ASIC1a is required for neuronal activation via low-intensity ultrasound stimulation in mouse brain.

Accumulating evidence has shown transcranial low-intensity ultrasound can be potentially a non-invasive neural modulation tool to treat brain diseases. However, the underlying mechanism remains elusive and the majority of studies on animal models applying rather high-intensity ultrasound that cannot be safely used in humans. Here, we showed low-intensity ultrasound was able to activate neurons in the mouse brain and repeated ultrasound stimulation resulted in adult neurogenesis in specific brain regions. In vitro calcium imaging studies showed that a specific ultrasound stimulation mode, which combined with both ultrasound-induced pressure and acoustic streaming mechanotransduction, is required to activate cultured cortical neurons. ASIC1a and cytoskeletal proteins were involved in the low-intensity ultrasound-mediated mechanotransduction and cultured neuron activation, which was inhibited by ASIC1a blockade and cytoskeleton-modified agents. In contrast, the inhibition of mechanical-sensitive channels involved in bilayer-model mechanotransduction like Piezo or TRP proteins did not repress the ultrasound-mediated neuronal activation as efficiently. The ASIC1a-mediated ultrasound effects in mouse brain such as immediate response of ERK phosphorylation and DCX marked neurogenesis were statistically significantly compromised by ASIC1a gene deletion. Collated data suggest that ASIC1a is the molecular determinant involved in the mechano-signaling of low-intensity ultrasound that modulates neural activation in mouse brain.

A 70-year-old woman with 10 years of markedly elevated alpha-fetoprotein measurements.

The incidence of hepatocellular carcinoma (HCC) is growing dramatically in the Western world. It is currently the fifth most common cancer worldwide, and the third most common cause of death from cancer. Studies clearly demonstrate that surveillance programs can increase the proportion of HCCs that are detected at an early stage, and improved therapeutic modalities, applied to early stage HCCs, improve cure rates and duration of survival in noncurable cases. What constitutes appropriate surveillance remains an unresolved issue. Measurements of serum alpha-fetoprotein and imaging, especially with ultrasound, are the most widely used elements in surveillance programs. The authors present a 70-year-old woman with chronic hepatitis C in whom elevated alpha-fetoprotein levels were first detected 10 years ago, reaching levels of >700 ng/mL. Frequent imaging studies by ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) have found only one lesion, which does not have radiographic features strongly suggestive of HCC. This lesion has been seen only intermittently, and when seen has shown no growth over an 8-year period. Segmental ablation did not alter the serum alpha-fetoprotein levels. The authors believe the patient does not have HCC. Alpha-fetoprotein as a screening test for HCC is known to lead to false-negative results. This case, and a review of the literature, emphasize that it is also subject to false-positives. In addition, interpretation of borderline imaging studies such as occurred in this case often causes controversy among the physicians involved. This case illustrates yet again the deficiencies of alpha-fetoprotein as a surveillance tool for HCC. It also highlights the need for more emphasis on developing new and improved tools for HCC surveillance if improved therapeutic modalities are to be exploited to the fullest.

Inhibition of platelet aggregation and expression of alpha granule membrane protein 140 and thromboxane B2 with pravastatin therapy for hypercholesterolemia.

The drugs in the group of the "statins" lower blood lipids, especially cholesterol, thereby reducing a risk factor for, and diminishing the incidence of, clinically important cerebrocardiovascular events. Cardiovascular events and stroke are significant causes of morbidity and mortality in China and the United States. Statins reduce platelet-mediated thrombus formation and atherosclerotic progression through mechanisms not completely elucidated. While important, the lipid-lowering action of statins does not completely explain their multifaceted benefits. Nonlipid related mechanisms are essential to such effects. The authors explore these nonlipid related mechanisms of action of pravastatin that may translate into clinically relevant benefits. This study was conducted in Guangzhou, China. Twenty-one hypercholesterolemic patients were treated with pravastatin--10-20 mg/day for 12 weeks. Blood for tests was obtained at baseline and after 8 and 12 weeks of pravastatin therapy. After 8- and 12-weeks of therapy, significant decreases were observed in the following: (1) total blood cholesterol and low density lipoprotein-C (P < 0.01), (2) ADP-induced maximum platelet aggregation (P < 0.01), (3) TXB2 or thromboxane B2 in platelets (P < 0.01), and (4) expression of GMP-140 or granule membrane protein-140 (P < 0.01). The therapeutic effects of the drug did not vary significantly with length of therapy. Pravastatin induces inhibition of platelet aggregation and expression of TXB2 and GMP-140, the likely causes of thrombus formation, atherosclerotic progression, and subsequently cardiovascular events. These potential beneficial events occur within 8 weeks of pravastatin therapy.