Stone clearance in lower pole nephrolithiasis after extra corporeal shock wave lithotripsy – the controversy continues

BACKGROUND: To determine factors influencing the clearance of fragments after extra-corporeal shock wave lithotripsy (ESWL) for lower pole calyceal (LPC) stones. METHODS: In the period between July 1998 and Oct 2001, 100 patients with isolated lower polar calyceal calculi ≤ 20 mm, in patients aged ≥ 14 years, were included in the study. Intravenous urograms (IVU) were reviewed to define the LPC anatomy (width of the infundibulum and pelvicalyceal angle). Study end points i.e. stone free status; number of shock waves used and number of sessions were correlated with variables like LPC anatomy, body mass index and stone size. RESULTS: At three months follow up the clearance for stone size ≤ 10 mm, 11–15 mm and 16–20 mm were 95, 96 and 90% respectively. Patients with acute LPC (<90°) and obtuse angle (>90°) had stone clearance of 94 and 100% respectively. For the infundibular width of < 4 mm, the stone clearance was 93% were as for > 4 mm, it was 100%. For body mass index (BMI) less than and > 30 kg/m(2), the stone clearance was 92 and 95% respectively. CONCLUSIONS: There is a trend towards more ESWL sessions and shock wave requirement in patients with acute pelvi-calyceal angle and narrow infundibulum but it is not statistically significant. Size (≤ 20 mm) and BMI has no relation with stone clearance. With modern lithotripter, stones up to 20 mm could primarily be treated by ESWL, irrespective of an un-favorable lower polar calyceal anatomy and body habitus

Constitutive MAP Kinase Activation in Hematopoietic Stem Cells Induces a Myeloproliferative Disorder

Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPNs) are a group of myeloid neoplasms in which abnormal activation of the Ras signaling pathway is commonly observed. The PI3K/Akt pathway is a known target of Ras; however, activation of the PI3K/Akt pathway has been shown to lead to neoplastic transformation of not only myeloid but also lymphoid cells, suggesting that pathways other than the PI3K/Akt pathway should play a central role in pathogenesis of Ras-mediated MDS/MPN. The MEK/ERK pathway is another downstream target of Ras, which is involved in regulation of cell survival and proliferation. However, the role of the MEK/ERK pathway in the pathogenesis of MDS/MPN remains unclear. Here, we show that introduction of a constitutively activated form of MEK into hematopoietic stem cells (HSCs) causes hematopoietic neoplasms that are limited to MDS/MPNs, despite the multipotent differentiation potential of HSCs. Active MEK-mediated MDS/MPNs are lethal, but are not considered a frank leukemia because it cannot be transplanted into naïve animals. However, transplantation of MDS/MPNs co-expressing active MEK and an anti-apoptotic molecule, Bcl-2, results in T-cell acute lymphocytic leukemia (T-ALL), suggesting that longevity of cells may impact transplantability and alter disease phenotype. Our results clearly demonstrate the proto-oncogenic property of the MEK/ERK pathway in hematopoietic cells, which manifest in MDS/MPN development

Femara® and the future: tailoring treatment and combination therapies with Femara

Long-term estrogen deprivation treatment for breast cancer can, in some patients, lead to the activation of alternate cellular pathways, resulting in the re-emergence of the disease. This is a distressing scenario for oncologists and patients, but recent intensive molecular and biochemical studies are beginning to unravel these pathways, revealing opportunities for new targeted treatments. Far from making present therapies redundant, these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance. Letrozole, one of the most potent aromatase inhibitors, is the ideal candidate for combination therapy; indeed, it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting. Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments. Microarray gene profiling studies, designed to detect letrozole-responsive targets, are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs

Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons.

An increasing number of studies show that the activation of the innate immune system and inflammatory mechanisms play an important role in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Intracellular pathways, linking immune and inflammatory response to ion channel expression and function, have been recently identified. Among ion channels, the transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes.In this review, we summarize current knowledge of interactions between immune cells and PRRs and ion channels of TRP families with PAMPs and DAMPs to provide new insights into the pathogenesis of inflammatory diseases. TRP channels have been found to interfere with innate immunity via both nuclear factor-kB and procaspase-1 activation to generate the mature caspase-1 that cleaves pro-interleukin-1ß cytokine into the mature interleukin-1ß.Sensory neurons are also adapted to recognize dangers by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. As immune cells, they possess many of the same molecular recognition pathways for danger. Thus, they express PRRs including Toll-like receptors 3, 4, 7, and 9, and stimulation by Toll-like receptor ligands leads to induction of inward currents and sensitization in TRPs. In addition, the expression of inflammasomes in neurons and the involvement of TRPs in central nervous system diseases strongly support a role of TRPs in inflammasome-mediated neurodegenerative pathologies. This field is still at its beginning and further studies may be required.Overall, these studies highlight the therapeutic potential of targeting the inflammasomes in proinflammatory, autoinflammatory and metabolic disorders associated with undesirable activation of the inflammasome by using specific TRP antagonists, anti-human TRP monoclonal antibody or different molecules able to abrogate the TRP channel-mediated inflammatory signals

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research