Gut microbiota imbalance and chaperoning system malfunction are central to ulcerative colitis pathogenesis and can be counteracted with specifically designed probiotics: a working hypothesis

In this work, we propose that for further studies of the physiopathology and treatment for inflammatory bowel diseases, an integral view of the conditions, including the triad of microbiota–heat shock proteins (HSPs)–probiotics, ought to be considered. Microbiota is the complex microbial flora that resides in the gut, affecting not only gut functions but also the health status of the whole body. Alteration in the microbiota’s composition has been implicated in a variety of pathological conditions (e.g., ulcerative colitis, UC), involving both gut and extra-intestinal tissues and organs. Some of these pathologies are also associated with an altered expression of HSPs (chaperones) and this is the reason why they may be considered chaperonopathies. Probiotics, which are live microorganisms able to restore the correct, healthy equilibrium of microbiota composition, can ameliorate symptoms in patients suffering from UC and modulate expression levels of HSPs. However, currently probiotic therapy follows ex-adiuvantibus criteria, i.e., treatments with beneficial effects but whose mechanism of action is unknown, which should be changed so the probiotics needed in each case are predetermined on the basis of the patient’s microbiota. Consequently, efforts are necessary to develop diagnostic tools for elucidating levels and distribution of HSPs and the microbiota composition (microbiota fingerprint) of each subject and, thus, guide specific probiotic therapy, tailored to meet the needs of the patient. Microbiota fingerprinting ought to include molecular biology techniques for sequencing highly conserved DNA, e.g., genes encoding 16S RNA, for species identification and, in addition, quantification of each relevant microbe.     

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility.     

LC-MS/MS测定人血浆中对乙酰氨基酚及其人体药动学和生物等效性研究

目的 建立一种快速、灵敏的高效液相色谱-串联质谱（HPLC-MS/MS）方法以测定人血浆中对乙酰氨基酚浓度,并应用于两种对乙酰氨基酚制剂的人体药代动力学和生物等效性研究。方法 以替硝唑为内标,200μL血浆样品经5倍于其体积的乙酸乙酯液液萃取,再经Waters XBridge? C18柱等度洗脱分离后导入串联质谱,以正离子多反应监测模式进行定量分析,对乙酰氨基酚和内标的选择性反应离子对分别是m/z 152→110和248→121。方法经验证后应用于19名健康受试者单剂量空腹口服两种对乙酰氨基酚制剂500mg后药代动力学和生物等效性的研究。结果 血浆中对乙酰氨基酚在0.1～8.0 μg·mL-1范围内线性良好（r2 > 0.99）,最低检测限为 0.1 μg·mL-1,提取回收率为91.0%～98.7%,日内和日间准确度分别为98.8%～111.3% （精密度：CV ? 9.03%）和94.9%～102.6% （精密度：CV ? 10.68%）。生物等效性试验中,受试制剂与参比制剂的主要药代动力学参数Cmax、AUC0-t和AUC0-∞ 几何均值比的90%置信区间分别为83.50%～105.79%,94.25%～101.54%和93.24%～101.02%,均落在生物等效可接受标准80.00%～125.00%范围内。结论 所建立测定人血浆中对乙酰氨基酚浓度的HPLC-MS/MS法具有快速灵敏、回收率高、选择性好的特点,适用于对乙酰氨基酚片人体药代动力学和生物等效性研究。受试制剂与参比制剂在人体内吸收速度和程度相似,两种制剂生物等效。     

What are Journals for?

‘The secret is comprised in three words – work, finish, publish.’Michael FaradayThere are many reasons doctors want to publish their work. For most at an early stage in their career, this may be to add a line to their curriculum vitae and advance their careers but for academics, publishing is an expectation. Many will believe they have something important to say, and wish to provoke debate and discussion; others wish to share knowledge and experiences, which in medicine can lead to a satisfying change in clinical practice. All serve to register one’s idea and educate others. However, for some, the reason is as basic as money. As we celebrate the 350th anniversary of the first academic publication, perhaps we have come full circle when it comes to why people publish?Publishing is a flourishing business. There were approximately 28,100 active scholarly peer-reviewed journals in mid-2012, collectively publishing about 1.8–1.9 million articles per year. The number of articles published each year and the number of journals have both grown steadily for more than two centuries, by about 3% and 3.5% per year respectively.¹ Journals have a responsibility to refine and define information and act as a scientific filter. Many of us will receive daily invitations in our email inbox from eclectic and new journals that are likely to take anything – is the filter now too porous? But this industry is like any other commercial activity and the supply still far outstrips the demand. Perhaps the internet revolution has merely fuelled our hunger to publish more?The launch of this exciting and innovative series about publishing coincides with the 350th celebration of the publication of the first academic journal. In the age of social media, the first question is ‘What are journals for?’, which Simon Rallison sets out to answer. Simon is Director of Publications at the Physiological Society, and was previously a journal publisher with Earthscan, Springer and Blackwell.Writing is hard work and, through this series, I hope the reader will get some useful insight into this service industry for academia.Jyoti ShahCommissioning EditorIn an age of the internet and social media, why are we still using (admittedly with refinements and improvements) a form of publication dating from 1665? What exactly is a journal in the 21st century and what role does it have to perform? Surprisingly, the academic journal has not evolved since it was invented 350 years ago.¹ The first issue of the Philosophical Transactions of the Royal Society was published in 1665, the brainchild of Henry Oldenburg and Robert Hooke. Since then, journals have digitised and now offer greater opportunity for research communication – but are authors taking advantage of what journals can offer? The academic and research community is generally very conservative about what it reads and how it views journals. There are, however, also frequent misunderstandings about the operation of journals.     

Antiidiotypic IgG crossreactive with Rh alloantibodies in red cell autoimmunity

IgG autoantibodies eluted from RBCs of antiglobulin positive normal blood donors contained at least two antibody populations, an IgG autoantibody (Ab 1), and an IgG population (Ab 2) that agglutinated RBCs coated with some Rh(D) alloantibodies. Eight of 24 autoantibody eluates tested agglutinated 3 of 10 anti-Rh(D) sensitized RBCs. The agglutinating activity was inhibited specifically by preincubation of the autoantibody eluate with the reactive anti-D. The reaction did not require the Fc domain of the anti-Rh(D), since autoantibody eluates agglutinated RBCs coated with F(ab')2 prepared from the reactive anti-D sera. These findings indicate that the RBCs of some antiglobulin- positive blood donors contain an immunoglobulin auto-antiidiotype (Ab 2) against the RBC autoantibody (Ab 1) which is demonstrable through its cross-reactivity with selected Rh(D) alloantibodies. Identification of auto-antiidiotypes in RBC autoimmunity lends support to the idiotype- antiidiotype network hypothesis of immune regulation and is consistent with the bizarre and complex serology of autoimmune hemolytic anemia. The absence of clinical hemolysis in antiglobulin-positive normal blood donors suggests that immunoglobulin idiotype-antiidiotype interactions may play a role in modulating the effects of RBC autoimmunity.     

Effects of androgen deficiency and replacement on prostate zonal volumes

BACKGROUND AND OBJECTIVES: Androgens play a key role in prostate development and disease. However the effects of androgen deficiency and replacement on the prostate during mid-life are not well understood, and there is no information on their effects on prostate zonal volumes. This study aimed to define the effects of androgen deficiency and androgen replacement therapy on prostate zonal volumes (central, peripheral & total) using planimetric prostate ultrasound with particular emphasis on the central zone of the prostate, the most hormonally sensitive and fastest growing region of the prostate and the zone where nodular benign prostate hyperplasia originates. PATIENTS AND MEASUREMENTS: Central and total prostate volume were measured directly, and peripheral prostate volume calculated, by a single observer using transrectal ultrasound in 71 hypogonadal men (aged 40 +/- 2, range 18-78 years) who were compared with individually age-matched health controls without prostate or gonadal disease. Among the men with androgen deficiency, 17 men had untreated androgen deficiency (never treated or no treatment for at least 6 months) and 54 men were receiving long-term androgen replacement therapy (median 32 months, 93% > or = 6 months) with testosterone implants (n = 27), testosterone ester injections (n = 24) or other testosterone treatment (n = 3). RESULTS: Compared with individually age-matched controls, untreated androgen deficient men (n = 17) had reduced central (4.0 +/- 0.5 vs. 6.2 +/- 0.5 ml, P < 0.001) and total (23.4 +/- 2.6 vs. 29.2 +/- 1.6 ml, P < 0.001) prostate volumes whereas the reduction in peripheral prostate volume (19.4 +/- 2.1 vs. 23.0 +/- 1.3 ml, P = 0.15) was not statistically significant. Men with treated androgen deficiency (n = 54) also still had significantly reduced central (4.8 +/- 0.4 vs. 6.8 +/- 0.4, P < 0.001), peripheral prostate volume (19.6 +/- 0.8 vs. 21.6 +/- 0.7 ml, P = 0.06) and total (24.4 +/- 1.1 vs. 28.4 +/- 1.0 ml, P = 0.008) despite prolonged restoration of physiological testosterone concentrations. Neither modality of testosterone treatment nor type of hypogonadism influenced prostate zonal volumes before or after treatment. In contrast, central, peripheral and total prostate volume increased with age among healthy controls and men with androgen deficiency regardless of androgen replacement therapy. Plasma PSA concentrations were reduced in men with untreated androgen deficiency and were similar to age-matched controls in men with treated androgen deficiency. CONCLUSIONS: We conclude that, during mid-life, chronic androgen deficiency due to hypogonadism is associated with reduced central, peripheral and total prostate volumes. Reduced prostate volumes persist even during long-term maintenance of effective androgen replacement therapy with physiological testosterone concentrations until the fourth decade of life. After that, prostate volumes increase with age regardless of androgen deficiency or replacement. These findings suggest that, during mid-life, age is a more important determinant of prostate growth than ambient testosterone concentrations maintained in the physiological range. The persistently subnormal prostate volumes despite adequate androgen replacement therapy may explain the apparent paucity of cases of overt prostate disease among testosterone-treated androgen deficient men who retain protection against prostate disease despite physiological androgen replacement therapy.     

Metformin increases fasting plasma peptide tyrosine tyrosine (PYY) in women with polycystic ovarian syndrome (PCOS)

Objective The beneficial effects of metformin in patients with type 2 diabetes mellitus (T2DM) and polycystic ovarian syndrome (PCOS) are thought to be in part due to weight reduction. However, the mechanisms by which metformin causes weight loss are unclear. We sought to determine whether circulating levels of the anorectic gut hormone peptide tyrosine tyrosine (PYY) show any correlation with metformin‐induced weight loss. Design and patients We examined the acute effects of orally administrated metformin on fasting PYY levels in eight healthy normal‐weight female subjects. Subsequently, we evaluated the effects of 6 months metformin treatment on fasting PYY levels and anthropometric measurements in 20 women with PCOS. Results In normal‐weight females 10 days’ metformin treatment increased fasting PYY levels (P < 0·01). Similarly, in PCOS subjects metformin treatment increased fasting PYY concentrations (P < 0·05). In both groups a marked variation in PYY increase in response to metformin was observed. Long‐term metformin treatment was associated with improvements in weight (P < 0·05), BMI (P < 0·05), fasting glucose (P < 0·05) and menstrual frequency (P < 0·01). Interestingly, change in PYY levels were correlated with change in waist circumference (r = 0·55, P < 0·05). Conclusions Acute and chronic oral metformin administration increase fasting PYY levels and may contribute to metformin's weight loss effect. Further studies are now required to clarify whether changes in circulating PYY levels in response to metformin treatment can be used to predict which patients will subsequently lose weight long‐term and gain cycle restoration.