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Preoperative Evaluation for Patients With Choroidal/CiliaryBody Melanomas: What Is Necessary?CHARLES C. WYKOFF, TIMOTHY G. MURRAY, ARNOLD M. MARKOE, LYNN G. FEUN,AMY C. SCHEFLER, AND STEVEN GAYERCmost common cause of death. The Collaborative OcularMelanoma Study (COMS) trials were a series of multi-center, randomized clinical studies examining treatmentsfor uveal melanoma. In the COMS, the presence ofmetastatic disease at the time of diagnosis was less than1%.2However, the melanoma-specific mortality rates at 5years were 10% for medium and 30% for large tumors.3Since rates of local tumor control, by either radiotherapyor enucleation, approximate 100%, the assumption madeby most researchers is that the majority of patients thatdied from metastatic ocular melanoma in the COMS trialshad micrometastases at the time of diagnosis that wereundetectable by the methods used in the COMS.4In the face of the low metastatic detection rate in theCOMS, many clinicians agree that preoperative screeningfor metastatic disease in patients with choroidal melanomais justified for 3 main reasons, each with significantcontroversy:1) Patients with metastatic disease have a limited survivalnot affected by local therapy and thus the presence ofmetastases at diagnosis may obviate, or alter the approachto, local therapy.5In contrast to this theory, somepatients with metastatic disease do have prolongedsurvival. For example, Rietschel and associates re-ported that 22% of 119 patients were still alive 4years after diagnosis of metastases.6Thus, it may bereasonable for patients to undergo local globe-con-serving therapy despite the presence of concurrentmetastatic disease in order to preserve vision andprevent ocular complications that may arise fromunchecked tumor growth.2) Patients with metastatic disease may respond better totherapy if the metastases are detected earlier. Recently,a meta-analysis of data from prospective studiesanalyzing survival in patients with metastatic uvealmelanoma revealed a median survival of 5 to 24months after diagnosis of metastases, with a reportedHOROIDAL MELANOMA IS THE MOST COMMON PRI-mary intraocular malignancy of adults,1and com-plications arising from metastatic disease are theprolongation of survival in selected patient groupssubjected to aggressive invasive interventions.7Thisapparent prolongation of survival, however, waslikely explained by surveillance and lead-time biasesand not directly by the screening itself or anysubsequent treatments. Therefore, the detection ofmetastatic disease at an earlier stage may only appearto prolong survival, but not actually extend it.3) Many patients desire prognostic information to better helpwith life planning.8Cook and associates reported that97% of patients who underwent cytogenetic testingdesired prognostic information about the possibilityof metastatic disease even if it would not prolongtheir survival. However, imaging studies may resultin false-positive results, subjecting patients to unnec-essary biopsies and additional procedures, and studiesof patient preferences with respect to screening havenot addressed the consequences of incidentalfindings.CURRENT SCREENING STRATEGIESNO PROSPECTIVE TRIALS HAVE COMPARED DIFFERENT PRE-operative screening regimens. In the COMS, preoperativemetastatic screening included liver function tests (LFTs)and chest radiographic imaging.2● LIVER FUNCTION TESTS: The liver is the initial site ofmetastasis in 46% of patients, and up to 93% of patientswith metastatic disease eventually develop hepatic metas-tases.9Because LFTs are a relatively insensitive marker formild liver dysfunction, these tests are generally normal,even in patients with known metastatic disease. Thesensitivity, specificity, positive predictive value (PPV), andnegative predictive value (NPV) associated with at least 1abnormal LFT before diagnosis of metastasis in patients inthe COMS after local treatment were only 14.7%, 92.3%,45.7%, and 71.0% respectively.2The laboratories ordered in an LFT panel typically includeaspartame and alanine aminotransferase, alkaline phospha-tase (Alk Phos), and lactate dehydrogenase (LDH). Amongthese tests, LDH may have the highest sensitivity andPPV.10,11Because both LDH and Alk Phos may reflect tumorburden, these tests may have prognostic significance as well.12Other serum markers such as osteopontin, S-100beta, andAccepted for publication Jan 26, 2011.From the Bascom Palmer Eye Institute (C.C.W., T.G.M., A.C.S.,S.G.), Department of Radiation Oncology (T.G.M., A.M.M.), Depart-ment of Oncology (L.G.F.), and Department of Anesthesiology (S.G.),University of Miami School of Medicine, Miami, Florida.Inquiries to Timothy G. Murray, Bascom Palmer Eye Institute, 900NW 17th St, Miami, FL 33136; e-mail: email@example.com© 2011 BY ELSEVIER INC. ALL RIGHTS RESERVED.0002-9394/$36.00doi:10.1016/j.ajo.2011.01.050921
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melanoma-inhibitory activity have been studied and mayplay roles in screening for metastatic disease.13● CHEST RADIOGRAPHY: The sensitivity and specificityof chest radiography (CXR) in a series of 235 choroidalmelanoma patients undergoing preoperative testing werereported to be 1.8% and 100% respectively.10In theCOMS, even when restricting the analysis to CXRsobtained within the 90-day period before diagnosis ofmetastasis, sensitivity, specificity, PPV, and NPV were35%, 98%, 65%, and 93%.2The COMS and other studies have recommended pre-operative CXR to rule out a primary lung tumor, but noroutine follow-up CXR.10,11However, since the PPV ofthe test prior to local treatment is even lower than whenused for follow-up, the usefulness of this test at diagnosis orfollow-up is questionable. Patients who are current orformer smokers or those who have pulmonary symptomsmay be particularly good candidates to undergo this testboth at diagnosis and on follow-up.● ABDOMINAL COMPUTED TOMOGRAPHY SCAN: Basedon the low sensitivity of LFTs, clinicians have explored theuse of abdominal imaging for metastatic detection. Fein-stein and associates reviewed the records of 91 patientswho underwent computed tomography (CT) scanningwithin 1 month of uveal melanoma diagnosis,9and anal-ysis of their data indicated a sensitivity, specificity, PPV,and NPV of 100%, 91%, 27%, and 100%, respectively.The low PPV was attributable to a variety of benignhepatic lesions detected with CT.● ABDOMINAL ULTRASOUND (US): Eskelinandassociatesreported on 46 uveal melanoma patients who developedmetastases after undergoing baseline screening examinationsfollowed by yearly examinations utilizing LFTs, CXR, andabdominal ultrasound (US).11Abdominal US revealed un-equivocal hepatic metastases in 36 patients (78%), of whom12 (33%) had normal LFTs. US was suggestive of metastasesin5additionalpatients(11%),allofwhomwereconfirmedtohave hepatic metastases by fine-needle aspiration biopsy, CT,or both. US was negative in 2 patients (4%), both of whomhad liver metastases and at least 1 abnormal LFT. Of 30metastases identified in 4 patients at diagnosis, US detected37%, magnetic resonance imaging (MRI) detected 67%, andCT detected 77%; however, the authors recommended USgiven its lower cost and easier accessibility. The authorsconcluded that screening with abdominal US, CXR, andLFTs at diagnosis and subsequent semiannual LFTs andabdominal US would result in detection of 98% of metastaticlesions prior to patients' reporting of symptoms.● POSITRON EMISSION TOMOGRAPHY/COMPUTED TO-MOGRAPHY: Positron emission tomography/computed to-mography (PET/CT) combines high-resolution anatomicand functional imaging by using radioactive glucose. Al-though early case reports and small series were encouragingin that they identified patients with metastatic diseasewhose LFTs were normal,14the prevalence of metastaticdisease in the largest published study was only 3.8%.Therefore, while PET/CT is an improvement over priorscreening techniques, with current resolution capabilities asignificant proportion of metastases are likely still beingoverlooked. Additionally, compared with the previousimaging modalities discussed, PET/CT is expensive and,like other imaging modalities, false-positive findings maylead to unnecessary imaging and biopsies.14● ABDOMINALWhile no studies have been published to date assessing thesensitivity of MRI for uveal melanoma micrometastases,several centers perform this test routinely. Advantagesinclude high-resolution images, relative accessibility com-pared to PET/CT, and lack of radiation exposure. Themain disadvantages are high cost and potential false-positive findings.MAGNETICRESONANCEIMAGING:● GENETIC TESTING: In attempts at genetic prognostica-tion, various approaches have been employed that involveacquisition of tumor tissue at the time of initial treatment.Initially, certain chromosomal alternations were recog-nized to portend poor prognoses, including monosomy 3,loss of 1p and 8p, and gain of 8q. More recently, patternsof tumor RNA expression15have been shown to be moreaccurate predictors of which patients are more likely todevelop metastatic disease. However, such genetic testingis not currently absolutely predictive of metastases andcollection of samples for analysis remains controversial.This is not preoperative testing per se, but has become anintegral part of the diagnostic algorithm at many centers.SCREENING FOR SECOND PRIMARYCANCERS AND OTHER PERIOPERATIVERISK FACTORSPREOPERATIVE SCREENING OF PATIENTS WITH CHOROIDALmelanoma is also important for the detection of secondprimary cancers. Patients should undergo age-appropriatecancer screening and continue such screening. The COMSreported a 7.7% rate of second primary cancer over 5 yearsin the medium-size tumor population.16Additionally, all patients with choroidal melanomashould undergo routine preoperative surgical screening.Age is a significant risk factor for the development ofchoroidal melanoma and many patients undergoing surgi-cal treatment are elderly. Although healthy, asymptomaticpatients undergoing elective surgery may require only athorough history and physical examination, elderly pa-tients have increased frequency and severity of comorbidconditions that may limit their functional capacity andincrease the risk of the perioperative period. PatientsAMERICAN JOURNAL OF OPHTHALMOLOGY922JUNE 2011
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should be assessed by a physician familiar with preopera-tive screening.RECOMMENDATIONS AND FUTUREDIRECTIONSIN SUMMARY, PREOPERATIVE EVALUATION OF PATIENTSwith choroidal melanoma should include age- and sex-appropriate cancer and routine surgical screening. Regardingthe metastatic evaluation, there is no consensus about thebest battery of tests. Limited published literature to dateindicates that a CXR, LFTs, and/or abdominal US representa reasonable first approach. The sensitivity of any individualtest is low, but when combined, the likelihood of diseasedetection increases. In some patients, particularly those withlarge tumors, we recommend an abdominal MRI (Table).One important consideration when ordering any im-aging study that uses radiation is the radiation-associ-ated risk conferred.17Radiation exposure, even inrelatively low doses such as those from a single CT scan,may increase a patient's lifetime risk of cancer. A recentestimate is that 1.5% to 2% of all cancers in the UnitedStates may be attributable to radiation from CTstudies.18Unfortunately, there is no clear evidence that earlydetection of metastases extends survival even in patientstreated aggressively. Multigene expression assays per-formed on tumor tissue are an exciting development, andwill be better suited for widespread screening once there isan effective treatment for metastatic disease. In the future,gene expression profiling of tumors may be able to reliablyidentify high risk patients who can then undergo furthergenetic stratification into subgroups linked to certainpatterns of metastatic disease. Armed with this type oftumor genetic signature, the clinician could reasonablyperform a more focused metastatic work-up thereby im-proving cost-effectiveness and sensitivity rates.PUBLICATION OF THIS ARTICLE WAS SUPPORTED BY THE HEED OPHTHALMIC FOUNDATION, CLEVELAND, OHIO (C.C.W.);National Institutes of Health center, Bethesda, Maryland (grant P30-EY014801); and unrestricted grants to the University of Miami from Research toPrevent Blindness, New York, New York. Funding sources had no role in design or conduct of this research. Dr Murray has served as a consultant forAlcon Surgical. Involved in design of study (C.C.W., A.C.S., T.G.M.); conduct of study (C.C.W., A.C.S., T.G.M.); collection of data (C.C.W., A.C.S.,T.G.M.); management, analysis, and interpretation of data (C.C.W., A.C.S., A.M.M., L.G.F., T.G.M.); and preparation, review, and approval of themanuscript (C.C.W., A.C.S., A.M.M., L.G.F., T.G.M.).REFERENCES1. Egan KM, Seddon JM, Glynn RJ, et al. Epidemiologicaspects of uveal melanoma. Surv Ophthalmol 1988;32(4):239–251.2. Diener-West M, Reynolds SM, Agugliaro DJ, et al. Screen-ing for metastasis from choroidal melanoma: the Collabora-tive Ocular Melanoma Study Group Report 23. J Clin Oncol2004;22(12):2438–2444.3. Hawkins BS. The Collaborative Ocular Melanoma Study(COMS) randomized trial of pre-enucleation radiation oflarge choroidal melanoma: IV. Ten-year mortality findingsand prognostic factors. COMS report number 24. Am JOphthalmol 2004;138(6):936–951.4. Eskelin S, Pyrhonen S, Summanen P, et al. Tumor doublingtimes in metastatic malignant melanoma of the uvea: tumorprogression before and after treatment. Ophthalmology2000;107(8):1443–1449.5. The COMS randomized trial of iodine 125 brachytherapy forchoroidal melanoma: V. Twelve-year mortality rates andprognostic factors: COMS report No. 28. Arch Ophthalmol2006;124(12):1684–1693.6. Rietschel P, Panageas KS, Hanlon C, et al. Variates ofsurvival in metastatic uveal melanoma. J Clin Oncol 2005;23(31):8076–8080.7. Augsburger JJ, Correa ZM, Shaikh AH. Effectiveness oftreatments for metastatic uveal melanoma. Am J Ophthal-mol 2009;148(1):119–127.8. Cook SA, Damato B, Marshall E, Salmon P. Psychologicalaspects of cytogenetic testing of uveal melanoma: prelimi-nary findings and directions for future research. Eye (Lond)2009;23(3):581–585.TABLE. Recommendations for Use of Available Preoperative Screening Tests for Patients With Uveal MelanomaRecommendationsPreoperative Screening TestsStrongly recommendedAge-appropriate cancer (colonoscopy, mammography, etc) & perioperative riskfactor screening (cardiovascular evaluation, etc)Liver function testsChest radiographyAbdominal ultrasoundAbdominal magnetic resonance imagingAbdominal computed tomography scanPositron emission tomography/computed tomographyGenetic testing (from tumor biopsy)RecommendedRecommended for patients with large tumorsTo consider only after extensive patient counselingand discussionEDITORIALVOL. 151, NO. 6923
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9. Feinstein EG, Marr BP, Winston CB, Abramson DH. Hepaticabnormalities identified on abdominal computed tomography atdiagnosis of uveal melanoma. Arch Ophthalmol;128(3):319-323.10. Hicks C, Foss AJ, Hungerford JL. Predictive power ofscreening tests for metastasis in uveal melanoma. Eye (Lond)1998;12(Pt 6):945–948.11. Eskelin S, Pyrhonen S, Summanen P, et al. Screening formetastatic malignant melanoma of the uvea revisited. Can-cer 1999;85(5):1151–1159.12. Eskelin S, Pyrhonen S, Hahka-Kemppinen M, et al. Aprognostic model and staging for metastatic uveal melanoma.Cancer 2003;97(2):465–475.13. Barak V, Frenkel S, Kalickman I, et al. Serum markers todetect metastatic uveal melanoma. Anticancer Res 2007;27(4A):1897–1900.14. Finger PT, Kurli M, Reddy S, et al. Whole body PET/CT forinitial staging of choroidal melanoma. Br J Ophthalmol2005;89(10):1270–1274.15. Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate,clinically feasible multi-gene expression assay for predicting metas-tasis in uveal melanoma. J Mol Diagn 2010;12(4):461–468.16. Diener-West M, Reynolds SM, Agugliaro DJ, et al. Secondprimary cancers after enrollment in the COMS trials fortreatment of choroidal melanoma: COMS Report No. 25.Arch Ophthalmol 2005;123(5):601–604.17. Fazel R, Krumholz HM, Wang Y, et al. Exposure to low-doseionizing radiation from medical imaging procedures. N EnglJ Med 2009;361(9):849–857.18. Brenner DJ, Hall EJ. Computed tomography—an increasingsource of radiation exposure. N Engl J Med 2007;357(22):2277–2284.AMERICAN JOURNAL OF OPHTHALMOLOGY924JUNE 2011
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Mario's Pizza
Mario's offers delicious pizza and other favorites, served by Mario's friendly staff.
Sleep Inn & Suites
Opened in November 2008, the Sleep Inn & Suites hotel quickly became know for exceptional customer service, cleanliness and value. Greenville's historical town square, offering many antique shops and art galleries, restaurants and the Globe Movie Theater is minutes away.
Wellness Matters, LLC
Relax and Rejuvenate with a full body deep tissue massage, theraputic facial treatments, Migun Far-Infrared Massage Bed. Health and Wellness Business/Practice. Retail includes Standard Process Whole Food Supplements, Tart Cherry Juice, Ezekial Bread, Celtic Sea Salt, Nordic Natural Fish Oil Supplements, Indigo Wild Products- all natural goats milk soaps infused with essential oils. Also includes room sprays, lotions, rubs. Swan Creek candles- all natural soy and lead free. Serrv products- fair trade program, handmade items from Third World countries. Located in Historic Downtown Carlinville off Route 66.
Greenville College
Greenville College's H.J. Long Gymnasium, a 2,000-seat venue, houses the varsity volleyball and basketball programs, and is capable of being configured for two additional courts. The Crum Recreation Center features a fantastic gym setup, and can handle two basketball, tennis or volleyball courts.
M Star Motel
44 rooms, outdoor pool, whirlpool, pets allowed, complimentary breakfast, wireless internet
Marcoot Jersey Dairy & Creamery
This working dairy has been in the Marcoot family for seven generations. Bring your family to see all aspects of the farm from raising calves through milk, ice cream, butter and cheese production.
My Sister's Closet
Distinctive women's and children's apparel - in business since 1974.
Quality Inn & Suites - Litchfield
The Quality Inn & Suites is conveniently located on historic Route 66, only 45 miles from Springfield and several historic points of interest, including the Abraham Lincoln Presidential Library and Museum.
Holiday Inn Express - Litchfield
Conveniently located between Springfield, IL and St. Louis, MO. Near the historic Old Route 66. Litchfield Lake Lou Yeager boasts a beautiful lake, nature trails and picnic areas, 3 mi from the hotel. There are a variety of restaurants nearby.
Country Side Inn
24-room property - two-story interior corridor hotel. Located near Lake Hillsboro, Glenn Shoals Lake and Coffeen Lake.
Loft and Home - Litchfield
Housewares and a variety of items.
Dimestore Antique Mall
General antique shop.
Gloria's Flowers and Gifts
Gloria's offers a large variety of fresh flowers, plants, contemporary and traditional arrangements, silk flowers, wedding arrangements, funeral designs, candles, and gourmet gift baskets.
The Sweetest Things
The Sweetest Things has so many decadent hand made chocolates as well as fresh bakery sweets to indulge in. There is a quaint dining area and a cozy lounge area where you can enjoy a specialty coffee drink or a delicious fruit smoothie. They serve delicious deli style lunches throughout the week, with a menu that always changes. But one item always remains, the loaded baked potato soup. A delicious secret recipe handed down to the owner through the generations that is prepared fresh daily as a side option for the "white bag special" lunch combo.
Powhatan Restaurant
Powhatan Restaurant has delicious diner dishes such as burgers and sandwiches. Located next to the Powhatan Hotel. Beer and wine available.
Hampton Inn - Litchfield
Brand New Hotel offers a variety of rooms from standard double queen rooms to king and whirlpool tub suites. Relax in the hotel indoor heated pool and whirlpool or host your next meeting in our executive conference room.
Lighthouse Lodge
21 room hotel, credit cards accepted, cable television, pets accepted, restaurant within walking distance.
Red Rooster Inn
Welcome travelers, wayfarers and refined persons. Celebrating 100 years, this historic inn is on the Courthouse Square in Hillsboro. Restaurant and bar at the facility.
Chang's Chinese Restaurant
Chang's offers delicious Chinese food in a family friendly atmosphere with affordable prices and excellent service.
The Turret Cafe
Great Coffees...Healthy Smoothies...Delicious Sandwiches, Soups, Salads & Desserts.
Adams Brother's Coffee House
Adam's Brother's Coffee House offers a variety of tasty American classics.
Cunetto's Restaurant
Cunnetto's is a full service restaurant that offers diverse menu of American cuisine for breakfast, lunch, and dinner. There is also a sports bar serving drinks nightly.
Hibachi Buffet
Asian buffet-style food.
Tomahawk Camp Ground
142 sites, electricity, water, sewer, showers.
Hillsboro Sherwood Forest Campground Montgomery County
Camping, Hiking, Fishing along with many special events. Call ahead for information.
Third Street Market
Third Street Market features a unique blend of new and old merchandise.
"Life is good at Kahuna's!" Come on by for a burger, shake, fries, and of course, your favorite flavored Ski! HOME OF THE COMET-KAZIE.
Funderburk's Gas Grill & Deli
Funderburk's offers delicious deli favorites.
Nuby's Steakhouse
Nuby's offers a great meal with excellent service and a large selection of appetizers, soups, salads, sandwiches, seafood, chicken and of course, steak! Relax with friends and family. Beer, wine, kids' menu.
Route 66 Half-Marathon
Race down memory lane during this one of a kind Route 66 Half Marathon hosted by the City of Litchfield and RaceMaker Productions. If a half marathon is too much for you, do not worry, we have a race for everyone. Try running the 5K or Mile Dash.
Litchfield Pickers Market
An open air market featuring vintage, antique, collectible and repurposed items for sale, with many additional special attractions during each Market! The Litchfield Pickers Market will be held the second Sunday of each month from April to October in Downtown Litchfield beginning on the corner of Union Avenue and State Street. The exact dates are April 12, May 10, June 14, July 12, August 9, September 13, and October 11.

subset: commoncrawl


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A second psychologist called as a witness for the defense testified Wednesday during the competency hearing of Curtis Martin that the defendant is mentally unfit to stand trial on charges he tried to kill a restaurant server because the employee is gay.
Case attorneys wrapped up heated rounds of questions posed to Dr. Jeffrey Davis on Wednesday afternoon before Senior Deputy Public Defender Robert Ikola called Dr. Robert Owen as his second witness.
Both psychologists testified they believe Martin, a 25-year-old parolee from Santa Maria, is unable to properly assist in his own defense as required under the law.
Owen, who met with Martin on three separate occasions, testified that the man suffers from paranoid schizophrenia, substance abuse problems, an anti-social personality and a mood disorder. Martin has shown himself to be in turn depressed or angry and volatile, depending on his state of mind, according to Owen.
"He is a man who struggles to control his feelings, his mood," Owen added.
The defense has the burden of proving during the competency trial that started Tuesday before Judge Patricia Kelly in Santa Maria that Martin is incompetent. In order to find Martin incompetent, the jury must agree that more evidence exists in favor of Martin's incompetency than his competency. The District Attorney's Office will present evidence that Martin is competent.
Typically, if a defendant in a criminal case is found incompetent to stand
trial, the person is sent to a state mental hospital and treated until doctors there determine he or she is able to appropriately assist his or her attorney in court.
Martin allegedly stabbed a man in his 30s because the victim is gay. The victim's name has not been released.
Martin faces charges of attempted murder, violating civil rights, and special allegations of infliction of great bodily injury, use of a deadly weapon, committing a hate crime and having a prior serious or violent felony conviction, also known as a "strike" under California's "three strikes" law.
The defendant is being held in county jail without bail because of a parole hold.
Prosecutors allege that Martin's murder attempt was willful, premeditated and deliberate, which could send him to prison for life if found to be true.
According to Santa Maria police, early in the morning hours of Sept. 14, 2010, Martin knocked on the window of the Denny's Restaurant on East Main Street, which was closed, and asked to use the restroom.
When he was let in, he approached a group of employees sitting at a table. Martin asked the victim, a waiter at the restaurant, if he was gay. When the victim replied that he was, Martin stabbed him twice, police allege.
The victim recovered from a throat cut and a puncture wound to the side of his neck.
Wednesday afternoon while Davis was still on the stand, Senior Deputy District Attorney Kevin Duffy vigorously cross-examined the psychologist about his finding that Martin is incompetent for trial despite the fact that Davis was only able to spend about 15 to 20 minutes talking to Martin before Martin refused to cooperate with him.
"He didn't express any delusional ideas in my time with him," Davis testified under Duffy's inquires, adding that he believes Martin understands the potential consequences he faces if convicted of attempted murder and the other charges.
Davis said his finding that Martin is incompetent for trial arises from his belief that if Martin continues to make angry outbursts in court as he has in the past, he could negatively affect the outcome of his trial.
Owen testified during questioning by Martin's attorney, Ikola, that the first time he tried to talk to Martin, the defendant was unwilling. However, Martin spoke with him on the second two examinations. Although Martin did seem to remain mostly logical during the interviews, the witness said, Martin did express some paranoid beliefs about his family and people who are gay.
Owen said his diagnosis of Martin as schizophrenic plays a large role in his finding that the defendant is incompetent for trial. Martin has refused medication for his mental illness, according to Owen.
Owen is set to return to the witness stand this morning.


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We had a wonderful stay and we were very comfortable at this spacious apartment completely equipped with a large bay view balcony and indoor parking place.
Leigh has been very helpful and nice.
I spent 4 nights here with my Mum and we thoroughly enjoyed our stay. The apartment was fab - and had everything we needed. We ate in most nights and had lovely mornings on the balcony for breakfast. The swimming pool was an absolute bonus and very nice. Would definitely recommend and use again!
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Loved the apartment - clean spacious great views but building site next door woke us before 8 every day. At the time of booking there was a photograph of a pool (it has since disappeared) so packed swimming things only to find no pool at all when we arrived. However we did go to the international pool which had 4...
Hi there, Sorry yes pool was closed for a while so it could be upgraded. It's open now and we pay a management company to look after it so yes it is sometimes closed but this is rare and when you book I email you if it's closed so you have a chance to cancel. I must show everyone how...
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Hotel Fuerte Miramar
Avda. Severo Ochoa 8 - 29603 Marbella (Málaga) - Show map
- Accessibility
- We offer rooms adapted to people with reduced mobility.
- All of the hotel's common areas can be accessed by ramp.
- Check-in / check-out
You can enter your room from 12 to 2pm on the day of arrival. Check-out is by 12 midday, with the option of late check-out depending on availability. You can consult prices and availability at Reception.
- Directions
Check all the information about how to get the hotel and the main places of interest.
- Pool towels
When you get to the hotel, Reception will give you a "towel card" for each guest. This card can be exchanged at the towel area, located by the pool from 10.00 until 18.30.
Until 6.30 pm you can bring the towel back here at any time and get your "towel card" back. After 6.30 pm youcan bring the towel back to reception.
Hand your "towel card" back to Reception when checking out; if not, or if it gets lost, there's a charge of 10€.
- Internet
We have free Wifi throughout the hotel.
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We have a FREE safe service in the rooms.
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Yes, please contact us or just ask at Reception
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The car-park has extra cost and does not need to be booked beforehand – request a space directly at Reception (depending on availability)
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For information on prices and vehicle hire, just ask at Reception.
- Beaches
The hotel has a gate leading on to the beach which you can open with your room card.
We have sun loungers on the beach for our clients, in front of our hotel complex. The sun loungers service has an extra cost.
- Restaurants
Make reservations on the same day, before 2pm. Visit our Beach Club web for further information.
- Alergic diets
Are you allergic and / or intolerant to some food? Indicate this in this form before your arrival.
- Spa
Visit our SPA & Beauty Mirarmar website.
- What to do?
On Our Blog you will be able to find a wide range of interesting information to allow you to get the most out of southern Spain: the best trekking routes, natural areas, unforgettable beaches, original restaurants and villages that shouldn't be missed, as well as the curiosities, stories and secrets hidden in the streets that make this land unique.
To activate the Spanish channels in your room, press the av/tv button on your remote control and then select the "tdT" option from the menu that appears; the "TV" option will activate the international channels. If they don't work, contact Reception.
- Medical centres
You'll find all of the information you need for any emergency during your stay at Reception. You can also find more detailed information on our website.
- Supermarkets
Yes, we can give you maps and tell you how to get there at Reception.
- Street markets
On Mondays there's the Marbella market, the San Pedro Alcántara market on Thursdays and on Saturdays in Puerto Banús, all from around 9am until 2pm.
The Hotel
The only hotel for adults located on the beachfront and near Marbella's old town
- Hotel RECOMMENDED FOR ADULTS, IDEAL DESTINATION FOR COUPLES, SINGLES AND GROUPS
- Amàre Club, private beach area, swimming pool (with free sun loungers) and restaurants
- Free Spa Circuit at our Spa by Germaine de Capuccini (for breaks lasting at least 2 nights)
- Free access to the Gym by Technogym
The sea and relaxation come together at the Amàre Club, a private area on theshores of the Mediterranean. Relax in a hammock or a sun lounger whilst the music creates a calming atmosphere. You can also enjoy our wide range of cuisine.
Our Spa centre by Germaine de Capuccini offers a variety of health and beauty treatments. Why not let yourself be pampered with a massage on the beach? The Gym by Technogym is available, free of charge, so that you can keep in shape and take care of your body whilst on holiday.
The hotel's Belvue Rooftop Bar offers a panoramic view of the Mediterranean where our guests can appreciate the most spectacular sunsets on the Costa del Sol.
Our wide range of entertainment activities and experiences are guaranteed to make your holiday in Marbella unforgettable.
The Hotel
Hotel Fuerte Miramar, Marbella, España
Hotel Fuerte Miramar
Avda. Severo Ochoa 8
29603 Marbella, Málaga. España
Tel: (+34) 959 76 84 00
- Personal service.
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The Atlanta-based carrier says it has no intention of swallowing up Alaska Airlines, but it has every intention of being a major player here.
Federal Way firm brings manufacturers and customers together and helps them see the light.
But its local impact depends on several variables.
It's not just a 'Star Trek' series; it's also the group that will be generalized and pigeonholed after the millennials move on.
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Total compensation climbed 4.3 percent, more than double the national average of 1.9%.
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{ Perspective }
Karen A. Henry
Counsel, Davis Wright Tremaine


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Conceived and designed the experiments: RP NvCT. Performed the experiments: RP NvCT. Analyzed the data: RP NvCT. Contributed reagents/materials/analysis tools: RP NvCT. Wrote the paper: RP NvCT. Collected the data: RP.
The spread of agriculture into Europe and the ancestry of the first European farmers have been subjects of debate and controversy among geneticists, archaeologists, linguists and anthropologists. Debates have centred on the extent to which the transition was associated with the active migration of people as opposed to the diffusion of cultural practices. Recent studies have shown that patterns of human cranial shape variation can be employed as a reliable proxy for the neutral genetic relationships of human populations.
Here, we employ measurements of Mesolithic (hunter-gatherers) and Neolithic (farmers) crania from Southwest Asia and Europe to test several alternative population dispersal and hunter-farmer gene-flow models. We base our alternative hypothetical models on a null evolutionary model of isolation-by-geographic and temporal distance. Partial Mantel tests were used to assess the congruence between craniometric distance and each of the geographic model matrices, while controlling for temporal distance. Our results demonstrate that the craniometric data fit a model of continuous dispersal of people (and their genes) from Southwest Asia to Europe significantly better than a null model of cultural diffusion.
Therefore, this study does not support the assertion that farming in Europe solely involved the adoption of technologies and ideas from Southwest Asia by indigenous Mesolithic hunter-gatherers. Moreover, the results highlight the utility of craniometric data for assessing patterns of past population dispersal and gene flow.
The debate over the origins of agriculture in Europe has mainly centred on two demographic models. The demic diffusion model (also known as the wave of advance) suggests a progressive dispersal of Southwest (SW) Asian Neolithic farmers into Europe [1]–[3]. This process involved region-specific and variable degrees of admixture between the incoming farmers and the local Mesolithic hunter-gatherers. Alternatively, a cultural diffusion model suggests that agricultural knowledge and technologies diffused from SW Asia into Europe but without a significant demographic expansion of SW Asian farmers [4], [5]. Various intermediate scenarios have also been proposed. Some suggest diffusion as the main underlying mechanism involved (e.g. [6]), while others argue that early European agriculture was developed independently by indigenous Mesolithic hunter-gatherer-forager populations with no diffusion of either knowledge or people from the core SW Asian regions [4].
The first mathematical analysis of chronometric archaeological data on early Neolithic European cultures demonstrated a southeast-northwest (SE-NW) temporal cline across Europe [1]. A re-assessment of the wave of advance model using a much larger data set and calculating the probability of various hypothetical centers of agricultural origin provided further support for the observed clinal pattern [7]. While this cline suggested that agriculture spread across Europe in a SE-NW fashion, the archaeological data alone cannot detect whether this is the outcome of a demic diffusion, cultural diffusion, or a palimpsest of complex demographic and historical processes. Subsequent genetic studies of classical allelic markers using principal components analysis (PCA) reported a similar SE-NW clinal pattern observed when plotting the major component of variation [8]. It has been demonstrated that PCA analyses of spatially correlated genetic data can produce highly structured results which are mathematical artifacts that do not necessarily reflect underlying historical migration and dispersal events [9]. However, partial correlations of classical genetic, temporal, and geographic matrices have also found support for the demic diffusion model [10] and hence imply that in this specific case, the clinal pattern is not artefactual but rather produced by demographic historical processes.
Studies of nuclear DNA polymorphisms [11], [12], autosomal microsatellite loci [13] and various sets of DNA markers [14] all confirm a substantial contribution of Southwest Asian populations to the European gene pool and report similar SE-NW clines across Europe. In contrast, analyses of mtDNA haplogroups [15]–[17] suggest a pre-Neolithic coalescence date and a limited contribution of SW Asian Neolithic farmers (~20%) to the European gene pool. Studies of Y-chromosome markers provide conflicting results. Semino et al. [18] estimate a contribution of ~22% from SW Asian farmers, which is in close agreement with the figures provided for mtDNA haplogroups. However, a recent reassessment using a different methodological protocol [19] report an average contribution of SW Asian farmers to the European gene pool of between 50 and 65%. Studies of biallelic Y-chromosome polymorphisms report clines that are in agreement with the demic diffusion model [20].
Employing modern European genetics to assess the nature of the spread of farming from SW Asia into Europe is inherently problematic for several reasons: the size and representativeness of modern samples may not match those of the actual populations affected; observed patterns of genetic variation could be explained by several different evolutionary scenarios [21]; any modern gene genealogy may not portray Neolithic and post-Neolithic population history unless founder effects eliminated pre-existing polymorphisms [21], and molecular coalescence dates of geographically patterned lineages do not necessarily correspond to the timing of arrival of a genetic variant in that region [22]. While ancient DNA studies allow for the direct comparison of archaeological and modern populations, they are also limited by constraining factors such as small and unrepresentative samples, limited authenticity methods, and contamination [23]–[25]. The analysis of ancient mtDNA sequences, extracted and amplified from 24 Neolithic central European specimens, points to a genetic discontinuity between these early farmers and current European populations [26]. The discontinuity is attributed to a negligible genetic contribution of Southwest Asian farmers to the modern European gene pool and hence supports the cultural diffusion model. In contrast, a more recent paleogenetic study of Neolithic samples from the Iberian peninsula [27] indicates long-term genetic continuity in this region since the Neolithic. These results suggest a heterogeneous Neolithic dispersal into Europe, which possibly involved acculturation in Central Europe and demic diffusion along the Mediterranean coast [27]. These conflicting results indicate that paleogenetic studies are, as yet, not extensive enough to provide conclusive results regarding the genetic contribution of SW Asian farmers to the European gene pool.
In contrast, the availability of extensive samples of Mesolithic and Neolithic skulls from SW Asia and Europe provide a unique opportunity to assess the biological relationship between pre-farming and early farming populations. In recent years, several studies have demonstrated that human cranial shape variation is largely congruent with an evolutionary model of neutral expectation (e.g., [28]–[38]). Therefore, patterns of human cranial shape covariation can be employed successfully as a proxy for neutral genetic evidence of past population history [34], [39]. Thus, we use this empirical relationship between craniometric and neutral genetic variation to test several alternative hypotheses of population change in Europe associated with the spread of farming from SW Asia.
Competing hypotheses regarding the nature of the spread of farming were tested using a Mantel matrix correlation approach [40], [41] and an extensive craniometric dataset representing Mesolithic and early Neolithic SW Asian and European populations (Table S1). These OTUs (operational taxonomic units) represent the best available craniometric data for Mesolithic and early Neolithic populations in these regions (Figure 1). In contrast with previous studies of this kind [40], [41], we do not use arbitrary values (0, 0.5, 1 etc.) to quantify the hypothesised morphological distances between OTUs in our alternative model matrices. Rather, we create a null model based upon evolutionary expectations of cranial differentiation according to the principles of isolation-by-geographic and temporal distance [42] (Figure 2). This is based on the observation that there is a strong correspondence between geographic distance and genetic distance in humans for neutrally evolving markers such as microsatellites [33]. Therefore, in the absence of non-neutral forces such as natural selection or directional long-range dispersal, the expected neutral pattern of craniometric diversity would correlate with geographic distance, once the effect of temporal distance is controlled for [42]. In turn, all alternative models are variations of the null model reflecting different hypothesised scenarios (see Materials and Methods). We conduct a series of partial Mantel tests [43] to assess the congruence between craniometric distance and each of the geographic model matrices, while controlling for temporal distance. We particularly chose to focus on the neolithization process in those European regions which preceded the further spread of agriculture into the northern and western parts after 5000 cal. BC [5], [44], [45]. The null model (Figure 2a) reflects the expected pattern of morphological distance between populations if the expansion of farming was largely an indigenous process involving minimal or no dispersal from SW Asia. We then test 5 alternative hypothesized scenarios (models 2 to 6) in order to determine: (1) the extent to which the transition to farming in Europe was the result of demic diffusion of SW Asian farmers; (2) whether the process involved single or continuous dispersals; (3) whether the dispersal origin of the SW Asian farmers was more likely located in the Southern Levant or Anatolia; and (4) the extent to which a demic diffusion process also entailed admixture with indigenous European Late Mesolithic populations. In each model, the distances between OTUs were modified according to the expected variation in gene flow between OTUs (see Methods section). In order to assess the effect of employing different geographic distances, dispersal events (i.e., models 3–6) were each modeled three times; as a decrease in geographic distance between the affected OTUs, of 500, 1000, or 1500 km per migration event. Similarly, limited gene flow (model 2) was modeled as an increase in geographic distance of 500, 1000 or 1500 km between the relevant OTUs (Figure 2b).
Figure 3 plots the first two principal co-ordinates of the craniometric distance matrix. The OTUs do not group according to any particular geographic or temporal pattern on the first or second principal co-ordinates. However, the first principal co-ordinate separates the archaeologically defined Neolithic OTUs from OTUs designated as Mesolithic plus the Natufian. Therefore, the principal co-ordinate analysis suggests that Neolithic and Mesolithic populations are biologically differentiated.
The results of the partial correlations (Table 1) show that the null model was not significantly correlated with the craniometric distance matrix, once temporal variation was controlled for. The null model reflects the degree of differentiation we would expect amongst OTUs under a model of pure cultural diffusion. Of the alternative scenarios modelled, all variants of the continuous dispersal models were significantly correlated with the craniometric data, regardless of whether the dispersals were modelled as originating in Anatolia or in the Levant, and regardless of which geographic parameter was employed to model dispersal (500, 1000 or 1500 km). In contrast, no model of a single dispersal from SW Asia was significantly correlated with the craniometric data. There was some support for a hypothesis of biological change due to a restriction on gene flow between contiguous Mesolithic and Neolithic populations, but only when this barrier was modelled to be relatively strong (i.e., increase of 1000 or 1500 km). These results support a model of demic dispersal from the Near East, as opposed to a model of pure cultural diffusion or sporadic single dispersal events.
The results of the Dow-Cheverud tests (Table 2) mirror those of the partial Mantel tests in showing that the continuous dispersal models and the model of restricted gene flow between Mesolithic and Neolithic populations are significantly more likely than the null model (Table 2, left column). In the comparison of pairs of alternative models, the Dow-Cheverud results also show that there is no statistical difference between dispersal models originating in Anatolia or the Levant (i.e., SD Levant=SD Anatolia; CD Levant=CD Anatolia). The results also show that models of continuous dispersal (i.e., CD Anatolia, CD Levant) fit the craniometric data significantly better than single dispersal models (i.e., SD Anatolia, SD Levant). Moreover, a continuous dispersal model from the Levant is significantly more likely than a model of restricted gene flow between Mesolithic and Neolithic populations when distances of 500 km and 1000 km are assumed (see Table 2, right column).
The results of both the partial Mantel and the Dow-Cheverud tests indicate that the Neolithic and Mesolithic craniometric patterns better fit a model which includes the active dispersal of people (and their genes) from SW Asia, when compared with a neutral model where no such migration(s) occurs. Similarly, modelling the initial spread of farming as once-off single migrations does not explain the craniometric pattern better than the null model of cultural diffusion. Even allowing for a decrease in contact between exogenous farmers and indigenous hunter-gatherers (i.e., the LGF model) does not account for the craniometric affinity pattern as well as a model of continuous dispersal from SE Asia. Currat & Excoffier [46] demonstrated using a series of genetic simulations that even a small percent of genetic admixture between hunters and farmers would result in an extensive amount of pre-Neolithic contribution to the current European gene pool. Our null model of cultural diffusion allows for admixture between Mesolithic and Neolithic populations living contemporaneously under a model of isolation-by-distance. However, the results show that it is more likely that the arrival of farming in Europe was accompanied by the active dispersal of people from SW Asia, which created a barrier to gene flow between hunters and farmers during the period of co-existence. We, therefore, do not rule out some gene flow between hunters and farmers but argue that the craniometric data does not support strong admixture between Neolithic and Mesolithic populations.
Our analysis could not resolve the question of the origin of the dispersal process or its most probable timing. A previous craniometric study [47] indicates that its centre of origin may have been central Anatolia, while spatial interpolations of the radiocarbon chronometric Neolithic record suggest a centre of origin in the Levant [7]. However, both regions fall within the primary core region in which agricultural societies first emerged more than three millennia prior to the emergence of farming in SE Europe [48], [49]. Recent archaeological research suggests that the diffusion of agriculture from the core region into SE Europe occurred in several waves. The earliest occurred during the early pre-Pottery Neolithic B (EPPNB) circ. cal. 8550-8150 BC, and involved the maritime colonization of Cyprus [50], and possibly Crete and the Peloponnese [51]. A probable second dispersal is associated with the appearance and diffusion of the Fikirtepe Culture (cal. BC 6450- 5900 [52]), which is characterized by dark surfaced monochrome pottery in sites in western Anatolia, eastern Thrace, and possibly further west into the Balkans [49]. A third dispersal occurred a few centuries later and involved the appearance of burnished red pottery, the use of anthropomorphic and zoomorphic vessels, clay figurines, and other stylistic characteristics. During this dispersal hundreds of new Neolithic sites appear in western Anatolia and the Balkans [49]. Despite the overall uniformity in artefacts and domesticated crops and livestock which were part of the "Neolithic package", archaeological research reveals some stylistic variations suggesting continuous endemic population movements and trade within and between these regions [53]. These movements would have involved extensive gene flow along the dispersal route from Anatolia to SE Europe.
In conclusion, our results indicate that the craniometric data best fit a model of continuous demic diffusion into SE and Central Europe from the SE Asian core region in which agricultural societies first emerged. These results are in agreement with most genetic studies which report a considerable genetic contribution of SW Asian farmers to the modern European gene pool [6], [14], [18], [19], [22], [46]. We found no strong support for significant admixture between contemporaneous Mesolithic and Neolithic populations, or for an indigenous adoption of agriculture by Mesolithic populations as has been proposed by some archaeologists (e.g., [5], [54]) and geneticists (e.g., [16], [26], [55]).
Our results illustrate the utility of craniometric data for assessing past population history and highlight the importance of testing hypotheses within a population genetics framework. Our study does not deny or contradict models that propose the existence of regional variability in Europe. In the northern and northwestern regions of Europe the transition to agriculture was possibly more complex and gradual, entailing a larger degree of genetic contribution from indigenous populations [47], [56]. In fact, the evidence amassed from a number of regional case studies indicate that the Neolithic transition process probably involved various demographic and biogeographic mechanisms such as leapfrog colonization, jump dispersals, range expansions, and folk migrations (cf. various contributions in [57]). Future model-bound and simulation analyses of craniometric and genetic data from a wider geographic range will shed more light on these issues. However, our results do not support the assertion that the initial spread of agriculture into Europe proceeded purely as a cultural diffusion event, but instead involved the active dispersal of people from SW Asia.
We utilise a set of 116 Mesolithic/Epipalaeolithic and 165 Early Neolithic crania from SW Asia and Europe. These were divided into 15 operational taxonomic units [OTUs] (cf. [41], Figure 1, Table S1), each comprising at least 10 individuals. These OTUs represent samples from biological populations that are defined according to their archaeological, spatial and temporal contexts (Table S1). In all cases, an OTU comprises specimens from a single major archaeological phase. Whenever possible, we construct OTUs using specimens from a single site (e.g., Çatal Höyük, Oleni Ostrov) or specimens from a well defined phase in a given region (e.g., Linienbandkeramik (LBK) East). Sampling was constrained by uneven spatial, temporal and archaeological representativeness of certain phases – for example the Aceramic (Pre-Pottery) sample from the Near East – yet this dataset comprises the best available cranial samples whose archaeological contexts and skeletal preservation facilitate their inclusion in these OTUs. The 15 OTUs provide a secure dataset for testing the contribution of SW Asian early Neolithic farmers to the southeastern and central European gene pool.
The craniometric data comprised 15 standard calliper measurements (see Table S2) taken on samples of skulls representing each of the 15 OTUs described in Table S1. Given the fragmentary nature of many of these archaeological specimens, some of the data were missing from the initial database. Only individual skulls with data present for at least 70% (i.e., 10 measurements) of all measurements were included in the analysis [58]. Missing data were estimated in SPSS v.16, within-sexes and within-OTUs, using a multiple linear regression algorithm. These data were adjusted for individual differences in isometric scaling by dividing each cranial variable by the geometric mean of all variables for that individual [59], [60]. Craniometric distance matrices were generated in RMET 5.0, software written by John Relethford to perform population genetics analysis using quantitative phenotypic traits [61]). Hence, multivariate biological D-matrices (based on a phenotypic analogue of Wright's [62] Fst) were calculated under the assumption that population phenotypic variances are proportional to genetic variances [61], [63].
The isolation-by-geographic distance model predicts a positive relationship between increased genetic (and phenotypic) population differentiation and geographic distance [42], [64]. However, the effect of temporal distance between archaeological OTUs is more difficult to model. There is empirical evidence to suggest temporal autocorrelation for craniometric data, implying a positive relationship between temporal distance and craniometric distance within individual archaeological sites [65]. However, the exact parameters of a model of isolation-by-time and space are currently unclear. Given these uncertainties, we base our null model on geographic distance only and employ partial correlations to control for the effects of temporal distance [42]. The null model matrix was subsequently altered to reflect five alternative scenarios of migration and/or restricted gene flow, based on competing hypotheses of whether the spread of farming proceeded primarily as a migration of people (genes) or of culture (Figure 1):
Geographic distances between all OTUs were calculated in kilometres as great circle distances based on the haversine [66], [67]. Hence, the distance (D) between two points specified by latitudinal (α1, δ1) and longitudinal (α2, δ2) co-ordinates with a central angle of θ between the two points was computed as:
Where hav (θ)=sin2 +cos δ1 cos δ2 sin2 and R=radius of earth (6,371 km).
As several OTUs were comprised of pooled specimens from different sites (Table S1), all pairwise geographic distances were rounded to the nearest 500 km. Where several sites were combined to create a single OTU, the average geographic coordinate was taken. Temporal distances were calculated, on a pairwise basis between all OTUs, as the square root of the squared differences between chronological estimates provided in Table S1. Table S3 provides the geographic and temporal distance matrices employed in the partial Mantel tests.
In order to tests the hypothetical scenarios described in the text, the null model was altered to create seven alternative model matrices, reflecting different migration and/or gene flow processes. The LGF model differs from the null model in assuming that the adoption of Neolithic practices by some European OTUs (4, 5, 6 and 7) caused a barrier to gene flow between these populations and contemporaneous un-acculturated Mesolithic populations (9, 10 and 12). Therefore, the biological distances between OTUs (4–7 and 9, 10 and 12) are modelled as lengthened by either 500, 1000 or 1500 km compared with the 'null' distances. In the Single Dispersal (SD) models, farming is spread by a once-off migration of people from Anatolia (OTU 3) or the Levant (OTU2) into Europe thereby decreasing the distances between these OTUs and OTUs 4–7 by either 500, 1000 or 1500 km. The Continuous Dispersal (CD) models hypothesises the spread of farming to result from the dispersal of people from Anatolia (OTU 3) or the Levant (OTU2) into Europe and then the repeated dispersal of people from SE to Central Europe according to Figure 2. This results in a decrease in distance of either 500, 1000 or 1500 km between all pairs of OTUs 3,4,5,6 and 7.
The correlations between the craniometric, geographic and temporal matrices were compared statistically using Mantel matrix correlations [68]. As with a standard Pearson correlation, coefficients (r-values) range from −1 (perfect negative correlation) to +1 (perfect positive correlation). However, because matrix elements cannot be considered independent, significance (p-values) was assigned through a randomisation test, where the observed matrix correlation was assessed against a distribution of correlations obtained by 9999 random permutations of the rows and columns of the matrices [43], [69]. The basic Mantel test allows for the comparison of two matrices (X and Y). However, a partial Mantel test can be performed to control for a third matrix (Z). This is achieved by regressing the elements of X and Y onto Z, and using the residuals from the regressions as the input for a standard Mantel test [43]. Here, we employed partial Mantel correlations to assess the fit of the craniometric data to the six alternative models based on a null model of geographic distance, while correcting for temporal distance. Bonferroni correction was applied to the partial Mantel tests, thereby lowering the accepted α-level to 0.017 [34], [37]. Partial Mantel tests were performed in PASSaGE 1.1, freely available from Michael Rosenberg (www.passagesoftware.net).
In order to determine whether or not any of the six alternative model matrices differed significantly in their congruence with the craniometric distance matrix, a series of Dow-Cheverud [70] tests were performed. Here, the null hypothesis is that the correlation of A (craniometric distance matrix) and B (Model 1) is equal to the correlation of A and C (Model 2). If the null hypothesis is rejected (p≤0.05), then one model is significantly more likely than the other. In order to control for temporal distance, each of the model matrices and the craniometric distance matrix were regressed onto the temporal distance matrix, and the resultant residual matrices were used as input for the Dow-Cheverud tests. All comparisons were performed in R, employing a code written by the lab of C.C. Roseman. As discussed in detail by Konigsberg [71], all matrix comparisons (Mantel and Dow-Cheverud tests) assume that the biological affinity matrices are known without error. Given that the biological matrices employed here were generated from relatively small samples (10–31 crania per OTU) there is an error inherent to the estimation of the biological relationships between OTUs. Therefore, we add the caveat that all significance values associated with Mantel and Dow-Cheverud tests reported here are minimum values.
Archaeological samples employed to construct the operational taxonomic units (OTUs).
Description and codes of craniometric variables employed
Null model matrices of geographic distance (km; lower triangle) and temporal distance (years; upper triangle).
We wish to thank Stephen Lycett, Tim Weaver, Lyle Konigsberg and an anonymous reviewer for constructive comments which helped improve this manuscript. Data were kindly provided by Winfried Heneke. Software was kindly made available by John Relethford (RMET) and Charles Roseman and Mark Grabowski (R code for Dow-Cheverud tests).
Competing Interests: The authors have declared that no competing interests exist.
Funding: The authors have no support or funding to report.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
When it comes to the nation's "fiscal cliff," congressional Republicans should play the role of "The Godfather" and make President Obama an offer he can't refuse without suffering severe consequences.
For example, the Republicans could present a package containing serious spending cuts together with a proposal not to renew the George W. Bush tax cuts for families making not $250,000, but $500,000 or more. If Mr. Obama rejects this compromise, Republicans could show that Mr. Obama's insistence on raising taxes on the rich is not about fixing the nation's fiscal mess but instead is a purely political maneuver designed to divide congressional Republicans and thereby weaken their party.
Mr. Obama says he is "open to ideas" — as long, of course, as they include tax increases on his terms and exclude any meaningful spending cuts and any entitlement reform. If Mr. Obama rejects the Republicans' offer, congressional Democrats intending to seek re-election are likely to be blamed if the president's rejection of the deal triggers another recession. Those Democrats, therefore, will be faced with a choice to join with the Republicans or go over the fiscal cliff with Mr. Obama.


text:
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text:
28090No Deep Cuts Tonight
Expand Messages
- Feb 20, 2014Hello everyone,There will be no Prog Rock Deep Cuts tonight. Deep Cuts will return next Thursday, February 27th, 7-10 PM EST on progrock.com.The next episode will feature the new record from Univers Zero entitled "Phosphorescent Dreams", as well as Atomic Ape's "Swarm" - a heavy instrumental record with influences in Eastern folk music, jazz, and hard rock. Additionally, we will be continuing our new 'In the Vinyl Vein' feature with Gong's "Flying Teapot" and much more.There will be a subsequent mailing next Thursday containing all of the gory details, but I wanted to get the word out about the cancellation. In the meantime, please enjoy this stream of last week's Deep Cuts (which featured the new Djam Karet), available for a limited time here: http://www.mixcloud.com/progrockdeepcuts/prog-rock-deep-cuts-25/.
If you want to receive instant updates via Mixcloud, you can get an account on mixcloud.com (absolutely free) and follow the show's account here: http://www.mixcloud.com/progrockdeepcuts/. This will allow you to be notified when a new episode is added. Additionally, you can also get the mixcloud app on your smart phone, which allows you to stream Deep Cuts anywhere ... I've even hooked it up to a car stereo for travel!In the meantime, I want to thank everyone who has tuned into Deep Cuts. With the aid of the chat room, we have built up a nice little community that I am extremely proud of and grateful for. This, above all, makes Deep Cuts worthwhile and I hope to continue to see it grow upon our return next Thursday.That's all for now. See you next week!Ian


text:
The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria
ABSTRACT Phosphatidylinositol glycan class A (PIGA) is involved in the first step of glycosylphosphatidylinositol (GPI) biosynthesis. Many proteins, including CD55 and CD59, are anchored to the cell by GPI. Loss of CD55 and CD59 on erythrocytes causes complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), a disease that manifests after clonal expansion of hematopoietic cells with somatic PIGA mutations. Although somatic PIGA mutations have been identified in many PNH patients, it has been proposed that germline mutations are lethal. We report a family with an X-linked lethal disorder involving cleft palate, neonatal seizures, contractures, central nervous system (CNS) structural malformations, and other anomalies. An X chromosome exome next-generation sequencing screen identified a single nonsense PIGA mutation, c.1234C>T, which predicts p.Arg412(∗). This variant segregated with disease and carrier status in the family, is similar to mutations known to cause PNH as a result of PIGA dysfunction, and was absent in 409 controls. PIGA-null mutations are thought to be embryonic lethal, suggesting that p.Arg412(∗) PIGA has residual function. Transfection of a mutant p.Arg412(∗) PIGA construct into PIGA-null cells showed partial restoration of GPI-anchored proteins. The genetic data show that the c.1234C>T (p.Arg412(∗)) mutation is present in an affected child, is linked to the affected chromosome in this family, is rare in the population, and results in reduced, but not absent, biosynthesis of GPI anchors. We conclude that c.1234C>T in PIGA results in the lethal X-linked phenotype recognized in the reported family.
Full-textDOI: · Available from: Robert Brodsky, Sep 27, 2015
- SourceAvailable from: Kathryn J Swoboda
- "mutation was demonstrated in an in vitro cellular assay, evidence that the role of PIGA in GPI anchor biosynthesis is critical for normal central nervous system development [Johnston et al., 2012]. Germline mutations in several other genes affecting the GPI anchor biosynthesis pathway cause syndromes encompassing an increasingly broad range of phenotype with widely variable neurologic involvement, including a new subclass of congenital disorders of glycosylation [Jaeken, 2011]. "
Article: A Novel Germline PIGA Mutation in Ferro-Cerebro-Cutaneous Syndrome: A Neurodegenerative X-Linked Epileptic Encephalopathy With Systemic Iron-Overload[Show abstract] [Hide abstract]
ABSTRACT: Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3-Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism. © 2013 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36189 · 2.16 Impact Factor
[Show abstract] [Hide abstract]
- "The manuscript by Harakalova et al. [2013] in this issue of the Journal is a confirmation of the findings of our group, when we showed that a leaky null germline mutation in PIGA caused a devastating neurologic disorder with death in infancy [Johnston et al., 2012]. The phenotypes of the patients in Harakalova et al., [2013] and Johnston et al. [2012] are substantially similar both to each other and to the syndrome family [Brunner and van Driel, 2004] of disorders caused by mutations in other members of the PIG gene family. "
ABSTRACT: Two research groups have published reports on PIGA (phosphatidylinositol glycan class A) mutations that validate and extend our understanding of the range of phenotypes of this phenotypic spectrum. One report is primarily confirmatory of the discovery in 2012 that mutations in this gene cause a phenotype of dysmorphic features, neurologic manifestations, and biochemical perturbations. The second report describes an intriguing family with a phenotypically distinct neurological picture, distinguished primarily by CNS iron accumulation. These reports address important lessons in judging causality in the exome age and bear on the question of syndrome nomenclature. © 2013 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36213 · 2.16 Impact Factor
- "In addition, the present patient had severe accelerated linear growth and obesity. Although germline mutations were initially thought to be lethal early in development, the first report on a germline (nonsense) mutation in PIGA was recently been published in two siblings with a similar constellation of abnormalities [Johnston et al., 2012]. In concurrence with the present patient, one of these affected brothers described by Johnston et al. [2012] was also born prematurely with polyhydramnios, presumably due to decreased swallowing associated with poor fetal muscle strength. "
Article: Expanding the Spectrum of Phenotypes Associated With Germline PIGA Mutations: A Child With Developmental Delay, Accelerated Linear Growth, Facial Dysmorphisms, Elevated Alkaline Phosphatase, and Progressive CNS Abnormalities[Show abstract] [Hide abstract]
ABSTRACT: Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family. © 2013 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36184 · 2.16 Impact Factor


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text:
Brett Banasiewicz Back on a Bike
I'm really stoked on this video Catfish posted up today. Brett Banasiewicz has been fighting his way back from that terrible crash he took earlier this year and today was the first time he was able to get back on a bike. Sure, he isn't throwing cash rolls just yet, but give him some time. This is pretty amazing. Hell yeah, Brett!
Tags: BMX bikes, BMX videos, Brett Banasiewicz, Daily
Posted: December 27th, 2012
Posted by Kurt with No Comments »


text:
Media Coverage of PPACA Implementation Failures: Answers from HHS
Tim Murphy (PA), Chairman
David McKinley (WV), Vice Chairman
Michael C. Burgess, M.D. (TX)
Marsha Blackburn (TN)
Morgan Griffith (VA)
Larry Bucshon (IN)
Bill Flores (TX)
Susan Brooks (IN)
Markwayne Mullin (OK)
Richard Hudson (NC)
Chris Collins (NY)
Kevin Cramer (ND)
Joe Barton (TX)
Fred Upton (MI) (Ex Officio)
Diana DeGette (CO), Ranking Member
Jan Schakowsky (IL)
Kathy Castor (FL)
Paul Tonko (NY)
John Yarmuth (KY)
Yvette D. Clarke (NY)
Joseph P. Kennedy, III (MA)
Gene Green (TX)
Peter Welch (VT)
Frank Pallone, Jr. (NJ) (Ex Officio)
As Obama Fends Off Fact Checkers, Oregon Officials Announce 150,000 to Lose Coverage Due to President's Law
Walden: President's Broken Promises are "Grossly Unfair"
Bloomberg Businessweek recently highlighted our nation's nuclear waste woes, noting that radioactive waste continues to pile up at plants across the country with the Yucca Mountain repository shuttered.
WASHINGTON, DC – During today's House Energy and Commerce Committee hearing on PPACA Implementation Failures: Answers from HHS, Rep.
Secretary Sebelius to Testify at 9 a.m. hearing on "PPACA Implementation Failures: Answers from HHS"


text:
For the same reason's women do.
Best Answer
Best Answer
Yeah,.......women don't. I know>.
Best Answer
Same reason women do!
Best Answer
Idk they're jerks
Best Answer
Monogamy is unnatural. People get bored.
Best Answer
low moral character meets horniness meets willing partner
Best Answer
women cheat too, they're just as capable of fault
Best Answer
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whitepine1 51-55, M 17 Answers 7 Jan 24, 2012
Your viewsNedKelly1 56-60, M 11 Answers 8 Oct 13, 2010
Why do men cheat and then pretend they are sorry when they get caught? why not be sorry before you cheat?janecef 26-30, F 23 Answers 8 Nov 3, 2011
Do you beleive there are double standards-----when men cheat-----when woman cheat----IF you answer yes-----PLease tell Ythe reason i am asking?while i was sick,for 13 yrs,and my husband and his mistress(also married)were flying all over the world together--------What did he lose,when his family...senecagirl11 61-65, F 13 Answers 8 Jan 26, 2012
RA257 31-35, F 13 Answers 1 Oct 1, 2013 in Dating & Relationships
Why does men cheat, and in my case when I wanted a divorce he didn't want one, if you cheat once you can do it again??
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text:
ProfExam Creator
editor's review
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text:
Work new-season texture and color into your look with rag & bone's skinny scarlet stretch-corduroy jeans. Let this vivid pair take center stage by teaming them with classic shades of charcoal and blue.
rag & bone jeans: scarlet stretch-corduroy, low-rise, skinny-leg, belt loops, five pockets, silver hardware. Designer-stamped button and concealed zip fastening at waist. 96% cotton, 4% roica. Machine wash cold inside out to avoid color transfer. Designer color: Crimson.
Product code: 168128 - Need help? Contact us


text:
Fearing for her safety, Rihanna has filed for and been granted a restraining order from an obsessed fan.
Rihanna Obtains Restraining Order From Fan
The singer obtained a temporary order against Steveland Barrow, 31, on Tuesday in Los Angeles Superior Court. According to paperwork acquired by ET, Barrow broke into a residence adjacent to Rihanna's (believing it was hers) where he "removed various items from the home and slept in a bed."
NewsOK.com has disabled the comments for this article.


text:
garrysmods.org is a repository of Garry's Mod downloads and a great alternative to the Workshop for those who like customisation, visibility, and tinkering.
The site is currently open for public testing, so please report any bugs you find using the contact page!
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text: The date range doesn't work wonderfully to choose posts -- when I choose a range of a year, it typically leaves out posts in December. Also, the field for original date of published post is not exported to the final PDF. This is elemental & it seems absurd that it isn't included. I'm trying to print a book for every year of my blog -- but this app seems more geared around grabbing posts centered around categories. Other than that -- it works fine. I can't find anything else that works like this for a self-hosted blog.


text:
The GCP Practical Implementation online course was developed last year and takes users into the workplace so they can see how to apply what they have learned in real-life situations. The need for training to advance from theory to practice was highlighted at last year's European Federation of Good Clinical Practice Annual Conference, held in Budapest, Hungary in February. The same objective was behind Infonetica's decision to develop that course. Author Nick Deaney - a chartered scientist in clinical research - has placed case scenarios strategically throughout the practical implementation course, taken from real-life examples encountered during his 30 years in the industry. As trainees progress through the course, they are presented with situations that apply and reinforce the principles they have learnt. These problems require careful analysis and response, preparing students for effective application in the workplace. The course is designed to give them the confidence that they are performing at the expected level, can deal with issues that may arise and are prepared for internal and external audits. Having worked up to Research Director level in a major pharma group, Nick has experienced numerous US FDA and UK MHRA inspections, so is well versed in compliance issues.
Successful trainees receive a certificate accredited by the Royal College of Physicians' Faculty of Pharmaceutical Medicine (London, UK), and 9 CPD points as well as the option of being added to a publicly accessible database of GCP-certified personnel who have passed the course.
Two versions of the GCP Practical Implementation course are available - one for the UK and one for the international market. The courses are available online (price £69 +VAT) at www.onlinegcp.com to individuals and organisations around the world who are dedicated to designing, conducting and monitoring trials.
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text:
Dam-Break Induced Debris Flow
- William McCaffrey,
- Ben Kneller and
- Jeff Peakall
Published Online: 17 MAR 2009
DOI: 10.1002/9781444304275.ch11
Copyright © 2001 The International Association of Sedimentologists
Book Title
Particulate Gravity Currents
Additional Information
How to Cite
Capart, H., Young, D.-L. and Zech, Y. (2001) Dam-Break Induced Debris Flow, in Particulate Gravity Currents (eds W. McCaffrey, B. Kneller and J. Peakall), Blackwell Publishing Ltd., Oxford, UK. doi: 10.1002/9781444304275.ch11
Editor Information
School of Earth Sciences, University of Leeds, Leeds, LS2 9JT, West Yorkshire, UK
Publication History
- Published Online: 17 MAR 2009
- Published Print: 24 APR 2001
ISBN Information
Print ISBN: 9780632059218
Online ISBN: 9781444304275
- Summary
- Chapter
- dam-break induced debris flow;
- initiation mechanisms for debris flows - en masse failure of water-saturated slopes;
- dam-break events with documented sediment deposits;
- physical and mathematical description;
- fundamental processes;
- dam-break wave starting out as clear water - rapidly picking up sediment from dam body and from valley floor;
- bulking and debulking processes, backwater effects, and channelization
The present report focuses on the hydrodynamic and geomorphic behaviour of dam-break induced debris flows. Based on a review of the literature, we first examine various instances in which abrupt floods released by the breaking of natural or constructed dams have been observed to develop into debris waves, picking up solid material both from the dam body and from the valley floor. We then assess the extent to which modelling and experimental approaches can account for the field observations gathered from these events. The modelling approach considered consists of a shallow-water, single-fluid physical description, while the experiments involve idealized laboratory analogues. Results of these two approaches are compared and discussed for the case of a dam-break induced debris wave propagating past a sudden channel enlargement.


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text:
To fall is unacceptable
Lyric Meaning
Allowing herself to fall for Abel or anyone for that matter is not allowed in her form of work. Hence she's a professional, she's only allowed to fulfill Abels physicals lusts, nothing else.
Improve the quality of Professional Lyrics by leaving a suggestion at the bottom of the page