text:
Minidoz
The pupils were widely dilated, and the sclerotic and cornea on each side highly sensitive: alcalin. The duration of the stance should be four to five minutes. These results have been effected with constant and generous cooperation of the laboratory and with birth vigorous bacteriological control. It often happens that only towards the close of an operation is "side" the patient's abdomen in a perfectly satisfactory condition from the surgeon's point of view. The author has presented in this work a conveniently arranged epitome of the modern application of remedial agents to the cure of disease.
What is the nature of these vomitings? In the first period, they represent simply an exaggeration of the natural secretion, brought about to make up the deficiency of the renal function. The friction of the blood or other excitant effects of the increased circulation in the surface of the body stimulate the sensory nerves leading This stimulation is taken heed of by the sensory terminal filaments, and this expression of activity is transmitted to the motor centers, and, being received by these centers, is responded to in sensory, motor, and secretory impulses. It regards the development of this practice as a comparatively modern habit, but concedes that it had its type in ancient times.
Earliest evidences of the extension arc yaz found around the vaginal vault, the bases of the broad ligaments, and in the connective tissue under the bladder.
Then while I pull on the handles an assistant pulls on the fillet in the direction of the coccyx. These cards were made out by the scribe in bib each operating room under the direction of the operating surgeon and sent with the swab to the laboratory. In daily outings, go towards the parks rather than to down-town streets and shops. A micro-organism that has given us the most trouble has been the bacillus icteroides.
He must familiarize himself with embryology as well as obsterics.
Minidozator - spontaneous pulmonay tuberculosis in man pi o identical evolution to that produced by the new bacillus, as numerous cases of death due to the pretuberculous inflammation prove. He was prepared, accordingly, for operation under spinal analgesia. In this way bere foreign substances seldom escape if present.
Hospital trains should then receive the same amount of splints, control etc., from the base hospital as that which is delivered with the patients. De - the cervix cannot be dilated aseptically without anesthesia. During October the numlier of surgical admissions gradually decreased toward the end of the month and it was soon observed we not operate contagious wards, the majority of medical admissions were of respiratory nature, although the early admissions involved several cases of dysentery: 28. Charcot's, or"blue," edema is limited to the neighborhood of the joints, as a rule; the hands and forearms, especially upon one side, may be affected. In brief, the malady has been treated on the following lines of therapy: fluids through the lungs effects and skin. Within five minutes they will turn white and be destroyed.
Isosorbide Dinitrate And Hydralazine Hydrochloride Tablets
Costo Del Danazol
Sore On My Arms From Coumadin


It's easy to get bogged down in daily activities that take us away from the important things in work and life. When that happens it's also easy to lose our focus and then the important things don't seem so important anymore. They merely get lost in all the activities and chaos that surround our lives.
1. What's the one thing I know I need to do?
2. What is the one area where I can make a difference?
3. What is the one thing I can't ignore?
Sometimes, I don't have time to address all three answers so I pick one to start with. It's usually the first one; the one thing I know I need to do. What about you, which one would you pick?


The first and only cinema in Spain dedicated to documentary film.
Built entirely inside the Madrid City Council's Matadero center for contemporary culture, the Cineteca was created in 2011 for the exhibition and promotion of national and international documentary film. It is the primary venue for the DocumentaMadrid film festival.
Great Ways was the company entirely in charge of its management, inauguration and functioning from September 2011 through May 2012.


LED (Light Emitting Diodes) therapy has been shown in over 30 years of independent research to deliver powerful therapeutic benefits. Scientists observed that light on its own had a stimulating effect on cell and tissue regeneration, which greatly improved the appearance of the skin. The light affects a group of cells at the cellular level causing the cells to release other cellular products. Which then open up blood vessels, therefore increasing blood flow, allowing nutrients and oxygen to flood the skin.
1. Stimulates the production of collagen: By increasing collagen production, less scar tissue is formed in damaged tissue.
2. Diminishes age spots or hyperpigmentation: The photons of light energy destroy or better disperse melanin.
3. Kill bacteria: Blue light has a powerful antibacterial, anti-inflammatory effect to help treat and prevent mild to moderate acne.
4. Increase lymphatic activity: Lymphatic drainage helps the lymphatic system function more efficiently by facilitating toxin removal and improving skin circulation.
5. Stimulates the release of ATP (Adenosine Triphosphate): Increases in ATP allows cells to accept nutrients faster and get rid of waste products quicker by increasing the energy level in the cell.
6. Stimulates fibroblastic activity: Fibroblasts are present in connective tissue, thus aiding in the tissue repair process.
We are happy to announce that we have an LED light machine in the Lounge. It works, it's not expensive, and you will see immediate results!
For more information or if you have questions, we are here for you! Feel free to call us at (925) 210-0300.
Next Article Get Your Brows Into Shape!


text:
Q: call an instance method from an interface class I am looking for a way to call an instance method from an other class and I wondered if/how I could could do the following
goal and context
The class I am writing is a data formater whose __rshift__ method should be able to adapt the format of a data batch to many data base clients without the user needing to change the method used. Here is how I would like the >> method to be called
batch  = SomeExtractor(config).extract("some")
db_client = InfluxDBClient()
# this would be awesome
DataFormater(batch)>>db_client.write_points

the DataFormater
class DataFormater(object):
  def __init__(self, batch: Batch):
    self.batch = batch

  @abstractmethod
  def __rshift__(self, db):
    db_client = some_way_to_get_the_called_client(db)
    method = some_way_to_get_the_method(db)

    if method == InfluxDBClient.write_points:
      db_client.write_points({"measurement": self.batch.origin,
                "time" : self.batch.date,
                "tags": dict(zip(self.batch.dimensions_names, row["dimensions"])),
                "fields": dict(zip(self.batch.metrics_names, row["values"])}
                for row in self.batch.rows))

Googling my problem, added stack = inspect.stack(db) in the __rshift__ method and got the following but I am not sure how to use it
frame = <frame at 0x7f6c2a1515c0, file '/usr/src/collector/collector.py', line 95, code __rshift__>
context = <bound method InfluxDBClient.write_points of <collector.InfluxDBClient object at 0x7f6c2a131510>>

How can I do this?

A: Elegant solution proposed by @sanyash using __self__:
class DataFormater(object):
  def __init__(self, batch: Batch):
    self.batch = batch

  @abstractmethod
  def __rshift__(self, db_method):
    if type(db_method.__self__) == InfluxDBClient:
      db_method( ({"measurement": self.batch.origin,
        "time" : self.batch.date,
        "tags": dict(zip(self.batch.dimensions_names, row["dimensions"])),
        "fields": dict(zip(self.batch.metrics_names, row["values"]))}) for row in self.batch.rows )

redpajama_set_name: RedPajamaStackExchange


U2 > News > Merci Paris!
'Thank you for so many nights in Paris, France....' This is what it was like at the Stade de France this past weekend.
Opening the show with Breathe.
Leaving it all behind... for tonight.
Once again, a dream come true!
Absolutely AWESOME! I was there with two of my friends who had never seen you! They were like crazy, and so was I actually! This concert was amazing: it felt like you were singing for everybody and each one of us at the same time. Thank you U2.com for the great seats we had, and for the beautiful view on this fantastic stage. The live adaptation for Crazy was so hot! Adam, that's such a pleasure to see you smile all the time. This band give us so much! Thank you from the bottom of my heart. See you back again! THANK YOU!
THANK YOU FOR ONE OF THE BEST NIGHTS IN MY LIFE!YOU LOOK AND SOUND BETTER NOW THAN YOU DID 15 YEARS AGO!JUST UNBELIEVABLE!ALSO YOUR STAGE WAS REALLY OUT OF THIS WORLD!
A beautiful night...I love the set list, a perfect balance between the old hits, and the new ones. So many emotions, so many tears...The music was amazing, and the lights were simply beautiful. So many colors...And the audience was simply great...Everyone was cheering, dancing, and singing...I had the feeling to be in the biggest choir of the world!
I was in Nice last night with my daughter (15 years old). Great show, very amazing. Thank you misters! Like we say in french : Chapeau bas messieurs!
Only two words: SO PERFECT !!! Everything was perfect : stage, sound, songs and the band of course ! We are already waiting for next time.... Thanks so much for all you've done for us.
Bono was right when he sais : "for some of you it is the best time of your life tonight", it was for me, my life is not the same after that concert, I can't get the images out of my head. Thank you a million times and even more for this moment that I wish to relive one day again!
Ultra Violet, baby come our way. A few days and the Arena will be Magnificent! I can hardly wait. But why oh why will they not play The Fly?
who ever said that age is bad for musicians is so wrong they rocked the stadium and i must say best sound and voice ever, i have seen a lot of concerts of them but stade de france and this stage was sooooo good, U2 for ever and Merci a vous!
Wish I was back in that tent in Paris 25 years ago , that rainy night I watched four guys from Dublin complain about the size of the venue , lack of air ect . I knew then I was witnising the start of somthing great , and that these four lads were the future of Rock N Roll. See ye all in Amsterdam . Can hardly wait.
I cannot find the words to describe how much I enjoyed the 2 Paris concerts, they were sooo amazing!! Had the best of times, adored the new songs live, and the band were in such good form ;-) THANK YOU, from the bottom of my happy heart!
I get goosebumps watching them walk out along with getting teary-eyed....they look and sound better than ever!!!!.....Only 60 days til Chicago!!!


text:
RNLI statement following €6 million bequest
The RNLI is deeply grateful and humbled by the generosity of Mrs Elizabeth O'Kelly to bequeath over €6 million in her will to the charity.
RNLI/Nuala McAloon
Gifts in wills, be they large or small, are vital to the charity's work in saving lives at sea, they fund six out of every 10 lifeboat launches.
Mrs O'Kelly who prior to her passing, lived in Stradbally County Laois, was a long-standing supporter of the RNLI. She held a high regard for the volunteer work carried out by the charity which appealed to her ethos and she herself for many years, volunteered her time to help out at an RNLI stall at the RDS in Dublin.
Throughout her life, she displayed great kindness towards her many friends and was most charitable in supporting those in need. This has been reflected in her generous decision to bequest the funds to five charities.
Mrs O'Kelly asked that her legacy be used to support the RNLI's lifesaving work in Ireland. The impact of her incredible generosity will be directly felt by our volunteer crews and the people whose lives they save for many years to come. As this is such a large legacy, the RNLI will be carefully considering all options to ensure the funds are used where they are needed most and with a view to how they can be spent to fittingly reflect Mrs O'Kelly's support for the charity.
The RNLI provides a 24-hour search and rescue service and has 46 lifeboats stations in Ireland and 59 lifeboats. In 2017, Irish lifeboats launched 1,088 times and our volunteer crews rescued 1,471 people, that's an average of four people aided each day.
As a charity, we rely on the generosity of the public to fund our lifesaving service and to ensure our lifeboat stations are properly equipped, our lifeboats are maintained and that our volunteers are highly trained and skilled to continue their work in saving lives at sea.
For more information please contact Nuala McAloon RNLI Regional Media Officer Ireland on 00353876483547 or email Nuala_McAloon@rnli.org.uk or Niamh Stephenson RNLI Regional Media Manager Ireland on 00353871254124 or Niamh_Stephenson@rnli.org.uk
Nuala McAloon
Regional Media Officer, Ireland

redpajama_set_name: RedPajamaCommonCrawl


text:
T95E6 — the American Hero
18. Dezember 2018 EN, Events
A huge vehicle with a brutal appearance. The authentic sounds of an American engine, light rear of a medium tank, and a solid turret all combined with an accurate and penetrating gun. Meet the XT95E6 collector vehicle — one of the fastest Tier X heavy tanks. The American Dream. Want to add this hero to your collection? Take part in the Lucky Draw!
To win the T95E6, you will need some Lucky Tickets for the Lucky Draw. You can get them from Candy Boxes or by decorating your New Year Tree on the portal.
When all else fails… he doesn't!
The first thing you notice about the T95E6 — its huge size and tall silhouette. But don't let that intimidate you. This new vehicle is quite speedy for its class. The 750 h.p. engine and high specific power guarantee good maximum speed and solid acceleration — this vehicle reaches 42 km/h in 7-8 seconds. Besides this, the tank boasts great terrain crossing capacity: it easily maintains a 35-40 km/h speed on different terrain types, be it forest roads, sand dunes, or snow.
However, it won't be easy to manage this monster. Given its size and weight, the T95E6 boasts the grace of a sledgehammer at high speed. It's not that hard to lose control of it. Negotiating corners may also cause some issues. This makes maneuvering in the streets of, say, Dynasty's Pearl or circling around an enemy at maximum speed a difficult task. At an average speed, however, the vehicle acts quickly and accurately, making it perfectly suited for dynamic second-line combat. The good maneuverability of its chassis and a fast turret make the T95E6 a formidable opponent for most Tier IX-X vehicles.
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The T95E6's hull resembles another "American"—the medium T95E2. And though the new Tier X collector vehicle is notably better armored, entering a close quarters battle with other same-tier heavies can be a dangerous endeavour.
The hull's frontal armor is just 114 mm thick. But thanks to the reasonable depression angle, its effective thickness in some areas reaches almost 350 mm. The sides and rear are less protected, though, so you should avoid exposing them to enemy fire.
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The turret boasts more reliable armor. The thickness of its frontal armor varies from 152 mm to 280 mm while the gun mantlet is 178 mm thick. The weakest spot is the commander's cupola. Despite being 220 mm thick at the front, it's quite vulnerable. Luckily, the tank has good dynamics that allow you to move quickly from cover to cover, and excellent depression and elevation angles (-10 and +20) that make it possible to expose only the most protected parts of your armor to the enemy.
Besides that, the vehicle boasts an accurate gun with excellent stabilization—so you can shoot on the move—and good penetration. The AP shells penetrate 258 mm deep and deal 400 HP of damage per shot, while the HEAT shells penetrate 340 mm deep and cause 340 HP of damage. Damage per minute reaches 2,400 HP, which goes up to 3,200 HP with equipment and provisions applied!
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The power of the T95E6 is in its versatility. Need to quickly take key positions on the map? No problem. Want to destroy a couple of medium tanks out in the open? Anytime. Want to quickly move from cover to cover, shooting down enemy heavies along the way? Nothing could be easier. The T95E6 is capable of a lot of things: it easily adapts to any situation in battle, and when others would surrender, this "American" goes all the way!


Friday Reads" is a blog written by reference librarian Faith Lee about great books, magazines, and the occasional reference work. Topics may be new titles added to the library, selections from the Staff Picks shelf or about something she recently read. Admittedly, there is a definite slant toward nonfiction, because, well, she's a reference librarian and likes to learn new things. Guest bloggers take a turn sometimes too. No matter the source, good reads are featured here. This blog was written by reference librarian, Donna Burgess.
What would the contents of your handbag reveal about you? Would your make-up kit reveal a woman who wears bright red lipstick or soft coral lip gloss? Do you carry a hand cleaner? A spritzer of perfume, your current read in book or e-book format? A notebook, a dry cleaner pick-up slip, earrings that you didn't have time to put on, keys, business cards? If your cell phone and wallet were stolen, how would someone identify you?
This small book intrigued me. Laurent Letellier, a bookseller, finds a beautiful leather handbag on a dumpster and so begins a story about his search to find the owner of the purse. Within the bag is a small red notebook with notes about the fears, likes and dislikes of the owner. Those jottings convinced Laurent he wished to meet the woman who owned it.
In the story we meet Laurent's daughter, his current girlfriend and a woman-chasing friend who cannot understand his fascination with a woman he never met.
Pick up this little gem, we have it on the Staff Picks shelf in both book and CD format.


text:
Get Ready: Rec And Park Wants To Raise SF Zoo Admission Prices
Rec and Park SF Zoo by April Siese | May 14, 2013 11:25 am	| in Business | 0
The SF Zoo is thriving. They've got an adorable Sumatran tiger cub, many of their exhibits have been refurbished, and life is only getting better for their animals. The good life comes at a price, though — a price that's about to be passed on to visitors.
As the Ex reports, this Thursday SF Rec and Park are looking to pass a proposal that will increase admission fees by $2 across the board. If passed, the proposal would take effect by September 1, marking the first admission increases in five years.
Those potential increases are expected to help beautify the zoo as well as fund temporary exhibits and animal wellness initiatives. According to the SF Zoo website, adult SF residents currently pay $12 per ticket, and nonresident adult admission is currently $15. Adults, by the SF Zoo's standards, are people between the ages of 15-64.
SF kids between 4-14 currently get in for $5.50 ($9 for non-SFians) and SF senior citizens currently get in for $7.50 ($12 for "outsiders").
Rec and Park says they believe that such prices are on par with similar zoos in the state, placing it in the middle tier of affordability. SF residents will still have twelve free zoo days a year as well.
Still, ticket prices add up fast. SF resident Margi Young tells the Ex that "if a family has two or three children, this really starts to become unaffordable. Personally, I think the zoo should be free."
Always in motion. April Siese writes about music, takes photos at shows, and even helps put them on behind the scenes as a stagehand. She's written everything from hard news to beauty features, as well as fiction and poetry. She most definitely likes pie.


Last weekend , the weather in Kuwait was dusty and dull , as many of you may know by now that I love outdoors especially when it's sunny and cool sunny cool days make me active and happy! Taurus syndrome. lol.
A sweet friend invited us over for a lovely brunch.The setup was beautiful overlooking the beach and food was so delicious .


Who knew that in one month our life could change so much. We are now parents and have a new understanding of love. Our first month has gone by so quickly. And Carter has already changed so much. He is looking around more and more each day. His smiles are still strictly gas related but are so cute. He is getting to be a champ at sleeping during the night. He usually has a 4 hour stretch followed by a 3 hour stretch. Bedtime starts anywhere around 8pm-11pm and he wakes up anywhere from 5am-8am. So there are no complaints form me. He also takes good napes during the day and I actually can get things done..like showering.
We have made a few trips tp the mall Carter has been great enjoying the ride in the stroller....the boy loves movement, walking, riding or bouncing. We have also had a few days of temps in the 30's so we bundled up and took the dogs for a walk. The babybjorn and the fleece cover is awesome!!
We have been very fortunate to have our family and friends come to visit us. Thank you for all you love, support, and cooking.


text:
Melons fetch £10,000 at Japanese market
In General Japan News,
Anyone who lives outside of Japan may well be surprised to learn that a pair of cantaloupe melons recently sold at an auction for an eye-watering 1.6 million yen (GB £10,386).
The pair were sold at the Sapporo Central Wholesale Market in northern Hokkaido and the sale will not have raised too many eyebrows among the Japanese community as the fruit is considered a status symbol in east Asia.
What is perhaps more surprising is that this is not the highest amount ever paid for a melon. That honour went to a pair sold at an auction in 2008 for 2.5 million yen (GB £16,227).
The Yubari melons weighed 3.7 kilogrammes or 8.1 lbs and were sold not to an individual but a wholesaler who clearly saw the value in the fruit and snapped them up on the first day of the season.
Yubari is famous for producing quality melons although the former coal-mining town is now bankrupt.
Related news stories:
Japanese melons reach new auction record (13th May 2008)
Two melons sold for the price of luxury car in Japan (22nd May 2015)
Kobe beef and Yubari melons become protected brands (22nd December 2015)


text:
Ali Erhan ÖZDEMİREL1, Hatice Rana ERDEM2, Barış NACIR3, Aynur KARAGÖZ3
1Department of Physical Medicine and Rehabilitation, Division of Rheumatology, Medical Faculty of Ankara University, Ankara, Turkey
2Department of Physical Medicine and Rehabilitation, Medical Faculty of Ahi Evran University, Kırşehir, Turkey
3Department of Physical Medicine and Rehabilitation, Ankara Training and Research Hospital, Ankara, Turkey
Keywords: Ankylosing spondilitis, Familial Mediterranean fever, Mediterranean fever gene mutations
Objectives: This study aims to investigate the role of Mediterranean fever (MEFV) gene mutations in the pathogenesis and clinical progression of disease in ankylosing spondylitis patients.
Patients and methods: The study included 88 patients (60 males, 28 females; mean age 38.7±8.7 years; range 19 to 56 years) diagnosed with ankylosing spondylitis according to modified New York criteria. The patients were evaluated for peripheral joint and hip joint involvement and treatment characteristics. Using multiplex/polymerase chain reaction reverse hybridization method, the presence of 12 different MEFV mutations was investigated.
Results: Of 29 patients, heterozygote mutation was detected in 24 (83%), mutations in both alleles were detected in three (10%), and combined heterozygote mutations were detected in two patients (7%). Three most common mutations were M694V (11.3%), E148Q (8%), and V726A (4.5%). In the group with mutations, symptoms had started earlier than in the other group, and the number of peripheral joints involved was higher. When both characteristics were compared with the characteristics of the group that did not have any gene mutations, the differences were statistically significant (p<0.001 and p=0.044, respectively). The highest correlation with the number of peripheral joints involved was determined for M694V mutation (p=0.034), while onset of symptoms at younger age was correlated with E148Q mutation (p=0.010).
Conclusion: Based on the findings of this study and our clinical experience, it can be said that the clinical progression of ankylosing spondylitis patients with MEFV gene mutations is more severe, and this suggests that MEFV gene mutations may be contributive to ankylosing spondylitis pathogenesis.
Ankylosing spondylitis (AS) is the most frequently encountered disease in the spondyloarthritis group. Typically, it is a chronic disease which affects the spinal column and sacroiliac joints, entheses, and less commonly, the peripheral joints. The major symptoms of the disease are inflammatory back pain, spinal stiffness and loss of spinal mobility, which are caused by the presence of inflammatory activity that engenders structural damage, in the axial skeleton.(1) In AS pathogenesis, genetic and environmental factors are thought to play an important role.(2) Studies on AS genetics have shown a relationship between human leukocyte antigen B27 (HLA-B27), a component of major histocompatibility complex, with AS, and this relationship is the strongest association defined for AS yet.(3) In fact, the concordance in monozygotic twin studies is reported as 70%, indicating the 30% role of environmental factors involved in AS predisposition. Remarkably, the entire genetic predisposition cannot be explained solely by HLA-B27, because the concordance in dizygous twins positive for HLA-B27 is around 25%.(4,5) Overall, among people positive for HLA-B27, the risk of AS is 1.3%.(6) This indicates the involvement of environmental and genetic factors other than HLA-B27 in AS development.
Previously, the Mediterranean fever (MEFV) gene on the short arm of the 16th chromosome has been associated with familial Mediterranean fever (FMF) which is an auto-inflammatory periodical fever syndrome.(7,8) There are data in the literature which support that pyrin protein encoded by MEFV gene takes a role in the intracellular control of inflammation.(9) Point mutations defined for this gene disrupt the normal function of pyrin protein and probably lead to a more severe inflammatory response. Although MEFV gene mutations are most frequently seen in FMF patients, they are also seen in patients with other inflammatory diseases such as rheumatoid arthritis (RA), juvenile idiopathic arthritis, Behçet's disease and Henoch-Schönlein purpura.(10-16) A recent study has shown that the presence of MEFV mutations associated with FMF in RA have been reported to be related to a more severe and erosive RA clinical profile.(10) Similarly, among juvenile idiopathic arthritis patients with MEFV mutation, the clinical prognosis has been reported to be more severe compared with the ones without MEFV mutation.(11)
The association of FMF and spondyloarthropathy (SpA) has been a focus of discussion for years. According to the literature, FMF patients may present with a clinical profile similar to that of SpA including sacroiliac joint involvement and other clinical signs, while such cases are generally reported to be negative for HLA-B27. On the other hand, positivity for HLA-B27 is generally recognized as a coincidental association of AS and FMF.(17-18) All these findings indicate that there might be common etiopathogenetic mechanisms involved in FMF and SpA diseases.
Mediterranean fever gene mutations may change the inflammatory response to infectious and inflammatory diseases and may contribute to the development of AS.(19) Moreover, they may influence disease course as well as disease activity, and so it is important to investigate the rate of MEFV mutations and the impact of these mutations on AS.(10,16,19) Thus, in this study, we aimed to investigate the role of MEFV gene mutations in the pathogenesis and clinical progression of disease in AS patients.
Patients and Methods
This single-center, cross sectional study included 88 patients (60 males, 28 females; mean age 38.7±8.7 years; range 19 to 56 years) who were diagnosed with AS based on the 1984 modified New York criteria(20) following MEFV gene analysis. The patients who met the revised Tel-Hashomer diagnostic criteria for FMF(21) as well as those who had a history of FMF were excluded. The patients who gave consent to participate in the study were evaluated with regard to inclusion and exclusion criteria (Table 1). Approval for the study was obtained from the local ethics committee and written informed consents were obtained from all the participants.
Table 1. Inclusion and exclusion criteria
The patients meeting the inclusion criteria underwent clinical evaluation and the data involving demographic characteristics, laboratory tests and physical examinations, clinical and functional activities, radiograms, and enthesis examinations were recorded. Clinical and functional activities were evaluated according to Bath Ankylosing Spondylitis Disease Activity Index (BASDAI,22) Bath Ankylosing Spondylitis Functional Index (BASFI23) scores. Progression of the disease was evaluated by Bath Ankylosing Spondylitis Metrological Index score,(24) whereas enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score(25) and radiological damage was assessed by modified Stoke Ankylosing Spondylitis Spine Score.(26) Laboratory investigations including, erythrocyte sedimentation rate (mm/h), and C-reactive protein levels (mg/L), HLA-B27 and MEFV gene mutations were carried out on all participants.
Patients were evaluated with regard to involvement of the peripheral and hip joints, and treatment characteristics. Patients who had MEFV gene mutation and those who were non-carriers were compared according to the demographic, clinical, and laboratory parameters. The above mentioned parameters were also compared among the subgroups of carriers.
The files of all participants were reviewed and the most recent hemoglobin (gr/dL), leukocyte (mm(3)), platelet (mm(3)), erythrocyte sedimentation rate (mm/h, measured by Westergren method), and C-reactive protein (mg/dL) values were recorded. The analyses of MEFV mutations were performed by reverse hybridization method in the Molecular Tests Laboratory of Clinical Biochemistry Department at our hospital. Deoxyribonucleic acid was purified from the anticoagulated blood and amplification was carried out by the polymerase chain reaction method using primers of the second and 10th exons of the MEFV gene. The amplification products were hybridized with test strips including oligonucleotide probes and mutation analysis was performed on 12 regions (M694V, E148 Q, V726A, F479L, R761H, M694I, K695R, P369S, M680I G/C, M680I G/A, A744S, 1692del).
The study data were analyzed by SPSS for Windows version 15.0 package program (SPSS Inc., Chicago, IL, USA). The Shapiro Wilk test was used to evaluate whether the distribution of continuous variables was close to normal or not. Descriptive statistics were expressed as mean ± standard deviation or median (min.-max.) values, whereas categorical variables were presented as numerical and percentage (%) values. The intergroup difference relative to mean values was analyzed by Student's t test and the intergroup difference relative to median values was evaluated by Mann-Whitney U test. Categorical variables were analyzed by Pearson's chi-squared or Fisher's exact test. A value of p<0.05 was recognized as statistically significant.
The mean duration of disease was 9.1±5.1 years. Positive HLA-B27 was determined in 71.6% of the patients and 29 AS patients (33%) had MEFV gene mutation. Regarding the related MEFV gene mutations among those 29 patients, 10 (34.5%) had heterozygous M694V, seven (24.1%) had heterozygous E148Q, four (13.8%) had heterozygous V726A, two (6.9%) had heterozygous M6801G/C, and one (3.4%) had heterozygous P3695 mutation. Only three (10.3%) of the patients exhibited homozygous mutation: two (6.9%) had homozygous M694V and one (3.4%) had E148Q mutation. Two patients had a compound heterozygous mutation: one with a heterozygous M694V-E148Q and the other with a heterozygous M694V-M6801G/C mutation (Table 2). The incidences of subtypes of MEFV gene mutation are shown in Table 2. The distribution of the most frequent three MEFV mutations among the AS patients was as follows: M694V (11.3%), E148Q (8%) and V726A (4.5%).
Table 2. Distribution of Mediterranean fever gene mutations in patients with ankylosing spondylitis
There were no significant differences between mutation carriers and non-carriers with regard to age, gender, duration of disease, acute phase reactant levels, BASDAI, BASFI and Bath Ankylosing Spondylitis Metrological Index scores, Maastricht Ankylosing Spondylitis Enthesitis Score, and modified Stoke Ankylosing Spondylitis Spine Score. The mutation carriers group demonstrated earlier onset of symptoms and an earlier age of diagnosis. There was a statistically significant difference between the mutation carriers group and non-mutation carriers group in terms of those three characteristics. (p<0.001 and p=0.004, respectively) (Table 3).
Table 3. Demographic comparison of ankylosing spondylitis patient groups with and without Mediterranean fever mutations
Table 4 represents the relationship between hip involvement, treatment characteristics and involvement of peripheral joints of the mutation carrier and non-carrier patients. The mutation carriers group demonstrated involvement of a higher number of peripheral joints (p=0.044) There was no statistically significant difference between the mutation carriers group and non-mutation carriers group with respect to hip involvement and treatment characteristics (Table 4).
Table 4. Comparison of mutation carrier and non-mutation carrier groups relative to peripheral joint involvement, number of involved peripheral joints, hip involvement, and treatment characteristics
The AS patients were divided into two groups based on being positive or negative for HLA-B27. In the HLA-B27 positive group, 23 (36.5%) of 63 patients had MEFV mutation; and in the HLA-B27 negative group, six (%24) of 25 patients. The two groups showed no statistically significant difference with regard to carrier rate of MEFV mutation (p>0.05). Similarly, the comparison of the two groups in terms of the three most common MEFV mutation subgroups in our study (M694V, E148Q, V726A, respectively), revealed no statistically significant difference (p>0.05) (Table 5). Furthermore, there was no statistically significant difference between the overall study population (n=88) and the HLA-B27 negative group (n=25) relative to the incidence of these three mutations (p>0.05).
Table 5. Comparison of the frequency of M694V, E148Q and V726A mutations in HLA-B27 positive and negative groups
Ankylosing spondylitis patients with the three most common MEFV mutations (M694V, E148Q and V726A, respectively) were separately compared with the non-MEFV mutation group with regard to age of onset of symptoms, peripheral joint involvement, number of involved joints, hip joint involvement, and current treatments (Table 6). Furthermore, the patients with M694V and E148Q mutations were compared with the patients with other MEFV mutations in terms of the same parameters (Table 6). The age of onset of symptoms was 39.3±8.2 years in AS patients with no heterozygous MEFV mutation, whereas, it was 25.9±3.8 years in AS patients with M694V mutation and 21.8±6.7 in AS patients with heterozygous E148Q mutation. AS patients with M694V and E148Q mutations had a statistically significantly earlier age of onset of symptoms compared to the AS patients with no MEFV mutation (p=0.022 and p=0.010, respectively). The AS patients with heterozygous M694V mutation and heterozygous E148Q mutation were separately compared with the AS patients exhibiting other MEFV mutations with regard to age of onset of symptoms, and no statistically significant difference was determined (p=0.085 and p=0.292, respectively) (Table 6). While the median value for the number of involved peripheral joints was 4 (0-20) in AS patients with heterozygous M694V mutation, it was 0 (0-14) in AS patients without MEFV mutations; the difference between these two groups was statistically significant (p=0.034). No relationship similar to that detected between heterozygous M694V mutation and the number of involved peripheral joints in AS patients was found between patients with heterozygous E148Q and heterozygous V726A mutations, and AS patients without a MEFV mutation (p=0.151 and p=0.135, respectively) (Table 6). There was no statistically significant difference between AS patients with heterozygous M694V mutation and the group with other MEFV mutations in terms of the number of involved peripheral joints (p=0.377).
Table 6. Comparison of ankylosing spondylitis patients with M694V, E148Q and V726A mutation with ankylosing spondylitis patients without mutation together with comparison of ankylosing spondylitis patients with M694 and E148Q mutations with ankylosing spondylitis patients with other Mediterranean fever mutations with regard to age at onset of symptoms, peripheral joint involvement, number of involved peripheral joints, hip involvement, and use of tumor necrosis factor-α blockers
Mediterranean fever mutations involved in the development of FMF lead to uncontrolled inflammatory response.(27) In a study focusing on FMF patients and their first degree relatives during intervals between episodes, both groups were shown to have higher acute phase reactant levels compared with the healthy controls, probably due to subclinical proinflammatory cytokine release.(28) This result suggests that MEFV may be counted among the genes that can affect the clinical course of inflammatory diseases other than FMF. Similarly, there are studies which indicate that MEFV mutations have a negative impact on inflammatory diseases such as Behçet's disease,(13,15) RA,(10) Henoch-Schönlein purpura,(14) multiple sclerosis,(29) and Crohn's disease.(30)
Ankylosing spondylitis and FMF are two clinical conditions affecting people of almost the same age group. The association of FMF with AS has been described in several previous reports (17,31-33) although the pathogenic mechanism of this association still remains unknown.(19)
In a study by Yilmaz et al.(34) conducted in 2001, the MEFV carrier rate in the healthy population was 20%. Studies performed in various regions of Turkey have produced similar values.(35,36) In the current study, the MEFV mutation rate was 33% among AS patients. Since these patients were from the same region as in the study by Yilmaz et al.,(34) the MEFV mutation rate among these people can be deemed to be raised. However, it is not possible to reach a definite conclusion because there was no control group in the current study. Similarly, Cinar et al.(19) demonstrated the MEFV mutation rate in AS patients to be 30.5%, but a control group was not used in that study either. Durmus et al.(37) compared the MEFV mutation rate in AS patients with that of healthy individuals, but no statistically significant difference was determined.
There are few studies in the literature focusing on the association between AS and MEFV mutation as well as the impact of MEFV mutation over disease severity.(19,37) In a study by Cinar et al.(19) of 95 AS patients, MEFV mutation was shown to have no effect on disease severity with regard to clinical symptoms and laboratory values. Durmus et al.(37) conducted a study on 80 AS patients and found that MEFV mutation was associated with higher BASDAI and BASFI scores. In the current study, MEFV mutation was found to have no influence over BASDAI, BASFI, and Bath Ankylosing Spondylitis Metrological Index scores, among AS patients. However, differing treatment protocols in our patients may be the underlying reason for this result, because although the difference was not statistically significant, a higher rate of tendency to use tumor necrosis factor-α inhibitor in patients with MEFV mutation was determined compared to those without MEFV mutation. These multiple and more aggressive treatment modalities may have resulted in stronger suppression of disease activity and functional status parameters in patients with mutations.
The most common MEFV mutations in our AS patients were M694V (11.3%), E148Q (8%), and V726A (4.5%), respectively. While the M694V mutation carrier rate is 3% in the healthy Turkish population, this rate increases to 50% in Turkish FMF patients.(34) The carrier rate for E148Q mutation is 12% in the healthy Turkish population, but 3.5% in FMF patients.(34) This remarkable increase of M694V mutation rate in AS patients compared to healthy individuals is associated with the fact that M694V mutation is seen in cases which show the highest penetration and most severe clinical course compared to other mutations.(38-41) M694V mutation has been shown to be associated with early onset, episode frequency, arthritis, erysipelas-like erythema, and poor prognosis.(34) On the other hand, E148Q mutation has not been shown to be associated with low penetration or severe clinical course in FMF patients. A previous controlled study investigating MEFV mutation rate in AS patients revealed increased M694V mutation rate in AS patients; the M694V rate was 2.9% in the control group and 12.4% in AS patients.(42) In a study by Cinar et al.,(19) the M694V mutation rate in AS patients was 15.8%, but there was no control group. In the current study, the M694V mutation rate among AS patients (11.3%) was substantially higher compared to the overall carrier rate in the general healthy Turkish population (3%).(42) However, this result was not of statistical significance since a control group was not used in the current study, although it is evident that the M694V mutation rate shows an increase in AS patients similar to that in FMF patients, when compared to the general population. This finding suggests that M694V mutation is directly involved in the primary pathogenetic processes of AS. In the current study, the E148Q and V726A mutation rates were also investigated, but no significant increase was observed in AS patients compared to the increased rate exhibited by M694V mutation. The reason behind that may be that both of those mutations were of lower genetic penetrance compared to the M694V mutation.
This study indicated an association between MEFV gene mutations and clinical symptoms by showing a statistically significant direct correlation between the presence of MEFV mutation and the number of involved peripheral joints in AS patients (p=0.044). The age at onset of symptoms was statistically significantly lower in AS patients with MEFV mutation than in patients without MEFV mutation (p<0.001). Furthermore, any correlation between the three most common mutations (M694V, E148Q, and V726A, respectively), and the number of involved peripheral joints and age at onset of symptoms was investigated. The number of involved peripheral joints demonstrated a significant correlation only with M694V mutation (p=0.034). The age at onset of symptoms showed a correlation both with M694V and E148Q mutations (p=0.022 and p=0.010, respectively). It is remarkable that a correlation was determined not only between age at onset of symptoms and M694V mutation, but also between age at onset of symptoms and E148Q mutation (p=0.022 and p=0.010, respectively); because E148Q mutation is known to be associated with low penetrance and a moderate level of clinical course in FMF patients.(43) To date, there have been almost no studies showing that E148Q mutation is associated with a severe clinical course and early onset of symptoms in inflammatory diseases. In one such study, Rabinovich et al.(10) investigated the impact of MEFV mutations on RA patients where E148Q mutation carriership was associated with a severe clinical course in RA patients. Since there are no similar reports in the literature supporting the association of E148Q mutation with early onset and poor clinical course, it is challenging to generalize the association between E148Q and early onset until further data has been gathered from more comprehensive studies focusing on this relationship.
Durmus et al.(37) showed the relationship between MEFV mutation carriership and involvement of the hip joint in AS patients. Early onset, involvement of the hip joint, and oligoarticular involvement are known to be negative prognostic factors for AS. In the current study, MEFV mutation carriership was found to be associated with early onset and a higher degree of peripheral joint involvement in AS patients. Furthermore, although no statistical significance was determined, being a carrier of M694V mutation was observed to generate a particular tendency toward hip joint involvement in AS patients, while AS patients were also found to require more aggressive treatment. These results support the hypothesis that MEFV mutations, particularly M694 carriership, may be a risk factor for AS development. However, further controlled and prospective studies with larger patient groups are required to verify this.
For many years, there have been ongoing discussions on the association of FMF and SpA. In the literature, many cases of FMF and sacroiliitis are known to be negative for HLA-B27. Some argue that the development of SpA clinical profile in FMF patients can be differentiated from classic AS clinical profile via the absence of lumbar spinal involvement signs and HLA-B27 negativity.(17,18,44) On the other hand, cases positive for HLA-B27 are generally recognized as a coincidental association of AS and FMF.(17) However, none of these assumptions are based on solid evidence, but only represent a tendency towards explanation. When these opinions are analyzed together with the results of this study, it can be said that FMF patients can be diagnosed with AS by modified New York criteria based on the symptoms of muscular/skeletal systems and radiological signs. Generally, cases exhibiting this association are observed to be negative for HLA-B27. This result suggests that etiological factors involved in FMF pathogenesis may also have a role in AS pathogenesis. On the other hand, there are opinions advocating that HLA-B27 positivity elevates the degree of sacroiliitis in FMF patients and leads to a more severe clinical course of FMF-related spondyloarthritis.(17) These opinions underscore the likelihood of the presence of common etiopathogenetic processes in FMF and SpA disease groups, which are yet to be explained.
In a previous study, the M694V mutation was thought to be involved in the development of AS in patients negative for HLA-B27.(42) In the current study, while the M694V mutation carrier rate was 11.3% in AS patients, it was 12% in HLA-B27 negative AS patients, with no statistically significant difference. However, considering the carrier rate (3%) of M694V mutation in the healthy population, the increased M694V rate in HLA-B27 negative patients appears to be remarkable. Similar clusterings in AS patients negative for HLA-B27 and positive for E148Q or V726A mutations were observed.
The findings of this study suggest that the presence of MEFV mutation in AS patients is associated with a more severe clinical prognosis. Moreover, we believe that the presence of MEFV mutation will not only trigger the current inflammatory process associated with the AS, but may also act as a direct factor contributing to AS pathogenesis. M694V mutation appears to be the MEFV mutation type that is most closely associated with the pathogenetic mechanism in AS. In AS patients, early onset and aggressive clinical course are the most important indicators of disabilities which are likely to occur. Therefore, particularly in juvenile-onset AS patients, it is essential to determine prognostic factors and commence treatment urgently. MEFV mutation might be a factor which has a direct effect on AS pathogenesis, while showing a negative influence on the prognosis.
Therefore, in countries with high MEFV mutation rates such as Turkey, MEFV mutation screening should be included in routine tests. However, further national and multicenter studies including larger populations and prospective follow-up of patients are required to support these results.
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At its heart, "Smile " is an autobiographical story of a girl who trips while leaving a Girl Scouts meeting, smashes her front teeth, and spends several years with dentists. But it's also a teen coming of age story, a documentary of the 1987 San Francisco earthquake, and a fun slice-of-life memoir. In documenting her "dental drama," Raina Telgemeier has created a wonderful, painful portrait of life as it revolved around friends, school, video games and dental procedures that lasted from sixth grade until high school.
What I liked most about "Smile" is how honest it is, including details both good and painful. Even on the 10th reading, I cringe at the pages that show Raina tripping and smashing her teeth. Likewise, when she's betrayed in little ways by her friends, I feel the shame and hurt. Also, although I wasn't a teenage girl in 1987, I identify with the details: Mario on Nintendo, the DuckTales video game, the 1987 SF Earthquake, and the faux MS yearbook signatures on the end pages. Even when young Raina and her friends see "The Little Mermaid " is its first release, we later see a figurine of Ariel on Raina's desk when she's in high school. Heck, even the details of the dental procedures are accurately captured in jaw-dropping detail.
Mom: Lots of kids wear funny stuff to help fix their bodies…you probably just don't realize it because no one talks about it.
Raina: Well, maybe someone should start talking about it!!
Raina (thinking): Maybe it would make us feel less like freaks.
The art is clean, and casually cartoony. Bug eyes, comic-book icons such as light-bulb ideas, helpful arrows labeling items ("oatmeal"), and the occasion character floating in love add to the ambience rather than detract. The backgrounds are almost architectural. I especially enjoyed the sense of timing, sometimes spending a full page to add emphasis to events. One example of this is when Raina skips out on the Valentine's dance without meeting her friend Sam. Telgemeier has two 1/6-page frames with setting up Raina's motivation outside the dance, two 1/3-page frames showing her indecision, and then a single page dedicated to Raina leaving alone while the "boomboom" of the music emanates from the gym.
I'd put Telgemeier in the same category as Judy Blume. While the audience for "Smile" is clearly younger teen girls, some middle-school boys will probably also enjoy it. One difference between Blume's books and "Smile" is that the publisher, Scholastic, has made an effort to omit anything scandalous from "Smile." At Stumptown Comics Fest in 2010, Telgemeier mentioned there was a bit of censorship in the publishing process where Scholastic wanted a reference to "PMS" removed from the book, which she assented to.
One more comment: In addition to middle readers, every dentist should have a copy of "Smile" in the waiting room. In comparison to Raina's journey, a cleaning or a filling for most patients should be a piece of cake.
"Smile" was nominated "Best Publication for Teens" for the 2011 Eisner Awards. Raina Telgemeier's website is http://goraina.com. You can read the entire story of Smile online, although it's not in color.
When I was a kid reading L. Frank Baum's "Wizard of Oz " books, I'd sometimes stop mid-story to look at John R Neill's drawings of fairies, gnomes and other magical creatures of the land, and get so entranced I'd lose all track of the time. The elegant lines of the dresses of the beautiful fairies, the curlicues embossing the Cowardly Lion, the pretty and mischievous smile of Ozma, the girl ruler, were so expertly rendered I saw them on the page as if they really existed. This sense of wonder and whimsy in the illustrations so perfectly matches Baum's stories that, even though other artists have had their turn illustrating the Oz stories, in my mind they are as intertwined as a climbing rose and trellis.
In "Return of the Dapper Men ," written by Jim McCann and illustrated by Janet Lee, the artists have tried to create a similar work of whimsy, combining a fairy-tale story with lavish artwork, bringing to mind Baum & Neill, the Brothers Grimm, Little Nemo and maybe a touch of William Joyce. The result hovers somewhere between a graphic novel and an extended picture book.
In the land of Anorev, time has stopped. The robots live and work aboveground, while the children play in the dark caves underground. Only two beings can travel between the two realms: the boy Ayden and a robot girl named Zoe. A robotic villain named Fabre tries to force Zoe to sprout wings and fly to the majestic broken angel that oversees the land on Anorev. Then, time starts again with the arrival of 314 dapper men, wearing bowlers and carrying umbrellas, flying into town. With their advent, dapper man 41 stirs Ayden, Zoe, and the rest of the beings in Anorev into working toward their destiny.
The artwork is definitely worthy of a modern classic fairy tale. The characters sprawl over the page, with bits of detail filling the crannies. The art continuously reminded me of a melding of Winsor McKay's Little Nemo meets Johnny Gruelle meets William Joyce's Robots, but was rendered with Lee's own style, too. A section at the end of the book explains Lee's meticulous process in "The Making of a Dapper Page." In this digital era, it's amazing to see an artist who, after doing the layout and illustration, then physically cuts out the images to overlay them on abstract painted backgrounds.
"'Return of the Dapper Men' is a transformational experience, a morality tale that is certain to become an instant contemporary classic. The narrative is instantly captivating and always multi-dimensional. The reader will find puzzles, riddles, and anagrams that serve as catalysts for further investigation and research. Be armed with Google and Merriam-Webster.com in order to enjoy the full-tilt experience of this wondrous read."
Frankly, the problem is that the story is both treated too preciously and not seriously enough. McCann has allusions to September 11th, and to tragedies such as Romeo and Juliet and the drama of Tristan and Isolde, but the characters never seem engaged in the story. There are many wide-eyed proclamations, such as "The only boy to write. That's why you are up here," and "There's always time for lessons, especially when you have time." Occasionally characters appear to talk to the "camera." Some of the characters seem to be cast as antagonists, but the conflict is all spoken, and never acted on. The only actual threat to all the characters is that time had stopped, and now it's starting again, which, I guess, means change? In time of no time, the children and the robots had forgotten how to share work and play, and now they have to move forward. Even in allegory, I didn't find the story very compelling.
According to Wikipedia, when Baum was writing the Oz books, his "avowed intentions with the Oz books, and other fairy tales, was to tell such tales as the Brothers Grimm and Hans Christian Andersen told, bringing them up to date by making the characters not stereotypical dwarfs or genies, and by removing both the violence and the moral to which the violence was to point." Although his books were less gruesome than the Brothers Grimm, Baum failed to completely remove the violence. Even in a land where no one dies, the threat of being cut into small pieces and left there for all eternity struck a chord in my imagination that stayed with me. Also, the Wicked Witch, the Nome King, and the other antagonists showed enough malice to keep the plot exciting. I can't same the same about "Dapper Men," which I found beautiful, but not compelling.
It appears that "Return of the Dapper Men" is a series, so perhaps this volume is only the prelude to a larger story. Given time, we may find out why time stopped in Anorev, and who sent the Dapper Men, and whether Zoe will ever speak and the answer to many more questions. But, while this book has the artwork of a classic, the story was whimsical without wonder, and left me unfulfilled. "Return of the Dapper Men" was nominated "Best Publication for Teens" for the 2011 Eisner Awards.
Weeks ago I bought Shannon Wheeler's newest book "I Thought You Would Be Funnier ," but I haven't reviewed it yet for a simple reason: I'm biased. I think that practically everything he does is funny. By way of explanation, I started to list all the work by Wheeler which I've admired, but it started to turn into a comic-artist version of A Fan's Notes (except, I hope, less crazy). Regardless, let's push on.
I started reading his Too Much Coffee Man strip years ago when it ran in the back of some local paper. TMCM was a new kind of superhero, similar to The Tick, except he didn't seem to have any powers other than a giant coffee cup attached to his head ( I know it's not part of the suit -- I've seen his skull!). The wry humor, interesting cast of recurring characters, and solid art grabbed and held my attention. TMCM had humor, insight, coffee and bathos. Well, I'm not sure if it had bathos, I've never understood bathos, but it had coffee. And Too Much Espresso Man.
Somewhere in the mid 90's, Wheeler traveled all the way from Austin, Texas to a comic book show in Portland, Oregon where I met him in person and discovered that "Shannon" was a skinny guy with long curly hair. Up until then I'd thought he was a she. Not a big deal. It's the body of work that's important, not the person. I got over it, and so did my wife. I even got him to sign a book.
I guess Wheeler liked his trip to Portland, since he moved to town, and I got more opportunities to buy the books and merchandise at local comic book shows, book signings, Wordstock, and eventually the Stumptown Comics Fest. The Too Much Coffee Man T-Shirts (I'm wearing the "pit of despair" shirt right now), the Too Much Coffee Man coffee cups, the Too Much Coffee Man cereal caddy. Ok, I'm joking about the cereal caddy. But I've got many of his books: Too Much Coffee Man's Guide for the Perplexed, for example, and Too Much Coffee Man's How to Be Happy .
Did I mention I wrote a TMCM screen saver? I know it was 1996, because Windows 95 had just come out, and it was late. I designed the program so you could configure the jitters, the anxiety, and how randomly TMCM would meander across the screen. I was so proud that I emailed a copy to Mr. Wheeler, who politely ignored the copyright infringement and wrote back that he owned a Mac, and wasn't sure whether anyone would be interested in a TMCM screen saver.
So, how far can the TMCM thing go? Pretty far, apparently, but before I could tire of it, Wheeler moved in a new direction: the boxed set of "Postage Stamp Funnies ." Designed to recall the look and feel of Maurice Sendak's Nutshell Library , it's a collection of Wheeler's weekly cartoons from The Onion. At the book signing at Oregon Historical Society, Wheeler told me that Dark Horse balked at the cost of binding and boxing the comics, but somehow he got the project completed. They're soooo cute!
Turned out the box set was part of a one-two punch, with the production of Too Much Coffee Man: The Opera. Announced as "the first opera based on a comic book," I thought it was a great idea. I heard early versions of the songs at Wordstock, but unfortunately missed the full productions in Portland and Astoria. Something to look forward to, I guess.
By that time Facebook had come out, and I'd friended Wheeler, and played a number of games of Jumble or WordTwist (something like that) with him. Like Homer Simpson to Mr. Burns, I don't think Wheeler remembered meeting me, but I was happy to see the occasional drawings he'd post on Facebook. Surprisingly, he started posting rejections from the New Yorker, and finally in 2009 announced his first sale to that esteemed, inscrutable, comic magazine. Frankly, the acceptance policy for comics at the New Yorker is a bit hard to fathom, but maybe that's the charm. There's something for everyone, whether you understand it or not.
Wheeler started collecting the comics rejected from the New Yorker, and voila, the result is "I Thought You Would Be Funnier. " It's a quick read - about 100 comics, all of them funny, and showcasing Wheeler's now-distinctive style. You won't find any Too Much Coffee Man, but there are a few that echo Too Much Espresso Man. In one cartoon workers are picking beans, and one worker asks another "Tell me again the difference between a cappuccino and a latte." In another, a clown confesses to his doctor "It hurts when I laugh."
But, as the great Dr. Emilio Lizardo once said, "Laugh-a while you can, monkey boy." Wheeler's upcoming project is not all humor and coffee. He's working with Oregonian columnist Steve Duin on a book called "Oil and Water," a graphic novel based on the Gulf Coast catastrophe of the Deepwater Horizon oil spill. Just like Wheeler's expansion from comics to opera, I look forward to this ambitious project mixing graphic novels with reporting.
In the meantime, "I Thought You Would Be Funnier " has two award nominations: in the running for the Eisner Best Humor Publication and the Harvey Special Award for Humor in Comics. Does that sound funny to you?
In "Ghostopolis " the relationship to the afterlife is slightly different than our own. Ghosts have a tendency to sneak back into the world of the living, and the living have the technology to visit the land of the dead. Agent Frank Gallows works for the Supernatural Immigration Task Force sending illegal ghosts back to the afterlife. While working on a case of a skeletal stallion, he accidentally sends terminally ill teen Garth Hale to Ghostopolis, which his boss Lieutenant Brock deems "a real screwup." Fired from the force, Frank enlists the help of his ghostly ex-fiancée Claire Voyant and her barrier-breaking Plasmapod, a sort of hot-rod that can travel to the land of the dead, to find Garth and bring him back. Meanwhile, Garth wanders the realm, encountering his grandfather, and learning about Joe, the mysterious Tuskegee Airman who created the world of Ghostopolis, and Vaugner, the Machiavellian ruler of the land.
The story has a lot of characterization, and the dialogue includes many kid-friendly jokes that are actually funny. In one running joke, Benedict Arnold betrays himself as a traitor to both sides on multiple occasions. TenNapel shows his skill at comedic timing during the climactic fight scene when Vaugner asks "You know what I've got that you don't?" In the next frame Garth replies "Diarrhea?" The exchange is made even funnier because the two combatants are in the shape of giant battling buildings.
The book is about death, but death taken in a comforting way. Given that, I guess it's no surprise that some Christian themes come through. The airman Joe is a barely disguised version of God, and the crack into the next realm, beyond Ghostopolis could be seen as Heaven. TenNapel has publicly written about using Christian themes in his works, and a story about the afterlife seems a pretty obvious place to discuss Christianity. But for comparison, I found Ghostopolis less about Christianity than, for example, Aslan in the Narnia books by CS Lewis. For the most part the points are integral to the story and don't seem moralistic or preachy.
TenNapel seems to have had a lot of fun with the seven territories of the afterlife: the Specters, the Will-O'-The-Wisps, the Mummies, the Goblins, the Zombies, the Boogeymen, and especially the Bone Kingdom. Dressed in Medieval armor garb, the Bone Kingdom reminded me of a perverse take on Prince Valiant.
The art is clean and comic, while moving toward realism when rendering the skeletons. I really enjoyed the scene where Garth and his nightmare are chased through the woods by the remains of velociraptors. Some reviews I've read complained about the coloring, but the addition of color seems to bring out the drawings where black and white might have been overly dark.
A truly great story, however, must have a truly great antagonist. In Ghostopolis, Vaugner turns out to be a tragic figure, but only in the final act. The extent of his powers, motivations and history is shrouded by the author until this time, and that weakens the character, leading to a slightly weaker story. In my opinion Vaugner would have been more tragic, more daunting if I'd known more about his motivation earlier. Also, his powers seem inconsistent: from atop his office building he's able to detect and pinpoint Garth's position in Ghostopolis. Later, however, he's unable to find the boy in a slightly crowded street. Also, his bug henchmen start out threatening, but end up comic. Vaugner as a villain seems a bit arbitrary, weakening the story.
Bottom line, "Ghostopolis" is a fun read, with interesting characters, a rich landscape of the afterlife, and a satisfying conclusion. I'd recommend it to any student from 3rd to 8th grade – and adults will probably enjoy it too. Ghostopolis was nominated "Best Publication for Teens" for the 2011 Eisner Awards. Doug TenNapel's website is http://tennapel.com/comics.html. A movie version of Ghostopolis is listed on IMDB as "In development" for 2013.


High altitude atmosphere at over 2,700m. Take the lifts to get there.
Steep sections, a very aerial itinerary, vertiginous, and with no escape routes. Part of the distinguished lineage of Dolomite via ferratas. The panorama is spectacular and overlooks the valleys. An unobstructed view of Mt. Blanc.
A second via ferrata is located under the Panoramic Restaurant at the top of the Courchevel gondola.
Not for beginners! It is a tough via ferrata and once you commit there is no going back. You need to be trained and familiar with the mountain environment.
Warm clothes, a rain jacket, hiking shoes, a charged phone or a radio in the event of a mishap, sunscreen and mountain sunglasses, munchies and something to drink, chocolate is not mandatory, but it tastes so good when you're on top.
Be sure to check with the Tourism Office for the gondola schedule before you leave. The last chance to go down: 16h30.
From Meribel: via the Burgin-Saulire Gondola.
Be careful, due to the altitude there may still be snowfields in June and at the beginning of July.
Start of the Via Ferrata 1,850 m.
Mid-June to Mid-October (when there isn't any snow) Be careful, snowfields can remain until the beginning of July.
Approach: 20 min from the gondola. 1h30 - 2h from the bottom.
Take the highway, go through Alberville and Moûtiers. Then Brides-les-Bains, then go either towards Méribel or keeping going for several kilometers to get to Courchevel.
Top of the Saulire Gondola (Courchevel 1,850m) which comes after the Verdons Gondola. From here it's 10 minutes of walking due north on a vague ridge.
At the foot of a buttress there is an information panel which denotes the start of the cables.
From Meribel: via the Burgin-Saulire Gondola: from Méribel-Mottaret via the Pas du Lac Gondola.
The 100 first meters of cable lead you to a very distinctive section, known as "La Porte" (The Door). After going down and traversing we come to the hightlight of the route: "le Curé" (The Priest), a 50 meter vertical monolith.
To summarize: high altitude atmosphere, steep sections that are almost overhanging but well secured in the downclimb from the "Curé." Some less steep, but quite aerial ledges and slabs.
A very mineral atmosphere and a route that ends at a rare altitude for a via ferrata. A discovery of the "Trois Vallées" (Three Valleys) site which we can only do from afar in winter. Somewhat resembles the Dolomites, birthplace of this sport.
You can take a trail that was purposefully made to arrive at the gondola.
Check with the tourism offices.


text:
If Penny got replaced or left the show.
By @jmclean1982,
February 29, 2012 in The Show
rickfromillinois
If Leonard had a serious problem with his height he wouldn't go out with any girl that was even close to his height. He would make sure that they were allot shorter then him. Missy being an aberration is your opinion only. Perhaps his ONE comment to Penny about wearing flat soled shoes was the aberration. I will go with what the writer's show us. I personally believe that Leonard is equal opportunity dater. He will overlook a woman being taller then him if he is attracted to her.
wayelrob 6 posts
cbolt 17 posts
rickfromillinois 22 posts
Moonbase 6 posts
The show would not be the same without Penny, Sheldon or Leonard. The characters and actors themselves are untouchable.
BillF63
I think Penny is as irreplaceable as both Sheldon and Leonard.
C-Trayne
I think its more the fact that the penny character seems to have the largest gap in terms of those who like her vs those who don't. There are two very emotionally strong sides who have their own opin
MissNobodyx
I think it would affect the viewings, there are ton of Penny fans
But if they replaced her with another hot blonde I'm sure after a few shows she would gain her own fans.
Pomita
I really can't imagine the show without Penny (and I mean Kaley as Penny). She's part of the core.
I don't think the show would work without Sheldon, Leonard, Penny or Amy, with the present actors.
It's pretty obvious about the core 3; might be more controversial about Amy, but at the end of the day, Sheldon needs her. And when Sheldon wants something, that's what the show wants.
It was fine pre-Amy and if there's a post-Amy it'll be fine.
My point is that Sheldon definitely will not be fine 'post-Amy'. After just knowing her for a few months, he got so mentally disturbed on losing her that he had to get 25 cats. At this point of time, Amy is a mainstay in Sheldon's life and he's probably more emotionally attached to her than he's been to anyone before (besides his Mee maw). One evening of not being able to contact her made him too distressed to be able to concentrate on anything else. And this is a man who is so afraid of change that he could hardly handle the Leonard/Penny break-up. Can you imagine what losing Amy would be like for him now?
Sorry for going off on a tangent from the topic of this thread.
SydNC
Plus, as he mentioned with Penny, he has put a lot of effort into accomodating Amy into his life and he would hate for it to be in vain.
Fruit Loop
Sorry but I can't agree with everything being said here. I see Kaley as a Hollywood Survivor both now and in the future. But I am not as deeply involved as some of you.
What's a "Hollywood Survivor"?
Yes. And the effort has indeed been great, for Amy! He's having to challenge many of his own set ways and beliefs (especially about himself), for her sake.
Shel_Ra_Ho_Le
I read this entire thread and its funny there is a thread of 'If Jim/Sheldon left the show' and everyone on there agrees no one could replace Jim Parsons as Sheldon but I come here and there is so many saying, they could replace Penny. What does that tell ya? Penny is not an irreplaceable character. The show would not die without her but it certainly would if Jim left. I really don't care for Penny nor Kaley but would I want her to leave? Not really because the dynamic of the 7 would be off but if she left it would not kill me either.
Another Penny hater topic. If you drop Penny you will loose viewers period. Leonard is suppose to be with Penny, not Pryia, Alex, Alice or anyone else. I even think later, after they marry, they could make a spin off series with Penny and Leonard, they could never do that with Sheldon and anyone because 22 minutes of straight Sheldon, once a week would never last one season. This show makes it because of the chemistry between the characters, all of them.
Nogravitasatall
I agree SRAM. I would probably not follow a changed ensemble. A simple swap is out too. Now I am so invested in L/P they would have to make one of them the grieving widow/ widower and run that for two seasons for me to forget. And I can't see that being funny. Edited December 29, 2012 by Nogravitasatall
Kutra
She is the only character with no growth in the show.She did not have a career at the beginning,5 years later she still does not have any professional accomplishments.She is a financial moocher of the other members who are all widely sucessful in their fields and lives.If Penny was a real person,she would have left the group on her own out of sheer embaressment!!

She is the only character with no growth in the show.She did not have a career at the beginning,5 years later she still does not have any professional accomplishments.She is a financial moocher of the other members who are all widely sucessful in their fields and lives.If Penny was a real person,she would have left the group on her own out of sheer embaressment!!

... And Howard would be working at Space X and only seeing his buddies two or three times a year. Lets watch that.
If Penny got replaced or left the show.....Then I would probably stop watching the show
Shamyfan
I'm not a big penny lover but she is meant to be with Leonard. She is the girl next door who falls in love with the nerd next door.
I so wish they would develop her character more.
A better job like Bernadette, a acting gig...something more than a hemmiroid commercial after 5 yrs. They made her come to LA to be a star. She's still a waitress 5 yrs later. If Penny was a real girl, she would have either gone back hm or chosen a diff job other than being at the Cheesecake Factory. At least she be a manager by now. Sheesh.
They show works because of all of them. None of them can be replaced.
Frankly I have always felt that Penny could be easily replaced. She leaves, they bring in some other good looking female character, and after a couple shows it will be "Penny who?".
Chrismo
That goes for Sheldon too. You get a Jim Carrey type to take his place you'd be going "Sheldon who?". Since Penny has been the second favorite character on the show (see polls) and the show being on for six years I think you are in the minority about her.
About the Sheldon part. Bazinga.
If they get rid of Penny, I'll quit watching because they will have changed the show completely from what it is.
. They made her come to LA to be a star. She's still a waitress 5 yrs later. If Penny was a real girl, she would have either gone back hm or chosen a diff job other than being at the Cheesecake Factory. At least she be a manager by now. Sheesh.
There's a couple things wrong with this statement. First, Penny may not like being a waitress and says she sucks at it, but the truth is, it is a pretty well-paying job and offers flexible hours, which is why people do it while they're in school or pursuing other interests. Second, management requires more hours and more responsibility, which is probably not something she's looking for as opposed to just going in for her shift and walking out with her cash.
They made her come to LA to be a star. She's still a waitress 5 yrs later. If Penny was a real girl, she would have either gone back hm or chosen a diff job other than being at the Cheesecake Factory. At least she be a manager by now. Sheesh.
Just to add to Europa's point, my daughter recently turned down a management position at a restaurant, due to the limits it would put on her ability to attend auditions, and accept roles. For instance, in Oct-Nov 2012, she was living about 300 miles from here(paid for by the theatre company), doing a show. She simply let her work know she would be gone during that time(she knew about the role 5-6 months ahead of time). As a manager, she wouldn't be able to leave for that amount of time, due to the limited number of managers.
While Penny hasn't had enough roles to worry about missing work, she is still AFAIK, although unseen, attending auditions. There is a reason there is a cliche about aspiring actors working as waiters or waitresses, there is a lot of flexibility in that job.
I don't care if Penny is a clown in the circus. They need to give her more to work with. It's a fictional character. They can make up anything.
A lot of the stuff on the show doesn't make sense, its made up. It's also silly how Sheldon said he couldn't afford rent on his own. If it was real life Sheldon is banking so is Leonard. I looked up how much real physicists make in California and at cal tech
I don't know how Penny is surving. I use to be a waitress many many moons ago. It's hard work and the pay isn't that great. Yes it can be flexible
I hope they give Penny more acting jobs or at least a different career since she's going back to school
Edited January 3, 2013 by Shamyfan
I hope they give Penny more acting jobs or at least a different career since she's going back to school.
Hey, the statements here are all right on and make a lot of sense. It was your previous one that wasn't quite right and why I commented. I'm not sure how many people you know that have tried to become actors, but five years or more working at it isn't unusual, although Penny's lack of jobs in the industry could be discouraging.
Guest I'm not dead Cheryl
Acting is hard. Even Jim himself has said in many interviews how many other jobs he had and how much time he was unemployed. Hence his joy on finding a stable job on TBBT. Jim was about 34 when he landed the job on TBBT, most of his previous work were some commercials and small roles.
The truth is, very few get to live off acting, and, at least according to what we see on the show, Penny is not especially talented, and while a pretty young blonde, there are thousands of pretty young blondes on the industry already.
I do think it is a good thing they had her go back to school, it is a start for her to shift her interest onto another carreer, on her finding satisfaction on another path that is not acting.
scifi_boy2002
Penny could not be replaced, but another character could fit nicely in her place. Of course the dynamics would change with a new female character, but it would not neccessarily ruin the show. It would be a mistake to have a new character copy penny, but you could have a non-nerd girl befriend the guys and the two girls. Maybe an athletic girl or a business lady. It could work. I, by no means, am saying that the character of Penny is not important or has little significance. Just that I think the show could survive without her. This is true for most of the other characters save for Leonard and Sheldon. It all depends on the writing and the actors they get to replace the others. I've used happy days as an example before. The show lasted four more season without Ron Howard and Donnie Post. Of course the show changed and had and brought new characters on the show, but it survied. Of course the show was never as good as it was in earlier episodes, but the show hit it's "jump the shark moment" even with Ron Howard still in the cast. TBBT could go on without penny, but I for one hope Kaley never leaves the show.
Engrprince
I think the Show would have a significant demise if Penny left more so than Sheldon and on par with Leonard. The core of the show and the major story Arc is Penny and Leonard followed closely by social maturity of Sheldon. If you replace her the Romantic comedy portion will be destroyed. The 6 year accumulation of trust and affection by Sheldon would be gone. I do not think the general audience would be patient enough to see something like that rebuilt and they would be angry in by having their investment in the characters fractured. How could Leonard really love someone else etc.
I would contend that if the New Girl could vacuum, dust and had a tertiary qualification she would be highly acceptable and indeed preferable.
In a way Priya sounds like the new character you described and in the beginning she did have the hots for Leonard, but the fans never really accepted her, and wanted Leonard back with Penny. I think if Penny did leave it would diminish the show and I don't think her character can be replaced at the same level in the show.


An "official Scouting activity" is an activity that is consistent with the established programs, values, charter, bylaws, and rules and regulations of the BSA. The BSA's Guide to Safe Scouting provides important planning guidelines, along with a list of unauthorized and restricted activities. These activities are not considered official Scouting activities.
There is insurance coverage through the BSA for a Scout meeting or event that qualifies as an official Scouting activity (see 8.20). The BSA provides primary comprehensive general liability insurance protection for registered Scout leaders, Scouting units, and chartering organizations.
For personal liability insurance guidelines within the Church, see Handbook 2, 13.6.9, which states: "Where possible, [members] should protect themselves by carrying reasonable amounts of liability insurance. Such insurance may be available through homeowners insurance or other policies.
The Church does not typically purchase primary liability insurance but uses Church funds to defend and pay claims. On a case-by-case basis, the Church may assist those who are sued in connection with Church activities. The Church will attempt to exhaust all available coverage before using Church funds. For official Scouting activities, there should be insurance coverage through the BSA.


Aditi Ramaswami is a public policy professional on a mission to advance health equity. Currently, she is a senior policy coordinator on the government affairs team at Children's Hospital Colorado. In this role, she fights at all levels of government for the health and well-being of kids. Prior to her work at Children's Colorado, Aditi championed public policies at Center for Health Progress, a Denver-based nonprofit working to ensure that every Coloradan can achieve good health, regardless of race, income, zip code, and other factors. Aditi believes firmly in centering people in society's institutions, from healthcare to education, and everything in between. Aditi holds a bachelor's degree in sociology from Colorado College. When she's not speed-dialing her members of Congress, she's dancing, preferably to 90s hip hop.