CaMKK2 as an emerging treatment target for bipolar disorder.

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.

Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders.

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle-brain, liver-brain and gut-brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise-brain communication and their benefits for physiology and brain function.

A streamlined approach to structure elucidation using in cellulo crystallized recombinant proteins, InCellCryst.

With the advent of serial X-ray crystallography on microfocus beamlines at free-electron laser and synchrotron facilities, the demand for protein microcrystals has significantly risen in recent years. However, by in vitro crystallization extensive efforts are usually required to purify proteins and produce sufficiently homogeneous microcrystals. Here, we present InCellCryst, an advanced pipeline for producing homogeneous microcrystals directly within living insect cells. Our baculovirus-based cloning system enables the production of crystals from completely native proteins as well as the screening of different cellular compartments to maximize chances for protein crystallization. By optimizing cloning procedures, recombinant virus production, crystallization and crystal detection, X-ray diffraction data can be collected 24 days after the start of target gene cloning. Furthermore, improved strategies for serial synchrotron diffraction data collection directly from crystals within living cells abolish the need to purify the recombinant protein or the associated microcrystals.

Echocardiographic aspects of hiatal hernia: A review.

It was realized 20 years ago that the sonographic appearance of a diaphragmatic hernia could simulate a left atrial mass. Many papers have appeared on this topic since then, but they mainly consist of single case reports. Clinical symptoms due to cardiac compression by the hernia are uncommon but may occur if the hernia is very large; such patients have presented with episodes of syncope or dyspnea, typically after a large meal. Sonographers, cardiologists, gastroenterologists, and internists are generally not yet aware that sonographic presentations can be varied and are often perplexing. These include the combination of hiatal hernia with gastroesophageal reflux demonstrable in the subcostal view, and hiatal hernia in patients with ascites.

Local intense mosaic pattern at site of flail mitral leaflet: report of a new color Doppler sign.

Color flow Doppler has been useful in diagnosing the presence and severity of mitral regurgitation (MR). We noted a hitherto unreported sign of MR due to flail mitral leaflet: intense local mosaic pattern at the site of the flail leaflet. This sign was seen well in 11 of 14 patients (79%) with the two-dimensional echocardiographic features of flail mitral leaflet, all with moderate or severe MR. In 3 other patients, the sign was absent; two of those had flail mitral leaflet with severe MR. No local mosaic pattern was seen on color Doppler in 20 other patients with MR but no flail mitral leaflet. We speculate that the focal intense mosaic color Doppler morphology may have been caused by intrusion of the flail leaflet into the MR stream, or to a Coanda-like effect of the MR jet "adhering" to the flail leaflet.

Palpable breast thickening: role of mammography and US in cancer detection.

PURPOSE: To determine the frequency of breast carcinoma and ascertain the diagnostic yield of mammography and breast ultrasonography (US) in the detection of breast carcinoma in women with palpable breast thickening. MATERIALS AND METHODS: One hundred twenty-three consecutive cases of breast thickening (103 patients) during a 1-year period were reviewed. Experienced breast examiners prospectively identified patients with breast thickening. Results of diagnostic mammographic work-up, breast US, breast biopsy, and clinical follow-up were retrospectively reviewed. RESULTS: Six (5%) of 123 cases had a diagnosis of breast carcinoma; five (83%) of the six had invasive carcinoma. Mammography was performed in all cases, US in 77 (63%) cases. Mammographic sensitivity for invasive cancer detection was 60% (three of five cases), specificity was 94% (102 of 108 cases), and negative predictive value was 97% (102 of 105 cases). Sensitivity of US alone was 100% (two of two cases), specificity was 96% (65 of 68 cases), and negative predictive value was 100% (65 of 65 cases). The combined negative predictive value of mammography and US was 100%. Patients with prior biopsies at the site of palpable thickening accounted for most false-negative mammograms. Median time to initiate follow-up of patients in whom biopsy was not performed was 14 months. CONCLUSION: Breast cancer was discovered in 5% of women with palpable breast thickening. Women with negative mammograms and US scans are at low risk for cancer but should, in our opinion, be followed up at short-term intervals with clinical examination and imaging if biopsy is not elected by their surgeon or clinician.