Researchers at the University of Helsinki have developed a new mouse model of congenital anomalies of kidney and urinary tract and disease progression.
About one in every 100 babies is born with some kind of developmental anomaly in the urogenital tract. In most cases abnormalities are mild, but sometimes life-long and even life-threatening disease develops.
Infertility is another important aspect that associates with urogenital anomalies. Therefore understanding how those features occur is instrumental in developing future treatments.
To date, diseases which scientist understand the best are those caused by mutations in the proteins involved. However, in many diseases such mutations are not found, and the disease is “idiopathic” or referred as without a known cause, and maybe triggered by e.g. environmental factors.
Classically scientists have studied such cases by injecting many copies of the gene of interest into fertilized egg of an experimental animal. However, the major problem with this technique is that scientist have almost no control over where in the genome the gene lands, and what cell types start to produce the encoded protein.
By employing an unconventional genome engineering trick that increased glial cell line-derived neurotrophic factor (GDNF) production 3-6 times, scientists revealed that ureter, which allows urine produced by kidneys to enter bladder, length is regulated by GDNF levels, and that tubes connecting testicles to reproductive organs are misplaced when there is too much GDNF, resulting in infertility in males.
GDNF is a secreted protein which signals growth and survival for many types of cells. In females, too much GDNF resulted in imperforated vagina or lack of vaginal opening, resulting in infertility.
The researchers were able to trace some of those defects back to altered stem cell behaviour in the developing urogenital block and identified some signalling pathways involved. Collectively these findings provide new information on altered stem cell behaviour in the developing kidney.
University of Helsinki https://tinyurl.com/y6oag6xr

The longest FlexLab automation system ever produced by Inpeco has been designed for a mega volume reference laboratory customer, Hermes Pardini group based in Minas Gerais, Brazil. Siemens Healthineers (Inpeco’s strategic automation partner who sold the solution) is implementing the FlexLab system for Hermes Pardini’s “Enterprise” project, which will result in the largest laboratory automation platform in the world, linking more than 100 analyzers and 7 clinical specialties.
The Hermes Pardini Group is highly innovative in diagnostics medicine, and will handle 110 million sample tubes every year to address diagnostic testing needs of patients and healthcare providers from all across Brazil. The Enterprise project is expected to be operating at its full capacity in 2019, and will automate the distribution of sample tubes to nearly 100 different analyzers with a total length of 330 meters, which will include more than 70 pre- and postanalytical modules to eliminate the need for error-prone and time-consuming manual interventions within the clinical laboratory. It is to be installed in the Vespasiano site (Belo Horizonte area) in the current laboratory testing area (3,500 square meters of floor space).
“Unlike conventional laboratory set-ups, where sample tubes must be moved manually between different analyzers, our enterprise lab will employ a ‘one-touch, one workflow’ concept to eliminate the need for manual interventions, ensure sample traceability, and reduce the turnaround time to results,” said Guilherme Collares, Chief Operations Officer of the Hermes Pardini Group.
Inpeco’s High Throughput FlexLab solution will contribute to make this concept a reality, and enable providers to receive results faster, thereby enabling better patient care. The project also includes refrigerated storage units, with capacity to hold more than 1.3 million samples, and a newly developed advanced vision system, which is able to detect sample deterioration such as hemolysis, icterus or lipemia. “We’ve been in touch with Hermes Pardini since they began 2 evaluating options to replace the automation system they were using – said Andrea Pedrazzini, President of Inpeco – and we are extremely proud and pleased that such a prestigious institution has decided to adopt the largest FlexLab system ever built to fully automate their samples process, from loading to storing and disposing.”

http://www.inpeco.com/en/

UK patients with N. gonorrhoeae (GC) now have the option of receiving the cheap and easily-administered oral antibiotic ciprofloxacin thanks to updated treatment guidelines and the availability of a novel molecular diagnostic and antimicrobial susceptibility test (AST). The new test can simultaneously diagnose gonorrhoea and provide information on whether a patient will respond to ciprofloxacin.

Global management strategies for antimicrobial resistance (AMR), such as those developed by the World Health Organisation, highlight gonorrhoea as a priority infection to manage, with more effective use of diagnostic tools listed as a key focus for future development. On 24 January 2019 the Health Secretary Matt Hancock, launched the UK government’s 20-year vision to combat antibiotic resistance at the World Economic Forum at Davos, Switzerland.

Ciprofloxacin was the first line antibiotic of choice for uncomplicated gonorrhoea in the past but was relegated to an alternative treatment due to increasing resistance.

The incidence of sexually transmitted infections (STIs) including gonorrhoea is increasing around the world, with corresponding increasing rates of resistance to commonly used antibiotics. The first two cases of multidrug-resistant (MDX) N. gonorrhoeae were reported in the UK at the start of 2019. These follow the first globally reported case of gonorrhoea with high-level resistance to azithromycin and resistance to ceftriaxone in England in 2018.

Called ResistancePlus® GC, the availability of the new test is timely, as the British Association of Sexual Health and HIV (BASHH) has launched its 2019 gonorrhoea management guidelines to include the use of ciprofloxacin, provided antimicrobial susceptibility results are available prior to treatment.

The new test could be critical in the battle against antibiotic resistance, helping physicians to prescribe an effective antibiotic using a resistance-guided approach. Prior to the new 2019 BASHH guidelines, ceftriaxone was the recommended front-line treatment for gonorrhoea together with azithromycin. Ceftriaxone is a painful intramuscular injection. It has long been considered the last readily available effective antibiotic for GC, and several extensively drug-resistant strains have now been isolated exhibiting resistance to ceftriaxone and many other available treatments.

“The new guideline now recommends giving double the previously recommended dose of ceftriaxone (now 1g stat). However, they also indicate ciprofloxacin as a first-line option when antimicrobial susceptibility is known prior to treatment.
Not only is this less painful for patients, it is preferable to doctors as it is a cheaper treatment that does not require specialised staff to administer the injection.

As the UK now has the lowest reported rate of ciprofloxacin-resistant gonorrhoea at 26%, over 70% of patients could now benefit from the new guidelines and receive oral therapy if they have a test result showing ciprofloxacin susceptibility, such as is offered by the test.
ResistancePlus® GC was invented by scientists in Australia and is now able to be accessed by clinicians in the UK. It is the first commercially available molecular diagnostic test providing ciprofloxacin susceptibility information and is well placed to support current laboratory molecular testing workflows. Currently, culture methods are the routine test to determine antimicrobial susceptibility, but results can take days to produce, and many rectal (50%) and the majority of throat (70%) samples can be difficult to culture; ResistancePlus® GC can overcome these limitations.

Treating gonorrhoea as soon as possible is very important because gonorrhoea can lead to serious long-term health problems including pelvic inflammatory disease (PID) in women, that may result in infertility, and infection in the testicles in men.

SpeeDx, the company behind the new test, received CE-IVD marking for its ResistancePlus® GC assay at the end of 2018, enabling it to be adopted in all countries where CE-mark is accepted – including the UK. It is based on a PlexPCR method that detects both N. gonorrhoeae (GC) and sequences in the gyrA gene of the bacteria associated with susceptibility to ciprofloxacin, in a single test.

Proteins that normally reside inside cell nuclei have never been found in the blood, until now. A new blood test developed at the Johns Hopkins University by Shih-Chin Wang and Chih-Ping Mao—graduate students in Jie Xiao’s lab in the Department of Biophysics and Chien-Fu Hung’s lab in the Department of Pathology—can identify individual molecules in human blood samples with minimal detection errors. Among the molecules that they used their new test to find was a mutated protein thought to be restricted to the inside of cells, mostly within the nucleus. It is the first time that single-molecule imaging has been applied to visualize disease-causing molecules in blood.
Wang and colleagues call their new approach Single-Molecule Augmented Capture (SMAC). They used this new technique to detect molecules commonly screened for in standard blood tests, like prostate-specific antigen. And they were also able to detect rare intracellular proteins, secreted proteins and membrane proteins, including the cancer-associated proteins mutant p53, anti-p53 autoantibodies and programmed death-ligand 1 (PD-L1).
Mutant p53 is a well-known tumour-specific nuclear protein and has never before been detected in the blood, likely because current tests cannot detect its extremely low blood concentrations. Wang and colleagues found mutant p53 or anti-p53 autoantibodies in samples from patients with ovarian cancer, but not in patients without cancer. PD-L1 is also found on the surface of some cancer cells and has recently been effectively targeted with immunotherapy to combat cancer. Knowing whether or not a patient’s tumour expresses PD-L1 is a crucial first step in this treatment—and SMAC may be able to identify cancers that have PD-L1 at low levels that are undetectable by standard blood tests.
“With SMAC, we have brought single-molecule imaging into the clinical arena. By visualizing and examining individual molecules released from diseased cells into the blood, we aim to detect diseases more accurately and gain new insights into their mechanisms,” Mao said.
Biophysics Society https://tinyurl.com/yynccngq

Rheumatoid arthritis (RA) is an autoimmune disorder that occurs when the immune system mistakenly attacks the body’s tissues. Unlike the wear-and-tear damage of osteoarthritis, rheumatoid arthritis affects the lining of the joints, causing painful swelling that can eventually result in bone erosion and joint deformity.
Most RA patients are positive for anticitrullinated protein antibodies (ACPA), and these antibodies are highly specific for RA diagnosis. ACPA recognizes various citrullinated proteins, such as fibrinogen, vimentin and glucose- 6-phosphate isomerase. Citrullinated proteins are proteins that have the amino acid arginine converted into the citrulline, which is not one of the 20 standard amino acids encoded by DNA in the genetic code. Autoreactivity to citrullinated protein may increase susceptibility to RA.
While many candidate citrullinated antigens have been identified in RA joints, the involvement of citrullinated proteins in blood serum remains mostly uninvestigated. To that end, a team of University of Tsukuba-centred researchers set out to explore the expression and commonality of citrullinated proteins in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA) and patients with RA, and went one step further to investigate its correlation with RA disease activity.
"We examined serum citrullinated proteins from pGIA by western blotting, and the sequence was identified by mass spectrometry. With the same methods, serum citrullinated proteins were analysed in patients with RA, primary Sjögren’s syndrome, systemic lupus erythematosus, and osteoarthritis as well as in healthy subjects," study corresponding author Isao Matsumoto explains. "In patients with RA, the relationship between the expression of the identified protein inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and clinical features was also evaluated, and the levels of citrullinated ITIH4 were compared before and after biological treatment."
The researchers found that citrullinated ITIH4 was highly specific to patients with RA, compared with patients with other autoimmune and arthritic diseases or in healthy subjects, indicating a potential role for citrullinated ITIH4 in RA pathogenesis. Notably, its levels were decreased in correlation with the reduction of disease activity score after effective treatment in patients with RA. Moreover, antibody response to citrullinated epitope in ITIH4 was specifically observed in patients with RA.
"Our results suggest that citrullinated ITIH4 might be a novel biomarker to distinguish RA from other rheumatic diseases and for assessing disease activity in patients with RA," Matsumoto says. "To our knowledge, this is the first report of its kind in the literature."

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