Follistatin is an activin-binding protein that prevents activin from binding to its receptors and neutralizes its activity. Follistatin also binds bone morphogenetic proteins (BMPs). In this study, we report the identification of a novel follistatin-like protein from mouse. The mouse cDNA encodes a 256-residue precursor and most likely a mouse homologue of human FLRG, which was found at the breakpoint of the chromosomal rearrangement in a B-cell line. Whereas follistatin has three follistatin domains, which are presumed to be growth factor binding motifs, FLRG possesses only two follistatin domains. Northern blotting revealed that mRNAs for FLRG were abundantly expressed in heart, lung, kidney, and testis in mouse. The recombinant mouse FLRG proteins were found to have binding activity for both activin and bone morphogenetic protein-2. Like follistatin, FLRG has higher affinity for activin than for BMP-2. The FLRG protein inhibited activin-induced and BMP-2-induced transcriptional responses in a dose-dependent manner. Glutathione S-transferase fusion proteins encoding various regions of FLRG were produced and studied. Ligand blotting using 125 I-activin revealed that the COOHterminal region containing the second follistatin domain was able to bind activin. Our finding implies that cellular signaling by activin and BMPs is tightly regulated by multiple members of the follistatin family.

OBJECTIVE The presence of disproportionately enlarged subarachnoid space hydrocephalus (DESH) on brain imaging is a recognized finding of idiopathic normal pressure hydrocephalus (iNPH), but the features of DESH can vary across patients. The aim of this study was to evaluate the utility of MRI-based DESH scoring for predicting prognosis after surgery. METHODS In this single-center, retrospective cohort study, the DESH score was determined by consensus between a group of neurosurgeons, neurologists, and a neuroradiologist based on the preoperative MRI findings of the patients with suspected iNPH. The DESH score was composed of the following 5 items, each scored from 0 to 2 (maximum score 10 points): ventriculomegaly, dilated sylvian fissures, tight high convexity, acute callosal angle, and focal sulcal dilation. The association between the DESH score and improvement of the scores on the modified Rankin Scale (mRS), iNPH Grading Scale (iNPHGS), Mini-Mental State Examination (MMSE), Trail Making Test-A (TMT-A), and Timed 3-Meter Up and Go Test (TUG-t) was examined. The primary end point was improvement in the mRS score at 1 year after surgery, and the secondary outcome measures were the iNPHGS, MMSE, TMT-A, and TUG-t scores at 1 year after surgery. Improvement was determined as improvement of 1 or more levels on mRS, ≥ 1 point on iNPHGS, ≥ 3 points on MMSE, a decrease of > 30% on TMT-A, and a decrease of > 10% on TUG-t. RESULTS The mean DESH score for the 50 patients (mean age 77.6 ± 5.9 years) reviewed in this study was 5.58 ± 2.01. The mean rate of change in the mRS score was -0.50 ± 0.93, indicating an inverse correlation between the DESH score and rate of change in the mRS score (r = -0.749). Patients who showed no improvement in mRS score tended to have a low DESH score as well as low preoperative MMSE and TMT-A scores. There were no differences in the areas of deep white matter hyperintensity and periventricular hyperintensity on the images between patients with and without an improved mRS score (15.6% vs 16.7%, respectively; p = 1.000). The DESH score did differ significantly between patients with and without improved scores on the iNPHGS (6.39 ± 1.76 vs 4.26 ± 1.69, respectively; p < 0.001), MMSE (6.63 ± 1.82 vs 5.09 ± 1.93; p = 0.010), TMT-A (6.32 ± 1.97 seconds vs 5.13 ± 1.93 seconds; p = 0.042), and TUG-t (6.48 ± 1.81 seconds vs 4.33 ± 1.59 seconds; p < 0.001). CONCLUSIONS MRI-based DESH scoring is useful for the prediction of neurological improvement and prognosis after surgery for iNPH.

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Fluoroquinolones represent a major class of antibacterial agents with great therapeutic potential. In this study, we designed m-aminophenyl groups as novel N-1 substituents of naphthyridones and quinolones. Among newly synthesized compounds, 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4) has extremely potent antibacterial activities against Gram (+) as well as Gram (-) bacteria. This compound is significantly more potent than trovafloxacin against clinical isolates: 30 times against Streptococcus pneumoniae and 128 times against methicillin resistant Staphylococcus aureus. The structure-activity relationship (SAR) study revealed that a limited combination of 1-(5-amino-2,4-difluorophenyl) group, 7-(azetidin-1-yl) group, and 8-Cl atom (or Br atom or Me group) gave potent antibacterial activity. An X-ray crystallographic study of a 7-(3-ethylaminoazetidin-1-yl)-8-chloro derivative demonstrated that the N-1 aromatic group was remarkably distorted out of the core quinolone plane by steric repulsion between the C-8 Cl atom and the N-1 substituent. Furthermore, a molecular modeling study of 4 and its analogues demonstrated that a highly distorted orientation was induced by a steric hindrance of the C-8 substituent, such as Cl, Br, or a methyl group. Thus, their highly strained conformation should be a key factor for the potent antibacterial activity.