Take us out to the ball game

Atlanta Braves came to town, take us out to the ball game at PNC Park last night.  More often than not did I write something after watching a game, but there is no good sport writing unless there is a good game; when the 'lowly' (it was not lowly the day before as Pirates' Frazier hits a walk-off homer in 11th inning against the formidable Chicago Cubs) Pirates was defeated 1 to 0, all I can do is just posting the photos, a thing rarely done in my blog.

人海戰術，a garden is too big to fail

我已說過我們的菜園今年出師不利, having an ignominious beginning.  很多菜瓜幼苗 withered and perished upon braving the new world (搬到外面的菜園就枯萎死亡）所幸那些幸存者還算爭氣, 現在已開始開花結果。他們好像在對 Jean and Charles 說 timing is every thing; 明年夏天要回賓州娘家, 要選在九月初甚或九月中旬.

Clostridium difficile associated diarrhea (CDAD), 吃抗生素引起的拉肚子

臨床上我使用 probiotics 的惟一情形是 clostridium difficile associated diarrhea (CDAD), which can be just a little bit diarrhea that doesn't amount to anything, or could be a severe case of acute pseudo membranous colitis that may lead to megacolon or even death. 這是大家都知道的吃抗生素引起的拉肚子（diarrhea).

我們的消化系統管道有很多種友善的, 不會讓我們生病的好細菌, 各種細菌維持一定的數目, 互相牽制, 和平共存。形成一個腸的 microbiome.

當我們的身體接觸到 clostridium difficile 細菌 （spore form) 時, 這些友善的細菌配合我們的免疫反應會把這外來的敵人（clostridium difficile) 消滅。我們使用抗生素時（吃或注射）, 若某些友善的細菌 （normal  intestinal flora) 被殺死, 這種情形叫 disruption of the balance of gut microbiome (也就是說 diversity 減少了）, 在此情形若接觸到 clostridium difficile spores, 這些 spores 會乘虛而入, 繼續繁殖, 而且產生一種毒素（toxin). 要診斷是否有 clostridium difficile associated diarrhea, 就是檢查大便裡是否有 clostridium difficile toxins (CDT).

如此説來, 吃抗生素引起的拉肚子, 吃益生菌（probiotics) 是理所當然, 應該有效.  UpToDate 有一篇文章叫「Clostridium difficile and probiotics」, 其内提到 2008 年 Cochrane review of probiotics including four randomized trials, 其結論是沒有確切的證據説可以用 probiotics 來治療吃抗生素引起的拉肚子.

但 UpToDate 又提到 2012 有兩個 meta-analyses 説是有效。所以有效或沒效 讀者自己下結論，我是照用不誤，尤其是那些會復發的病人（這種病好了後 有時會 relapse 復發, 尤其是那些身體虛弱 沒有病本的人--老美說 those in debilitating state.

另一個問題是使用抗生素時（吃或注射）同時吃 probiotics 是不是可以避免拉肚子或 CDAD?  UpToDate 說他們 do not recommend, 下面是他們説的。我個人的看法是那些得過 CDAD 的人要這麼做的話, 我絕不會反對。

Prevention of CDAD — We do not favor administration of adjunctive probiotics for routine treatment of CDAD. Thus far, no randomized trials have demonstrated benefit associated with routine probiotic administration for prevention of CDAD [61]; some meta-analyses suggest that use of probiotics may be beneficial for prevention of CDAD [62-68].

其實 UpToDate 也有提到一個 meta-analysis 分析 20 個 randomized trials 說使用抗生素時（吃或注射）同時吃 probiotics 可以減低 clostridium difficile associated diarrhea by 66%. 但是 UoToDate 科學標準非常高，對這些 studies / trials 有很多批評。

下面一篇 2013 Lancet 的一篇文章也説使用抗生素時（吃或注射）同時吃 probiotics 來避免 clostridium difficile associated diarrhea 沒有效。

While reading medicine, one needs to keep an open mind.

{Cochrane review is known to be very conservative, yet non-biased and influential.  Meta-analysis is the analysis of several similar studies/trials, trying to draw some conclusion}

Talk about probiotics 談談養生菌

楊錚送來這個 link 問我的看法，這些年來養生菌（probiotics) 是 high fashion, 而且越來越流行, 相信我們的 email 群組的人可能會有興趣。要先讀 自由時報的文章才讀我部落格的文章。 

http://m.ltn.com.tw/news/world/breakingnews/2512513

這篇文章有幾點不可思議的地方，令人沒辨法解釋：

（1）其所報告的吃養生菌的副作用（ brain fogginess, D-lactic acidosis 或乳酸中毒）都是potentiously serious (有可能變成很嚴重的）其他消化系統的毛病雖不嚴重但也不好受。千千萬萬的人都在吃養生菌（FDA 不管，不用醫生處方）為什麼沒有更多的病例報告呢？

（2）我對這篇又章的最大批評 (critique) 是這 42 病人（其實只38個病人，因為有 4 個病人因種種原因不能參加這個 study) 都有在吃養生菌，但沒有説吃多少，只説「All patients with brain fogginess (30 patients) take probiotics (3 months to 3 years), some were taking 2-3 different varieties containing Lactobacillus species and/or bifidobacterium or streptococcus thermophilles. 10/30 (36.7%) was using cultured yogurt daily, 2/30 (6.7%) large amount (20 ounces daily)」

（3) 這篇文章所報告的副作用 早已就有報告發生在 ones with short bowel syndrome, 即那些大部分的小腸被切除或其他種種原因吸收營養的小腸大大的減少。但是這篇文章的全部 38 個人是全部正常的。若胃鏡，大腸鏡，電腦掃描，或血液檢驗不正常或仕何消化系統的毛病都不能參加這個study, 也就是說這參加的 38 人都是正常的人。我認為這篇文章應該詳細報告這 38 個病人每天吃多少養生菌.

這篇文章發表在 clinical and Translational Gastroenterology, 是屬於 Nature publishing Co, Nature 是medical science 最有權威的. 其作者是MD, PhD 是 Medical College of George at Augusta University的 神經消化系統的 director. 其血液檢驗是送到 Mayo Clinic 的 Special Labs 檢測的。以科學嚴謹程度度是不能批評的。

Article in CTG: https://www.nature.com/articles/s41424-018-0030-7

Article in ScienceNews reporting above article: https://www.sciencedaily.com/releases/2018/08/180806095213.htm

By the way, Translational Science 是 硏究如何把基礎科學的硏究成果轉於及運用到臨床醫學。

所有醫學大學醫院都是 tertiary refer center (我在 Waynesburg 的病人較複雜的話,若我送病人去Washington, PA, 他們又送去 UPMC, 那麼 UPMC 就是 tertiary refer center) 在三年期間轉送到George Augustan U 的病人有 brain fogginess 及各色各樣消化系統的症狀的人選 38 病人來硏究。這些病人都已在外面的醫院看了很久找不出病因，轉轉送到大學醫院 tertiary refer center 來。

（一） 如果有下列的兩個或更多的症狀表示有 brain fogginess (可說是頭腦渾渾沌沌）：

 Mental confusion, cloudiness, impaired judgment, poor short term memory, difficulty concentrating （且這些症狀超過三個月以上）

(二）消化系統的症狀包括：bloating, abdominal pain/distention/fullness, belching, indigestion, nausea, vomiting, constipation, gas. （上面已提到：這些病人的胃鏡，大腸鏡及電腦 CT scan 及所有有血液檢驗都正常）

這 38 個病人有 30 位 有 brain fogginess, 8 位沒有，但全部都有消化系統的症狀。

有 brain fogginess 的病人，68% 有 small intestinal bacterial overgrowth (SIOB)；沒有 brain fogginess的人，只有28% 有 SIOB.

有 brain fogginess 的病人，77% 有 D-lactic acidosis (乳酸中毒）；沒有 brain fogginess 的人，只有25% 有 D-lactic acidosis (乳酸中毒）。

是否有 small intestinal bacterial overgrowth (SIOB) 是用 duodenal aspirate (即從十二指腸抽胃液出來檢查及用 Glucose breath test 來決定，所以是非常科學化的。

那些有 brain fogginess 的病人停止吃益生菌 （若有 SIBO 的話也使用抗生素）所有的病人症狀消失。23/30 （77%）的病人其消化系統的症狀也改善。再給他們吃益生菌的話 20/30 (66%) brain fogginess 症狀復發。

説了一大堆，這篇文章到底可信不可信。這不是 controlled, randomized double-blind study, 這是observational study.  當然 observational study 也是 scientific  study, 只是 rigor of Science 沒有 double-blind study 那麼高。所以這個報告應該可以相信的，只是 it raises more questions than it answers.  

作者 （Dr Satish Rao) 有提到這些吃益生菌而引起毛病的人，主要是 small intestinal bacterial overgrowth （SIBO) and D-lactic acidosis 引起的。而 SIBO 的原因包括：intestinal dysmotility (腸蠕動不正常），Gastroparesis (胃下垂），吃某些藥也可能增加這 risk: 如 proton pump inhibitor (Protonix, Nexium, Prilosec) 及 opioids.

我的看法是 那些因某種因在吃益生菌或喜歡吃 yogurt 的人也不必因此而改變你的習慣，除非你有上段（paragraph)的情形。

NY Times 有一篇文章說 Activia 是真正的 “live and active culture” 含有 probiotics: 4 ouncesv的Activia 含有 billions of probiotics.

反過來說，this is the best time to think about why you are taking probiotics. 應該想想你為什麼在吃益生菌。應該多了解什麼是益生菌。我們常説 “not all fats are bad” 不是所有的 fats 都是不好的，polyunsaturated or monounsaturated fats 是 healthy 的。有些細菌是「friendly」及 「good」它們寄生在我們的消化腸道，維持一個非常 delicate balance, 比戰國時代還更複雜。是歒或友，有時看情形而定，friendly bacteria (probiotics) 有時候會反臉成仇。

 Probiotics 的 selling point 是「maintain intestinal flora balance」及「promote intestinal health」whatever that means.  Rigor of Science is simply not there. 我們對 probiotics 已知道了不少，但是還是很多我們還是不知道的，很多硏究正在進行中，may be a bit early to jump into clinical use.

UpToDate (一年訂費$500，開業醫師的權威）有一篇文章叫「Probiotics for gastrointestinal diseases」我抄些其結論讓你們作參考。

Ulcerative colitis — A benefit of probiotics in ulcerative colitis remains unproven, but E. coli Nissle 1917 shows promise in maintaining remission and could be considered as an alternative in patients intolerant or resistant to 5-ASA preparations. No other probiotic preparation has been validated for this indication.

Infectious diarrhea — We suggest the use of probiotics in adults and children with presumed infectious diarrheal illness (Grade 2B). If probiotics are used, treatment should consist of regimens with Lactobacillus GG and S. boulardii.

Crohn disease — A benefit of probiotics in Crohn disease remains unproven.

Constipation — A few small randomized controlled trials suggest improvement in defecation frequency and stool consistency in patients with chronic constipation. However, larger studies are needed before probiotics can be routinely recommended in the management of severe chronic constipation

Irritable bowel syndrome — More convincing evidence of a benefit of probiotics for irritable bowel syndrome is accumulating, although there is still considerable disagreement as to which agent or group of probiotics is most beneficial and which patient subgroups should be targeted. A definitive therapeutic role remains unproven and needs to be further investigated in defined patient subset

Lactose intolerance — A benefit of probiotics for lactose intolerance remains unproven.

Hepatic encephalopathy — Initial studies were associated with an improvement in hepatic encephalopathy. However, a large meta-analysis has shown no demonstrable benefit with regard to clinically relevant outcomes (eg, mortality and quality of life)

Allergy — A definitive role of probiotics for allergic conditions remains unproven, although initial results in studies of children with a variety of preparations for atopic dermatitis are promising.