) ever reported with F98 glioma model were obtained by combining i.c. administration of carboplatin by means of Alzet osmotic pumps followed by synchrotron X-irradiation tuned at 78.8 keV. Therefore, it was important to carry out another study under similar conditions with 6 MV X-rays using a LINAC instead of synchrotron radiation to demonstrate that this effect was independent of the X-ray source. In the present study we have shown the equivalency of synchrotron X-rays [11,26] and 6 MV photons in combination with prolonged i.c. administration of carboplatin to produce prolonged survivals and cures of F98 glioma bearing rats.
All operative procedures related to animal care strictly conformed to the Guidelines of the French Government (licenses #380324 and #A3818510002). The protocol was approved by the Grenoble Institute of Neurosciences Ethical Committee (H. Elleaume, PhD, permit #381026). Experiments were performed under anesthesia, and every effort was made to minimize the number of animals used and to alleviate pain and suffering during the experimental procedures.
Tumor model
F98 rat glioma cells (American Type Culture Collection #CRL-2397) were cultured in Dulbecco's modified eagle's medium (DMEM, Invitrogen, France), supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. For tumor cell implantation, male Fischer rats (Charles River Laboratory, L'Abresles, France), weighing 260–310 g, were anesthetized with isoflurane, followed by an i.p. injection of ketamine (60 mg/kg body weight (b.w.) and xylazine, 7 mg/kg (b.w.). The animals' eyes were coated with an ocular lubricant prior to surgery to prevent the development of keratitis. The rats were placed in a stereotactic headframe (David Kopf Instruments, Tujunga, California) and a Hamilton syringe (#701 N 10μL) was mounted on it and this was attached to a syringe pump to control the injection rate. A skin incision was made, the scalp was reflected and a burr hole was drilled 3.5 mm to the right of the bregma. A 4 μL suspension of 1000 F98 glioma cells in serum-free DMEM was injected stereotactically into the right caudate nucleus of syngeneic Fischer rats using a syringe pump (KDS310; Geneq, Inc., Montréal, Quebec, Canada). The cells were injected over 8 min via a 26 gauge needle, which was inserted to a depth of 7 mm from the skull surface and then withdrawing it to the target depth of 6.5 mm. After tumor cell implantation, the needle was left in place for 2 min and then slowly withdrawn. The burr hole in the calvarium was sealed with bone wax, and the operative field was cleansed with povidone iodine before closure of the scalp incision by sutures.
Intracerebral delivery of carboplatin and experimental plan
Carboplatin (M.W = 371.25 Da, Faulding Pharmaceuticals, Asnières, France) was diluted in 5% dextrose to obtain a final concentration of 0.5 mg/mL. ALZET osmotic pumps (model #2001, Charles Rivers Laboratories, L'Abresles, France) and brain infusion kits (Bilaney, Dusseldorf, Germany) were assembled and filled with carboplatin. The pumps were stored in the dark in a sterile solution of 0.9% saline at 37°C for 24 h prior to their use. Seven days after tumor cell implantation the animals were anesthetized and the scalp incision was re-opened. The bone wax was removed with a needle, and the infusion cannula was introduced to a depth of 6.5 mm through the hole made at the time of tumor cell implantation. The brain infusion kit was fixed in place with surgical glue, and the pump was implanted in a subcutaneous pocket in the midscapular region, with a sufficient amount of catheter tubing to permit free motion of the animal's head and neck. The pumps were left in place from days 7 to 13, during which time the animals received an infusion of 144 μL of carboplatin (72 μg, 194 nmol), delivered at a flow rate of 1 μL/h over 6 days, after which the pumps were removed.
The rats, were stratified into four groups and treated as follows: Group 1, Untreated controls; Group 2, Received a 6 days infusion of carboplatin (72 μg/144 μL) beginning on day 7 following tumor implantation; Group 3, Received a single 15 Gy dose of 6 MV X-rays on day 14; Group 4, Received a 6 days infusion of carboplatin, beginning on day 7 following tumor implantation in combination with a single 15 Gy dose of 6 MV X-rays administered on day 14. We have compared the survival times of these animals with the experimental groups irradiated with synchrotron X-rays tuned at 78.8 keV, as reported in detail in our previous report [12].
Irradiation with 6 MV photons
Irradiations were performed at the University Hospital of Grenoble using a 6 MV LINAC (SLi, Elekta Oncology Systems, Ltd., West Sussex, UK). Rats were placed in a polystyrene box and were irradiated, two at a time. The head of each animal was aligned in the middle of an 8 × 4 cm2 aperture, defined by the beam collimator, and only the right cerebral hemisphere was irradiated. A wax block was positioned between the rats' heads and a 0.5 cm tissue equivalent bolus was placed on top to ensure full build up of the dose at the skin surface. A dose of 15 Gy was prescribed at a 1.5 cm depth and delivered at a dose rate of 200 cGy/min (treatment planning system: Dosigray, DosiSoft, Cachan, France). After irradiations were completed, the animals were transferred to the Animal Care Facility at the ESRF. These irradiation parameters were chosen to be as close as possible to the Stereotactic synchrotron radiotherapy carried out at the European Synchrotron Radiation Facility (ESRF), which was previously described [12].
Tumor imaging
To confirm the presence of tumor, contrast-enhanced imaging was performed after radiotherapy using a conventional CT scanner (Siemens Somatom Plus 4 Volume Zoom scanner, Siemens Medical Systems, Iselin, NJ, USA). All of the animals received an intravenous (i.v.) injection of 1.5 mL of Iomeron® (350 mg/mL of iodine), followed by 0.5 mL of a saline solution (NaCl 0.9%) via the tail vein 10 minutes before computed tomography. Four animals showed no evidence of tumor at this time and they were excluded from the therapy studies.
Statistical methods
Kaplan-Meier survival plots were compared with the log-rank test (JMP, SAS Institute Grégy sur-Yerres, France). The log-rank test statistic compares estimates of the hazard functions of the two groups at each observed event time. It is constructed by computing the observed and expected number of events in one of the groups at each observed event time and then adding these to obtain an overall summary across all time points where there is an event. The rats'survival were considered as significantly different when p < 0.05.
Therapeutic response following i.c. of carboplatin in combination with 6 MV X-irradiation
Survival data are summarized in Table 1 and Kaplan-Meier survival plots are shown in Figure 1. The survival plots of all treatment groups were significantly different from those of untreated controls (p < 0.02). Untreated rats had a mean survival time (MST) of 32 ± 2 d compared with 40 ± 3 d for 6 MV X-irradiated animals. Rats that had received carboplatin alone had a median survival time (MeST) of 52 d and a censored MST of 71 ± 7 d, with 1 rat surviving more than 180 d, at which time the study was terminated. Animals that had received carboplatin, followed by X-irradiation with 6 MV photons, had a MST of > 126 ± 8 d and a MeST of > 180 d, with 6 of 11 rats (55%) alive at the end of the study. This was significantly different from irradiated animals (p <0.01) or those that had received carboplatin alone (p = 0.07).
Table 1. Survival times of F98 glioma-bearing rats after prolonged infusion of carboplatin with or without 6 MV X-irradiation from a LINAC source
Figure 1. Kaplan-Meier survival plots for glioma-bearing rats after chemoradiotherapy. The origin of the x-axis corresponds to tumor implantation. Group 1: untreated (×); Group 2: Carboplatin alone (◆); Group 3: 6 MV X-irradiation alone (▴); Group 4: Carboplatin in combination with 6 MV X-irradiation (■).
Rats that received 6 MV photon irradiation alone or in combination with i.c. carboplatin were compared with animals that received synchrotron irradiation (data taken from our previous study [12]) (Figure 2). Although we could not repeat the synchrotron study due to an inability to schedule beam time, all the control groups (radiation alone, carboplatin alone and untreated groups) had equivalent survival times. Both radiation sources, 6 MV photons and synchrotron irradiation, resulted in equivalent survival data with p = 0.66 for the "irradiated only" groups and p = 0.88 for the "chemo-radiotherapy" groups. Similarly, equivalent survival data (p = 0.52) were observed in both experiments for those animals that received carboplatin alone (data not shown).
Figure 2. Kaplan-Meier survival plots for glioma-bearing rats after chemoradiotherapy using either 6MV or 78.8 keV X-rays. The origin of the x-axis corresponds to tumor implantation. Group 3: 6 MV X-irradiation alone (▴); Group 4: Carboplatin in combination with 6 MV X-irradiation (■). The empty symbols correspond to the experiments carried out at the European Synchrotron Radiation Facility in our previous study at 78.8 keV [12]. 78.8 keV synchrotron irradiation alone (Δ); Carboplatin in combination with 78.8 keV synchrotron irradiation (□).
In the present study we have demonstrated that equivalent survival data were obtained in F98 glioma bearing rats that had been treated with the combination of i.c. infusion of carboplatin in combination with radiation therapy using either 6 MV photons from a LINAC or a monoenergetic beam of 78.8 keV X-rays from a synchrotron. Bernardt et al. have described the influence of relaxations of atoms attached to DNA on radiation-induced cellular DNA damage by low energy photons using Monte Carlo track structure calculations [24]. They found that the number of inner shell relaxations produced by photon irradiation generally was small in comparison to the total number of double strand breaks (DSBs) generated by the radiation itself, when the number of high Z atoms introduced by Pt containing cytotoxic drugs was small and compatible with cell survival studies.
Using atomic absorption spectroscopy, Guarnieri et al. and Kahn et al. have mapped the distribution of platinum after i.c. infusion of carboplatin with ALZET pumps into F98 glioma-bearing rats, with delivery parameters similar to those that we used. Platinum concentrations were maximal in brain sections corresponding to the infusion site, with diminished amounts (5 to 1 μg/g tissue) in sections that were 3 mm from the point of infusion [27,28]. The importance of the DNA damage is dependent on the number of Pt atoms intercalated with DNA molecules. At the molecular level, a larger number of DSBs were detected when cells were pretreated with cisplatin and subsequently irradiated with synchrotron X-rays above the Pt K-edge, compared to those below the K-edge [23,29]. Three times more DSBs were detected when human SQ20B squamous carcinoma cells pretreated with 30 μM cisplatin (3 ×× 108 atoms of Pt atoms per cell) for 6 h [29], and 1.3 times more DSBs with the same treatment of F98 cells [23]. However, no such an enhancement was observed (even at the molecular level) with the much lower Pt concentrations that would not have been tumoricidal, when the SQ20B cells were pretreated with 3 μM cisplatin (4 × 106 Pt atoms per cell) for 6 h [29]. In our studies, i.t. injection of cisplatin (3 μg in 5 μl), followed 24 h later by 15 Gy of X-irradiation, also produced similar long-term survival of F98 glioma bearing rats, irrespective of whether the synchrotron X-rays had energies below or above the Pt K-edge [23]. Comparable long term cure rates (17% and 18%) also were observed when the animals were irradiated with 78.8 keV synchrotron X-rays or 6 MV photons after cisplatin (6 μg in 20 μl) was administered i.c. by CED [13]. Overall, the present data and those previously reported [11-13,23,29] are in good agreement with Bernhardt et al's. predictions [24]. They strongly suggest that the therapeutic gain obtained by the direct i.c. administration of Pt compounds, followed by X-ray irradiation, was not due to the production of Auger electrons and photoelectrons emitted from the Pt atoms, but rather involved other mechanisms. Only molecular studies performed using extremely high Pt concentrations, which were not attainable in vivo, demonstrated energy dependence. However, this is not an adequate explanation for the in vivo therapeutic efficacy of the combination of Pt based chemotherapy with X-irradiation. In order for synchrotron radiation therapy to be successful, a sufficient, but not lethal, concentration of high Z number atoms must be incorporated into or localized nearby tumor cells, to produce enough photoelectrons or Auger electrons. Other elements, such as iodine, in the form of contrast agents, or iodo-deoxyuridine (IUdR), gold, platinum or gadolinium nanoparticles are under investigations as radiation sensitizers for synchrotron stereotactic radiotherapy [30-35]. In a recent review, Kobayashi et al. [36] discussed the enhancement of radiobiological effects by heavy elements, in particular gold and platinum. Auger enhancing phenomena to electron and Hadron therapy is also suggested which broadens furthermore their therapeutic applications.
In another study [37] we have used the same chemotherapy protocol, but a different irradiation scheme: the dose was delivered in three fractions of 5 Gy using 6 MV photons and the whole brain was irradiated, beginning on the day after drug administration, using the same Alzet osmotic pumps. The results are very consis-tent with the data presented here, the chemotherapy groups had the comparable survival rates (MST of 77 d ± 23.0 and 71 d ± 7 and 16%, 14% long term survival rates, respectively). Rats bearing tumors, treated with carboplatin and X-irradiation had MST and (MeST) of 111.8 d (78 d), with 40% surviving more than 180 d (i.e. cured), compared to 77.2 d (59 d) for pump delivery of carboplatin alone and 31.8 d (32 d) for X-irradiated alone. There was no microscopic evidence of residual tumor in the brains of all long-term survivors. The biologically equivalent dose-fraction (BED) can be calculated using the classic linear quadratic equation [38,39]:
where n is the number of fractions, d is the dose per fraction in Gy, and α and β are two variables that indicate the sensitivity of tumor or normal tissue to changes in dose fractionation. The α/β ratio is usually taken to be 10 for tumor and early-reacting tissues and 3 for late-reacting tissues like brain. The biologically effective dose (BED) for 15 Gy, delivered in a single fraction, using the α/β ratios indicated above, is 37.5 Gy in acute and tumor effects and 90 Gy in late effects (37). In comparison, the BEDs for 15 Gy delivered in three fractions of 5 Gy each are largely lower: 22.5 and 40.0 Gy, for tumor and normal brain, respectively. The dose per fraction should be 8 Gy, for obtaining BEDs in a three fractions regimen equivalent to those of 15 Gy delivered in a single fraction [11]. The enhanced survival results obtained using a single fraction of 15 Gy, using either 6 MV X-rays (this study) or synchrotron radiation [12], in comparison with 15 Gy delivered in 3 fractions [37] is in good agreement with the calculated equivalent BEDS of these irradiation schemes.
The present study firmly establishes the equivalency of i.c. administration of carboplatin either by infusion via osmotic pumps or CED with irradiation with 6 MV X-rays and synchrotron X-rays. Since medical LINACs are widely available worldwide, this could provide the opportunity to clinically evaluate this combination therapy at multiple centers. Intracerebral CED of carboplatin in patients with recurrent glioblastomas (GBM) will be evaluated in a soon to be initiated Phase I at The Ohio State University. If successful, this could lead to a Phase II clinical trial evaluating the combination of i.c. of carboplatin and radiation therapy to treat patients with recurrent GBMs, for whom unfortunately there are presently no good therapeutic options.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
LB and HE carried out the studies and drafted the manuscript. ME, PD, JFA and FE participated to the experimental studies. JLR participated in the design of the study and in the drafting. JB participated to the irradiation and help to draft the manuscript. JR and RFB participated in the drafting. All authors read and approved the final manuscript.
We are indebted to the European Synchrotron Radiation Facility and medical beamline, particularly to Dominique Dallery for the animal care. We are also grateful to Dominique Charlety (Grenoble CHU pharmacy) for providing carboplatin.
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Br J Radiol 1985, 58:515-528. PubMed Abstract | Publisher Full Text
Douglas BG, Fowler JF: Letter: Fractionation schedules and a quadratic dose-effect relationship.
Br J Radiol 1975, 48:502-504. PubMed Abstract | Publisher Full Text


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Eighty thousand tiny houses dot the cities and countryside in the capital and other parts of Haiti devastated by the January 12, 2010, earthquake that killed up to 230,000, damaged or destroyed 171,584 homes and displaced over a million people.
The Bill Clinton-led Interim Haiti Recovery Commission (IHRC) has approved $254.5 million worth of housing repair and reconstruction projects that will reportedly fix, upgrade or build about 41,759 housing units.
The new government – led…
ContinueAdded by Ayiti Kale Je on August 23, 2011 at 12:30pm — No Comments
Kick-backs, sexual blackmail, nepotism.
All in a day's work for "bosses" and many of the "beneficiaries" of a "Cash for Work" program in the Ravine Pintade slum run by a US "non-profit organization."
Students from the Journalism Laboratory at the State University of Haiti's Faculty of Human Sciences (FASCH) and Haiti Grassroots Watch dug up these scandals and asked hard questions in a new report published on…
Added by Ayiti Kale Je on July 21, 2011 at 6:00pm — No Comments
PORT-AU-PRINCE, Jun 14, 2011 (IPS/Haiti Grassroots Watch) - Almost 17 months after the Jan. 12, 2010, earthquake that devastated Port-au-Prince and three other cities, reconstruction of the capital's downtown appears stalled, and over 800,000 people still live in tents – some 30,000 of them right across from the collapsed National Palace.
Can the slow pace of rebuilding, and of relocating refugees, be blamed on the lack of funding, as some would have it? Or on foreign…
ContinueAdded by Ayiti Kale Je on June 20, 2011 at 8:39pm — No Comments
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Photo by Romulo Yanes
YIELD: Makes about 8 dozen cookies
ACTIVE TIME: 2 hr
TOTAL TIME: 5 hr
Make dough:
Whisk together flour, salt, and cardamom in a bowl.
Beat together butter, cream cheese, and granulated sugar in a large bowl with an electric mixer at medium-high speed until fluffy, about 3 minutes, then beat in yolk and vanilla. Reduce speed to low and add flour mixture in 3 batches, mixing until dough just comes together. Quarter dough and flatten each piece into a block, then chill, wrapped in plastic wrap, until firm, 2 to 3 hours.
Put oven rack in middle position and preheat oven to 350°F. Line 2 large baking sheets with parchment paper.
Keeping remaining 3 pieces chilled, roll out 1 piece of dough 3/4 inch thick on a lightly floured surface with a lightly floured rolling pin, then trim edges to make a 12- by 8-inch rectangle. Chill scraps, wrapped in plastic wrap. Cut rectangle into 2-inch squares with pastry wheel.
Form and bake pinwheels:
Make a 1-inch-long cut in 1 square from tip of each corner in toward center with a small knife, halving each corner. (You will have 8 points.) With tip of knife, lift every other point and gently fold into center, overlapping ends slightly. Press center lightly to form a small well. Put 3/4 teaspoon of jam in center and transfer with a spatula to a lined baking sheet. Repeat with remaining squares, arranging pinwheels 2 inches apart on sheet.
Brush cookies with lightly beaten egg white and sprinkle with decorative sugar.Bake until edges are pale golden, 10 to 15 minutes. Cool 5 minutes on sheet, then transfer from parchment to a rack to cool completely.
While first batch is baking, form pinwheels with another piece of dough. Bake in same manner, then gather scraps and chill until dough is firm enough to reroll, 15 to 20 minutes. Make more cookies with remaining 2 pieces of dough and with scraps in same manner (reroll scraps only once).
Cooks' notes:
Cookies keep, layered between sheets of parchment or wax paper, in an airtight container at room temperature 4 days.
Dough can be chilled up to 2 days or frozen, wrapped in plastic wrap and then foil, 1 month.


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Trigeminal Neuralgia Medications
Definition of Trigeminal Neuralgia:
Trigeminal neuralgia is an extremely painful inflammation of the trigeminal nerve which causes severe lightening-like facial pain and spasm of the facial muscles on the involved side.
These painful attacks may occur after lightly touching different skin areas of the face, along the course of this cranial nerve. Specific medications can be very effective in reducing the rate of attacks, but surgical intervention may be necessary.
Drugs (by generic name) associated with Trigeminal Neuralgia
The following drugs and medications are in some way related to, or used in the treatment of Trigeminal Neuralgia. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.
Drug Name (View by: Brand | Generic ) | Reviews | Ratings | |
oxcarbazepine systemic (Pro, More...) class: dibenzazepine anticonvulsants | 22 reviews | 8.9 | |
gabapentin systemic (Pro, More...) class: | 16 reviews | 8.2 | |
phenytoin systemic (Pro, More...) class: group I antiarrhythmics, hydantoin anticonvulsants | 3 reviews | 8.0 | |
baclofen systemic (Pro, More...) class: skeletal muscle relaxants | 4 reviews | 7.5 | |
carbamazepine systemic (Pro, More...) class: dibenzazepine anticonvulsants | 41 reviews | 7.3 | |
topiramate systemic (Pro, More...) class: carbonic anhydrase inhibitor anticonvulsants | 7 reviews | 7.1 |
Learn more about Trigeminal Neuralgia
Micromedex® Care Notes:
Related encyclopedia articles:
Symptoms and treatment for:
Mayo Clinic Reference:
Synonym(s): Tic Doloureux; TN Pain


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How to Request an MCC Transcript
To request an MCC transcript, we must have your transcript request in writing. You may visit the Student Information Centers on either campus to obtain a form or you may mail a request to us. We need to have your name and date of birth, Student Identification number, your approximate dates of attendance and the complete address where the transcript will be sent. We also need to have your signature in order to release your transcript. There is a fee of $2.00 per transcript.
Display/download the Transcript Request Form.


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"Dave Kraft has written a thorough and enlightening book on leadership that is easy to read and practical, full of great illustrations and stimulating quotations. This is a book for leaders who want to keep growing in their understanding of leadership, finish strongly, and lead with passion."
—Mike Treneer, International President, The Navigators
"Drawing from three decades in ministry and coaching ministry leaders, my friend and fellow Mars Hill pastor Dave Kraft has combined his best insights into Leaders Who Last."
—Mark Driscoll, Founding Pastor, Mars Hill Church, Seattle; President, the Resurgence; President, Acts 29 Church Planting Network
"I love it when a practitioner not a theorist writes a book on leadership. I have known Dave for many years and his personal as well as his professional life is exemplary. He is someone you want to follow. He is a leader that knows how to last. He leads from conviction and character. He is a leader that understands how to place Christ at the center of his world and lead with purpose, passion, priorities, and proper pacing. Leaders Who Last is a powerful tool written by a respected leader who knows how to finish well."
—Greg Salciccioli, Founding President of Ministry Coaching International
"Leaders Who Last is filled with practical principles to develop leaders who will influence others."
—Scott Thomas, Director, Acts 29 Network
"This book carefully constructs a scriptural approach to leadership in a manner that is both accurate and practical. When you combine Dave's sound scriptural basis with his many years of successful leadership, you get a book that should become a handbook for Christians who are serious about learning to lead well. Christians at all levels of responsibility in their organizations will find this information invaluable to their personal growth and effective leadership."
—Keith McGuire, retired director for a federal agency
"Dave Kraft is a proven leader, but he's also a keen observer of leaders and leadership principles. In this valuable book, Dave passes on foundational lessons that will help any leader continue growing, learning, and adapting to our rapidly changing world—a world desperate for what true leaders have to offer. He challenges leaders to live with passion and vision flowing from their God-given design and calling—essentials for those who hope to serve and influence others for a lifetime."
—Pete Gerhard, Professional coach of emerging leaders
"I could have used your book when I began volunteering at Saddleback Church in the Children's and Jr. High Ministry. I believe this book to be an essential tool for any church volunteer starting to serve in their prospective ministry."
—Dave Makela, VP of Sales, Ministry Coaching International
"I must say that it is exceptional. It is superbly written—very readable, great flow, one thought building on another, excellent use of Scripture and illustrations, some very practical ideas that the reader is sure to remember, apply and pass on. Thanks for being in my life, Dave, and for all that you have added into my life as a Christian leader."
— --Coppersmith, Mike, Lead Pastor, Our Savior's Community Church
Dave Kraft served with the Navigators for thirty-eight years. Currently Kraft runs his own coaching practice. He is the author of two books, Leaders Who Last and Mistakes Leaders Make. He and his wife, Susan, have been married for over four decades and have four adult children and seven grandchildren. Learn more about Dave at DaveKraft.org.


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It seems to me that UEFA, the leading governing body for all European football has no care towards the most pressing issue in the sport today. Racism has been creeping back into football now for a number of years all across Europe, but yet UEFA seem undeterred to want to do anything logical about it. They seem to think by throwing a fine at the problem is the solution, seemingly failing to understand or even realise that football today is run by billionaires and a fine in this climate is nothing more than a 'spit in the ocean'. In my opinion UEFA need to get real and really tackle this issue head on, or else this cancer we have growing will eventually kill 'the beautiful game'.
Serbia under 21's vs England under 21's on Tuesday night was just another story in a long line of racist related events in recent times, with Serbia yet again at the forefront. It was in 2007 where England under 21's came up against racist taunts especially at players such as Nedum Onuoha, who went on to describe his abuse as 'one of the toughest 90 minutes he's ever experienced'. The Serbian federation were only fined £16,500 for their role in the chanting and abusive behaviour back then, which I find laughable, now I fear that this time around the worst that will happen is UEFA will implement ANOTHER fine, albeit a heavier one, but to them that is where the case will rest, what I suggest is as follows – 1. Ban Serbia from all European and World based competitions until they learn their lesson.2. Avoid playing any international matches in Serbia.3. Sanction the heaviest fine they can on the Serbian FA for not controlling their crowds.Ideas like the ones I just mentioned would not only be a start with the means to go on, but it would make other nations around Europe take notice for future reference that this kind of behaviour is not acceptable and can not under any circumstances carry on the way it has been.I suppose the only question you have to ask the governing bodies is 'Do you have the guts?'. It has become apparent that the answer to that question right now is NO, which is a crying shame, because if this issue continues to be over looked then what is the point of having a governing body?
John Terry has been fined and was given a minimal ban of 4 matches by an independent panel of the English FA, I'm not so convinced that he will learn his lesson from that and I'm not sold on his pathetic attempt of an apology either, to me he's only doing it because he feels he has too in regards to his credibility and maybe because he was told too by his club, yet no apology has been offered to Anton Ferdinand personally, the man he racially abused. It's an absolute joke.7
Luis Suarez was banned for 9 matches and got a heavy fine for racially abusing Manchester United's Patrice Evra by the FA, though there was no concrete evidence of Suarez actually calling Evra anything, it was more of an 'Evra vs Suarez word against word' – which lead to Suarez being made an example out of, which I (if Suarez did racially abuse Evra) would condone because it is not right and it never will be tolerated in my eyes and that's the stance that UEFA, the FA and every other governing bodies need to undertake and implement sooner rather than later.
When Will England Learn?You can cover it up in as many versions as you like, supporters and pundits alike need to understand very quickly that the ENGLAND national team are no longer competing in the top tier of European or World football. I do however agree that the Premier League is the best league in the world as far as excitement goes, but I draw the line at saying that England are still a major force in International football. The fact is the Premier League right now is the best league in the world because of the foreign talents that have come and plied their trades here, you can say that because of this the result has been the younger English talents haven't had the chance to showcase what they're made of, which in some aspects is true.But take into consideration that for the best part of a decade now, maybe longer, the three lions haven't really lived up to their billing, tournament in tournament out huge expectancy is placed on their shoulders to deliver – with the same predictable outcome. There is no flair, no real quality and no real ideas of how to unlock the best defences in the world.The problem with England is (and I have been saying this for years) is there are too many individuals, that doesn't make a team, it never has. Players over the years have all been of the highest quality, you name them, Seaman, Hart, Ferdinand, Terry, A Cole, Rooney, Linekar, Gascoigne, Adams, Beckham, Scholes, Gerrard, Lampard, Shearer, Owen, there are so many of the 'golden' era or generation that I have missed that just couldn't seem to get the job and that's not down to coincidence, sometimes you have to admit that you're just not good enough anymore.So many managers that have come to the A fore to manage England have had the same philosophy, never kept the same shape but effectively have had the same idea of getting the ball down to play football, of course it's the right way but there are teams who clearly do it better – BECAUSE technically they are better equipped, take Spain for example, freedom to roam, passing is crisp, flow is quick, it's the movement, the pattern and philosophy they play that makes them so successful, they are the blueprint that others including England should follow.I credit Roy Hodgson for what he is trying to do, but he just doesn't have the players at his disposal to implement the way he wants the team to play and I feel even with the imminent comeback of Jack Wilshere, England are still some way off.
Well written!
Great article! Well written!
By Whitehouse Address
By The Football History Boys


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Dowd: Cruz takes Republicans down the rabbit hole
Published October 12, 2013 4:19 pm
This is an archived article that was published on sltrib.com in 2013, and information in the article may be outdated. It is provided only for personal research purposes and may not be reprinted.
This article cannot be shown due to contract restrictions.


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Sunbutter Frosting
prep:5 minutes
ready in:5 minutes
- 1 cup 1 cup 1 cup Sunbutter
- 1/2 cup 1/2 cup 1/2 cup Organic [*Spectrum Brand, sustainably sourced] Palm Oil Shortening
- 1/2 tsp 1/2 tsp 1/2 tsp Pure Vanilla Extract
- 1/2 tsp 1/2 tsp 1/2 tsp Salt
- 1 tsp 1 tsp 1 tsp Grade B Maple Syrup
Note, these instructions are written assuming the standard serving size, since you have modified the number of servings, these steps may need to be modified for best results
- Whip all ingredients with a hand blender until fluffy.
- Refrigerate frosting until use.
- Whip again before frosting the cupcakes.
Our recipes are created using Paleo, Primal and Gluten-free guidelines. Learn more about our diet and lifestyle at www.primalpalate.com.


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See all The Hairy Bikers' Food Tour of Britain recipes (75)
Simon King and Dave Myers get on their bikes to find the best of each county's larder
Type the ingredients you want to use, then click Go. For better results you can use quotation marks around phrases (e.g. "chicken breast"). Alternatively you can search by chef, programme, cuisine, diet, or dish (e.g. Lasagne).


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Editors' Review
+SmadAV2013 provides decent antivirus protection, even if its scans take a while to finish up. It offers proactive protection in addition to some neat security features that protect your computer from onsite saboteurs. There aren't many unturned stones in the world of antivirus software, though, and this program doesn't seem to find any of them.
In addition to scanning and actively protecting your computer from viruses, SmadAV2013 can scan your registry for nasty information, but not generic errors like a true registry cleaner would. The program's installation process and license agreement seem to be written in Indonesian and you won't get a chance to change the language to English until you've completely installed the program. SmadAV2013's layout organizes all of its features into easy-to-understand tabs, but it's not very easy on the eyes. It doesn't help that there's a big ad for other developers' programs taking up a lot of space. The program's virus scan took about 40 minutes to complete, which isn't terribly fast compared to competitors. It makes up for that lack of speed by giving you a process manager that's more detailed than Windows and letting you lock any of your hard drives.
This program isn't bad AV software, but it's too late to the party to win users over the dozens of great options around it. It doesn't offer enough bonuses over the top downloads, either. SmadAV2013 just won't wow enough people to compete with avast!, Avira, or the other great security software that's widely available and easier to use for English audiences.
Publisher's Description
+SmadAV is an additional antivirus software that is designed to protect your computer.
1) Additional protection for your computer, 100% compatible with other antivirus software! Works with your primary antivirus as an extra layer of defense.
2) Best USB Antivirus (Total Protection USB drives)Prevent viruses that spread through USB stick drives.
3) Best for offline use (no need to update very often) Designed to be used with computers that are rarely or not even connected to the internet. SmadAV does not need to be updated as often as other antivirus. (Regularly updates once a month).
4) Cleaner and tools to clean the virus. SmadAV not only removes viruses but can also fix registry problems in infected machine.
What's new in this version:
- Changes in appearance and language.
- New virus database 212.
- Completion of immunization methods via USB flash.


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Kasab and nine other gunmen entered Mumbai by boat on Nov. 26, 2008. Carrying cellphones, grenades and automatic weapons, they fanned out across the city, targeting two luxury hotels, a Jewish center, a tourist restaurant and a crowded train station. The attack was broadcast live on television, transfixing the nation and the world. A photo of Kasab striding through Mumbai's main train station, an assault rifle in hand, quickly became the iconic image of the siege. An Indian judge sentenced Kasab to death in May 2010 for waging war against India, murder and terrorism, among other charges. Kasab cried as he heard the sentence. In his confession, Kasab said he was recruited by Lashkar-e-Taiba after he left a low-paying job as a shop assistant in search of greater fortune as a bandit. The attackers were in regular phone contact with handlers in Pakistan during the siege. Some in India felt Kasab should have been hanged publicly. Others complained that the government had spent too much money on the care and feeding of a vilified criminal and said that for justice to be done, the attack's masterminds
-- not just their foot soldier -- must be punished. Mukesh Agarwal, who was shot in his right arm during the attack, called Kasab's execution "the best possible gift" from the Indian government. But he said "instead of secretly hanging him, they government should have hanged him publicly." "I am sad and happy both," said Sonu, an office clerk in New Delhi who uses one name. "Sad because I wonder what forced him do such things and happy because this will be a good example to all the terrorists in the future."
Copyright 2012 The Associated
Press. All rights reserved. This material may not be published,
broadcast, rewritten or redistributed.
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Called out for poor behavior today!
View Single Post
Join Date: Sep 2007
Location: Columbus, OH
Posts: 812
We all play for different reasons; some of us for exercise, some for competitiveness, etc.
I used to go crazy when I was a kid. I've been on both sides. It's ridiculous either way. Have you noticed how stupid, childish, foolish, etc. the other guy looks while carrying on? Guess what? You did too. I can see why someone wouldn't want to be associated with that person. I wouldn't want to be there either; especially, when you are sailing balls into the net behind me instead of just hitting them to me. I certainly don't want to have to chase down your tantrums. You can throw and break stuff on your side of the court which is unsportsmanlike but when you bring it to my side, I'm going to let you know just as your opponent did. I'm sure he has other people he can play and not have to deal with antics.
If you couldn't tell, I think he made the right choice. That said, I'm glad you apologized and he gave you another chance.
In this instance with the details as we know them, I think you both did the right thing.
Back to using POGs. Why did I ever leave you dear friend?
View Public Profile
Find More Posts by dak95_00


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- Filed Under
The third in a series of hearings to consider approving Jackson's first all-girls Orthodox Jewish high school will be held Wednesday before the township Zoning Board.
Testimony on Oros Bais Yaakov - a 400-student, two-story school proposed to be built on Cross Street - began in early October and drew more than a thousand spectators to its last of two hearings.
Many Jackson residents oppose the plan, fearing the school could pose a risk to wells in the surrounding residential neighborhoods and would significantly increase traffic. But parents hoping to enroll their daughters argued the ...


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user functionsCurrent Ithaca College community members may contribute stories and comments as well as view additional topics by logging in. sectionsrelated linksroundup
NCAA Championships Highlights to Air July 2Contributed by Michael Warwick on 06/28/2005 The NCAA spring sports championship highlight show will air Saturday, July 2, at 5:00 p.m. on CBS. The show features highlights of NCAA spring sport champions in all sports and all divisions, including the IC womens crew which won its second straight national title. |


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Follow Me - Punta San Carlos Slideshow
A Mountain Biking video by Mpora - 5,085 views
Some shots from our trip to Punta San Carlos, as seen in the DVD extras from Follow Me. Featuring Cam McCaul, Matt Hunter and Geoff Gulevich.
Photos: Haruki "Harookz" Noguchi harookz.com.
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Created in this Craftsy class
Donna teaches basic sock knitting, but even experienced sock knitters will pick up new tricks, including the Kitchener stitch and figure-8 cast-on.
Other projects made as part of this class:
View all class projects »Offer some kudos...
Join the conversation...
Ask a question...
Add your comment...
Here are some details about my project: | |
Category | Knitting |
Type | Accessory |
Yarn Weight | Fingering (4 ply) |
Sizing | Women |
Style | Casual, Classic, Traditional, Cute |
Well these look wonderful on you! Great job making them long over the knee. I now know that I can make them for my daughter and daughter -in-law and grandchildren. Much to my surprise, I have old lady legs. That was a shock!!!
Love your socks. Now thinking about if I have enough yarn to do the same thing... :)
These look really good! They should use them for the class example as they are much more attractive than the red ones she has in there. did you do extra increases over the leg above the knees sock ending area or just continue straight? I agree it would be better to make them longer with more ribbing at the top. I'm a dancer and I like long leg warmers which these remind me of with feet! You are obviously a dancer too ( your feet and legs tell me!) Having made leg warmers a few times now I make them about 4" longer than your socks and end with 2.5 -3 inches ribbing at the top. I do insert elastic and they do stay up now.