Efficacy and Safety of Switching Prostaglandin Analog Monotherapy to Tafluprost/Timolol Fixed-Combination Therapy

Purpose. To assess the efficacy and safety of switching from prostaglandin analog (PGA) monotherapy to tafluprost/timolol fixed-combination (Taf/Tim) therapy. Subjects and Methods. Patients with primary open-angle glaucoma, normal-tension glaucoma, or ocular hypertension who had received PGA monotherapy for at least 3 months were enrolled. Patients were examined at 1, 2, and 3 months after changing therapies. Subsequently, the patients were returned to PGA monotherapy. The examined parameters included intraocular pressure (IOP) and adverse events. A questionnaire survey was conducted after the switch to Taf/Tim therapy. Results. Forty patients with a mean age of 66.5 ± 10.3 years were enrolled; 39 of these patients completed the study protocol. Switching to Taf/Tim significantly reduced the IOP from 18.2 ± 2.6 mmHg at baseline to 14.8 ± 2.5 mmHg at 1 month, 15.2 ± 2.8 mmHg at 2 months, and 14.9 ± 2.5 mmHg at 3 months (P<0.001). Switching back to the original PGA monotherapy returned the IOP values to baseline levels. Taf/Tim reduced the pulse rate insignificantly. No significant differences were observed in blood pressure, conjunctival hyperemia, or corneal adverse events. A questionnaire showed that the introduction of Taf/Tim did not significantly influence symptoms. Conclusions. Compared with PGA monotherapy, Taf/Tim fixed-combination therapy significantly reduced IOP without severe adverse events

Cerebral Venous Air Embolism due to a Hidden Skull Fracture Secondary to Head Trauma

Cerebral venous air embolism is sometimes caused by head trauma. One of the paths of air entry is considered a skull fracture. We report a case of cerebral venous air embolism following head trauma. The patient was a 55-year-old man who fell and hit his head. A head computed tomography (CT) scan showed the air in the superior sagittal sinus; however, no skull fractures were detected. Follow-up CT revealed a fracture line in the right temporal bone. Cerebral venous air embolism following head trauma might have occult skull fractures even if CT could not show the skull fractures

Intravenous phosphate loading increases fibroblast growth factor 23 in uremic rats.

Oral phosphate loading and calcitriol stimulate Fibroblast growth factor 23 (FGF23) secretion, but the mechanisms underlying the stimulation of FGF23 remain to be studied. We compared the effect of intravenous phosphate loading with that of oral loading on FGF23 levels in normal and 5/6 nephrectomized uremic rats. Uremic rats (Nx) and sham-operated rats were fed a normal phosphate diet for 2 weeks and then divided into 3 groups: 1) with the same phosphate diet (NP), 2) with a high phosphate diet (HP), and 3) NP rats with intravenous phosphate infusion using a microinfusion pump (IV). Blood and urine were obtained 1 day (early phase) and 7 days (late phase) after the interventions. In the early and late phases, serum phosphate levels and fractional excretion of phosphate (FEP) were comparable in the HP and IV groups in both Sham and Nx rats. Serum phosphate levels in the HP and IV groups were equally and significantly higher than those in the NP group only in the late phase in Nx rats. In the early phase, FGF23 levels were comparable in the NP, HP, and IV groups, but were significantly higher in the HP and IV groups compared to the NP group in the late phase in Nx rats. 1α-hydroxylase and sodium dependent phosphate co-transporter 2a expression levels in the kidney in Nx rats were equally and significantly decreased in the HP and IV groups compared with the NP group, while 24-hydroxylase expression was equally and significantly increased. These results show that chronic intravenous phosphate loading increases bioactive FGF23, indicating that an alternative pathway for FGF23 regulation, in addition to the dietary route, may be present. This pathway is clearer under conditions produced by a kidney injury in which phosphate is easily overloaded

Identification of SCAN domain zinc-finger gene ZNF449 as a novel factor of chondrogenesis.

Transcription factors SOX9, SOX5 and SOX6 are indispensable for generation and differentiation of chondrocytes. However, molecular mechanisms to induce the SOX genes are poorly understood. To address this issue, we previously determined the human embryonic enhancer of SOX6 by 5'RACE analysis, and identified the 46-bp core enhancer region (CES6). We initially performed yeast one-hybrid assay for screening other chondrogenic factors using CES6 as bait, and identified a zinc finger protein ZNF449. ZNF449 and Zfp449, a counterpart in mouse, transactivated enhancers or promoters of SOX6, SOX9 and COL2A1. Zfp449 was expressed in mesenchyme-derived tissues including cartilage, calvaria, muscle and tendon, as well as in other tissues including brain, lung and kidney. In limb cartilage of mouse embryo, Zfp449 protein was abundantly located in periarticular chondrocytes, and decreased in accordance with the differentiation. Zfp449 protein was also detected in articular cartilage of an adult mouse. During chondrogenic differentiation of human mesenchymal stem cells, ZNF449 was increased at an early stage, and its overexpression enhanced SOX9 and SOX6 only at the initial stage of the differentiation. We further generated Zfp449 knockout mice to examine the in vivo roles; however, no obvious abnormality was observed in skeletal development or articular cartilage homeostasis. ZNF449 may regulate chondrogenic differentiation from mesenchymal progenitor cells, although the underlying mechanisms are still unknown

Histological analyses of <i>Zfp449</i> knockout mice.

<p>(A) Safranin-O staining and immunofluorescence of Sox9, Sox6, Col2a1 and Zfp449 in proximal tibia of <i>Zfp449</i> null (−/−) and WT littermate embryos (+/+) (E18.5). Enlarged immunofluorescence figures on the left are from the areas indicated in the yellow inset box on Safranin-O staining. The further magnified views on the right are from the areas indicated in the blue inset boxes. Scale bars, 100 µm (Safranin-O stainings and immunofluorescence images), 10 µm (maginified views of immunofluorescence). (B) mRNA levels of <i>Sox9</i>, <i>Sox6</i>, <i>Col2a1</i> and <i>Zfp449</i> in primary chondrocytes from <i>Zfp449</i> null and WT littermate mice (6 d). Data are expressed as means (bars) ± SDs (error bars) for three wells/group. ^#<i>P</i><0.01 versus WT. (C) Safranin-O staining of knee joints in <i>Zfp449</i> null mice and WT littermates 8 weeks after the surgical induction of OA. Scale bars, 100 µm. (D) Safranin-O staining of knee joints in 17-month-old <i>Zfp449</i> null mice and WT littermates. Scale bars, 100 µm. (E) Immunofluorescence of GFP and Zfp449 in elbow joints of <i>Zfp449</i> heterozygous mutant. Scale bars, 200 µm.</p

Enhancement of chondrogenic differentiation of hMSCs by ZNF449.

<p>(A) mRNA levels of <i>ZNF449, SOX9, SOX6 and COL2A1</i> during chondrogenic differentiation of hMSCs. Data are expressed as means (bars) ± SDs (error bars) for three wells/group. *<i>P</i><0.05, ^#<i>P</i><0.01 versus 0 d. (B) mRNA levels of <i>SOX9, SOX6 and COL2A1</i> during chondrogenic differentiation of hMSCs transduced with GFP or ZNF449 by adenovirus. Adenoviral transduction was performed 2 days before the differentiation. Data are expressed as means (bars) ± SDs (error bars) for three wells/group. *<i>P</i><0.05 versus GFP. (C) Protein levels of the transduced ZNF449 (HA) and Actin during the differentiation of hMSC.</p

Expression pattern of Zfp449 in mouse tissues and cartilage.

<p>(A) mRNA level of <i>Zfp449</i> in mouse tissues. Data are expressed as means (bars) ± SDs (error bars) for three wells/group. (B) Immunofluorescence of Zfp449 in limb cartilage of mouse embryo. Inset boxes in the top panel indicate the regions of the bottom three rows representing periarticular (Per) zone, proliferative (Pro) zone, and hypertrophic (Hyp) zone. Scale bars, 100 µm (top), 20 µm (bottom). (C) Immunofluorescence of Zfp449 in articular cartilage of 8-week-old mouse knee joint. Inset box in middle panel indicates the regions of the bottom three rows. Scale bars, 100 µm (top and middle), 10 µm (bottom).</p