Treatment satisfaction with molidustat in CKD-related anemia in non-dialysis patients: a post-hoc analysis of two clinical trials.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa. METHODS: This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia. RESULTS: Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant. CONCLUSION: These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia. REGISTRATION OF CLINICAL TRIALS: ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017). CLINICALTRIALS: gov Identifier: NCT03350347 (November 22, 2017).

[A case of difficult treatment of infected pseudoaneurysm of the femoral artery during hepatic arterial infusion chemotherapy for hepatocellular carcinoma].

For advanced hepatocellular carcinoma, an 80's woman underwent right inguinal reservoir port implantation and hepatic arterial infusion chemotherapy. The patient developed sepsis caused by methicillin-resistant Staphylococcus aureus 40 days after starting treatment. After the reservoir port was removed, an infected pseudoaneurysm developed. Interventional radiology treatment could not be completed because of the shape of the aneurysm, and deep femoral artery suture closure was conducted surgically. Unfortunately, the pseudoaneurysm recurred two months after surgery, and treatment for hepatocellular carcinoma was discontinued. It is important to remember that the formation of pseudoaneurysms is a complication after reservoir port placement.

Singularity-free internal conversion golden-rule rate with application to correlated triplet pair recombination in bipentacenes.

We introduce a singularity-free golden-rule rate expression for internal conversion (IC), a spin-conserved radiationless relaxation process, expressed as the product of a nonadiabatic coupling term and the time integral of a vibration correlation function. For a set of small polyatomic molecules (acenes and azulene), we show that our calculated rates are in near quantitative agreement with the rates derived from experiments. Interestingly, we find that our rates do not agree with previous golden-rule-based theoretical efforts; detailed analysis shows that while the level of electronic structure theory can play a role, the more significant error is from not fully converging the numerical time integral over the oscillatory vibration correlation function. We then use our singularity-free IC rate expression to compute the rate of recombination of the correlated triplet pair state generated by intramolecular singlet fission in a trio of bipentacenes. We show that the recombination rates are in good agreement with experimentally observed trends-specifically, the rates are robust to temperature changes and decrease rapidly with increasing inter-monomer dihedral angle. Finally, we use a pair-wise breakdown of normal mode contributions to the rate to identify the key vibrational modes that drive recombination in bipentacenes.

The Effects of Antenatal Corticosteroids on Short- and Long-Term Outcomes in Small-for-Gestational-Age Infants.

AIM: To evaluate the effect of antenatal corticosteroids (ANS) on short- and long-term outcomes in small-for-gestational age (SGA) infants. METHODS: A retrospective database analysis was performed. A total of 1,931 single infants (birth weight <1,500 g) born at a gestational age between 22 weeks and 33 weeks 6 days who were determined to be SGA registered in the Neonatal Research Network Database in Japan between 2003 and 2007 were evaluated for short-term outcome and long-term outcome. RESULTS: ANS was administered to a total of 719 infants (37%) in the short-term outcome evaluation group and 344 infants (36%) in the long-term outcome evaluation group. There were no significant differences between the ANS group and the no-ANS group for primary short-term outcome (adjusted odds ratio (OR) 0.73; 95% confidence interval (CI) 0.45-1.20; P-value 0.22) or primary long-term outcome (adjusted OR 0.69; 95% CI 0.40-1.17; P-value 0.17). CONCLUSIONS: Our results show that ANS does not affect short- or long-term outcome in SGA infants when the birth weight is less than 1500 g. This study strongly suggests that administration of ANS resulted in few benefits for preterm FGR fetuses.

Long-term outcomes of antenatal corticosteroids treatment in very preterm infants after chorioamnionitis.

PURPOSE: To evaluate the effect of antenatal corticosteroids (AC) therapy on short- and long-term outcomes among very low birth weight preterm infants after histologic chorioamnionitis (HCA). METHODS: We performed a retrospective analysis of 5240 single very low birth weight (VLBW) infants born at 22 + 0 and 33 + 6 weeks of gestation between 2003 and 2007, who registered to the Neonatal Research Network Japan. The effects of AC therapy on mortality, neurodevelopmental outcomes at 3 years of age and neonatal morbidities were analyzed in the groups with or without HCA using logistic regression analysis. RESULTS: In the study subjects, 840 were with HCA, 2734 were without HCA, and 1666 were excluded without data for HCA. AC therapy was significantly associated with decreasing mortality before 3 years of age; [0.52 (0.32-0.86)], [odds ratio (95 % confidence intervals]. There were no differences between the two groups regarding neurodevelopmental outcomes, including cerebral palsy [0.90 (0.41-1.99)], development quotient <70 [0.93 (0.48-1.81)], visual impairment [0.46 (0.04-5.18)], and severe hearing impairment [4.00 (0.30-53.4)] in the group with HCA as well as without HCA. Regarding neonatal morbidities, AC therapy was associated with a lower incidence of respiratory distress syndrome [0.67 (0.50-0.91)], sepsis [0.62 (0.41-0.94)], late-onset adrenal insufficiency [0.62 (0.39-0.98)] and an increased incidence of chronic lung disease [1.62 (1.18-2.24)] in the group with HCA. In the group without HCA, AC therapy was associated with decreasing respiratory distress syndrome [0.60 (0.43-0.84)] and increasing chronic lung disease [1.34 (1.11-1.62)]. CONCLUSION: AC therapy is significantly associated with reduced mortality before 3 years of age in VLBW infants with HCA, but not with neurodevelopmental outcomes, which was same as the results found in infants without HCA. AC therapy is recommended for women with suspected chorioamnionitis, as well as those without chorioamnionitis.

Fetal heart rate pattern interpretation in the second stage of labor using the five-tier classification: impact of the degree and duration on severe fetal acidosis.

AIM: The aim of this study was to clarify the association between fetal heart rate (FHR) tracing interpretation levels in the second stage of labor and poor fetal acid-base balance. MATERIAL AND METHODS: The database at one tertiary hospital in Nagoya, Japan, was retrospectively reviewed for women with singleton fetuses in cephalic presentation and vaginal labor at ≥37 + 0 gestational weeks between 1 June 2011 and 30 April 2012. Continuous FHR tracings in the second stage of labor were subdivided into 15-min intervals, each of which we called a window, from the beginning of labor through delivery, and were assessed according to the five-tier classification proposed by the Japan Society of Obstetrics and Gynecology, in which level 1 is normal, level 2 is subnormal, and levels 3-5 are abnormal patterns. RESULTS: In total, 777 parturient women were eligible for the study protocol. The numbers of women with maximal levels of 1, 2, 3, 4, and 5 were 3, 77, 341, 349, and 7, respectively. No cases of severe fetal acidosis (pH < 7.0 or base excess <-12 mmol/L) were recorded when the maximal levels were below 3. Both the pH and base excess of the umbilical artery decreased with higher levels of FHR tracings interpretation (P < 0.001). Both the summations of level-4 windows and level-3 and level-4 windows were significantly higher in women with severe fetal acidosis than in women without (P < 0.001), indicating that the duration of abnormal levels is associated with severe fetal acidosis. CONCLUSIONS: Both the degree and duration of FHR tracing abnormalities correlate with severe fetal acidosis.

The effects of antenatal corticosteroids therapy on very preterm infants after chorioamnionitis.

PURPOSE: To evaluate the effectiveness of antenatal corticosteroids (AC) therapy on outcomes of very low birthweight infants with histologic chorioamnionitis. METHODS: We performed a retrospective analysis of 10,935 single infants born at a gestational age between 22 + 0 and 33 + 6 weeks and birth weight <1,500 g. Clinical data were obtained from the Neonatal Research Network that included the tertiary neonatal intensive care units throughout Japan between 2003 and 2008. RESULTS: Data of 7,896 infants were available for the period 2003-2008 and were included in the analysis. According to logistic regression analysis, AC were significantly associated with reduced mortality [odds ratio (OR) = 0.50; p < 0.001], lower incidence of respiratory distress syndrome (OR = 0.72; p < 0.001), neonatal seizure (OR = 0.65; p = 0.003) and intraventricular hemorrhage (OR = 0.68; p = 0.001) in cases after histologic chorioamnionitis compared with the cases had no AC therapy (n = 3,271 vs. 4,625). Antenatal corticosteroids were significantly associated with reduced mortality [odds ratio (OR) = 0.60; p < 0.001] among the cases without histologic chorioamnionitis. CONCLUSION: In the retrospective population-based study in Japan, AC exposure was significantly associated with a lower rate of death and neurological morbidity in cases with histologic chorioamnionitis. These outcome data in Japan will be important for further improvement of antenatal practice and care.

Mixed Quantum-Classical Dynamics under Arbitrary Unitary Basis Transformations.

A common approach to minimizing the cost of quantum computations is by unitarily transforming a quantum system into a basis that can be optimally truncated. Here, we derive classical equations of motion subjected to similar unitary transformations and propose their integration into mixed quantum-classical dynamics, allowing this class of methods to be applied within arbitrary bases for both the quantum and classical coordinates. To this end, canonical positions and momenta of the classical degrees of freedom are combined into a set of complex-valued coordinates amenable to unitary transformations. We demonstrate the potential of the resulting approach by means of surface hopping calculations of an electronic carrier scattering onto a single impurity in the presence of phonons. Appropriate basis transformations, capturing both the localization of the impurity and the delocalization of higher-energy excitations, are shown to faithfully capture the dynamics within a fraction of the classical and quantum basis sets.

[Granulosa cell tumor of the ovary - analysis of 15 cases in a single institution].

The best treatment for recurrent granulosa cell tumor(GCT)is considered to be surgical resection, because the effects of chemotherapy or radiation on GCT are obscure. The common site of recurrence is the pelvic cavity, including the surface of the liver and intestine as tumor-dissemination-patterns. Between June 1988 and June 2011, we treated 15 patients with GCT at our hospital. The median follow-up time was 56(22-286)months. Ten patients were stage I, 3 were stage II, and 2 were stage III. No patients had residual lesions at the primary surgery area. Six patients have recurred, and the median disease free survival(DFS)was 85(15-128)months. Six patients had relapses in the pelvic cavity, 2 in the retroperitneal lymph nodes, and 1 in the upper abdomen. Two patients relapsed more than twice; however, the rapid detection of recurrence and surgical resection have kept all patients alive. Thirteen patients have no evidence of disease(NED), 2 are alive with disease(AWD), and no one has died of the disease(DOD). We suggest that maximal debulking surgery to achieve complete cytoreduction of recurrent GCT is the most important treatment for prolonging survival.

Validation of the prediction model for success of vaginal birth after cesarean delivery in Japanese women.

AIM: To validate a previously developed prediction model for vaginal birth after cesarean (VBAC) using a Japanese cohort. METHODS: We performed a cohort study of all term pregnant women with a vertex position, singleton gestation, and one prior low transverse cesarean delivery attempting a trial of labor between April 1985 and March 2010. Variables necessary for the prediction of successful VBAC were maternal age, pre-pregnancy body mass index, ethnicity, prior vaginal delivery, prior VBAC, and indication for prior cesarean delivery. They were extracted from medical records and put into the formula that calculates an individual woman's predicted VBAC success rate. The predicted rates were then partitioned into deciles and compared with the actual VBAC rates. The predictive ability of the model was assessed with a receiver operating characteristic and the area under the curve (AUC) was determined. RESULTS: Seven hundred and twenty-five women who met the inclusion criteria had complete data available, of which 664 (91.6%) had VBAC. The predicted probability of VBAC, as calculated by the regression equation, was significantly higher in those who had a successful trial of labor (median 80.1%, interquartile range 71.5-88.7) than those who did not (median 69.4%, interquartile range 59.9-78.9, P<0.001). The predictive model had AUC of 0.80, which was comparative to the originally described one. When the predicted rates were each deciles of over 70%, the actual success rates were more than 90%. CONCLUSION: The previously published prediction model for VBAC developed in the USA is also available to Japanese women.

Aggressive intervention of previable preterm premature rupture of membranes.

OBJECTIVE: To assess the neonatal and maternal outcomes of pregnancy complicated by previable preterm premature rupture of membranes (PPROM). DESIGN: Retrospective study. SETTING: Tertiary referral hospital. Sample. Forty-five women having aggressive intervention with antibiotics, amnioinfusion, cerclage and tocolysis. METHODS: The hospital database between July 2001 and December 2009 was reviewed for women with singleton fetuses and PPROM before 23(+0) weeks of gestation. We analysed maternal and neonatal characteristics. MAIN OUTCOME MEASURES: Neonatal survival without major morbidity. RESULTS: Thirty-eight infants were delivered alive and seven were stillborn. Ten infants died in the neonatal intensive care unit and one in the labor ward. Twenty-seven live-born infants survived to discharge from hospital. The survival rate of pregnancies with aggressive management was 60% (27 of 45); that of live-born infants was 71.1% (27 of 38). The median gestational age at PPROM and at delivery were significantly lower in the non-surviving group than the surviving group. Thirty-seven women (82.2%) had an amniotic neutrophil elastase level >0.15 µg/mL. Only four women (8.9%) developed clinical chorioamnionitis. Overall, 90.7% of the women showed histological evidence of chorioamnionitis. Eighty-three per cent of the surviving children had bronchopulmonary dysplasia. Nine infants had serious sequelae at a corrected age of one and a half years. Maternal complications were uncommon. CONCLUSIONS: An aggressive treatment protocol for women with previable PPROM resulted in a high neonatal survival rate. Neonatal survival was associated with higher gestational age at delivery and with more frequent use of antenatal corticosteroids. The prognosis is still bad in PPROM before 22(+0) weeks of gestation.

Prevalence of absolute pitch: a comparison between Japanese and Polish music students.

Comparable large-scale surveys including an on-site pitch-naming test were conducted with music students in Japan and Poland to obtain more convincing estimates of the prevalence of absolute pitch (AP) and examine how musical experience relates to AP. Participants with accurate AP (95% correct identification) accounted for 30% of the Japanese music students, but only 7% of the Polish music students. This difference in the performance of pitch naming was related to the difference in musical experience. Participants with AP had begun music training at an earlier age (6 years or earlier), and the average year of commencement of musical training was more than 2 years earlier for the Japanese music students than for the Polish students. The percentage of participants who had received early piano lessons was 94% for the Japanese musically trained students but was 72% for the Polish music students. Approximately one-third of the Japanese musically trained students had attended the Yamaha Music School, where lessons on piano or electric organ were given to preschool children in parallel with fixed-do solfège singing training. Such early music instruction was not as common in Poland. The relationship of AP with early music training is discussed.

Singlet fission and triplet pair recombination in bipentacenes with a twist.

We investigate triplet pair dynamics in pentacene dimers that have varying degrees of coplanarity (pentacene-pentacene twist angle). The fine-tuning of the twist angle was achieved by alternating connectivity at the 1-position or 2-positions of pentacene. This mix-and-match connectivity leads to tunable twist angles between the two covalently linked pentacenes. These twisted dimers allow us to investigate the subtle effects that the dihedral angle between the covalently linked pentacenes imparts on singlet fission and triplet pair recombination dynamics. We observe that as the dihedral angle between the two bonded pentacenes is increased, the rates of singlet fission decrease, while the accompanying decrease in triplet recombination rates is stark. Temperature-dependent transient optical studies combined with theoretical calculations show that the triplet pair recombination proceeds primarily through a direct multiexciton internal conversion process. Calculations further show that the significant decrease in recombination rates can be directly attributed to a corresponding decrease in the magnitude of the nonadiabatic coupling between the singlet multiexcitonic state and the ground state. These results highlight the importance of the twist angle in designing systems that exhibit rapid singlet fission, while maintaining long triplet pair lifetimes in pentacene dimers.

Efficacy and Safety of Intravitreal Aflibercept Injection in Japanese Patients with Neovascular Glaucoma: Outcomes from the VENERA Study.

INTRODUCTION: Neovascular glaucoma is characterized by neovascularization of the iris and anterior angle chamber. Intravitreal anti-vascular endothelial growth factor agents may decrease intraocular pressure (IOP) and improve neovascularization. The VENERA study assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in patients with neovascular glaucoma. METHODS: This was a 5-week, single-arm, nonrandomized, open-label, phase 3 study performed at 7 study sites in Japan that enrolled Japanese patients with anterior segment neovascularization and IOP > 25 mmHg who had not undergone (within 30 days prior), nor were imminently scheduled to undergo (within 8 days following) intraocular surgeries, including panretinal photocoagulation (PRP). Patients received background therapy plus 2 mg IVT-AFL at baseline. Background therapy with systemic IOP-lowering drugs was prohibited for 3 days before day 1 and until IOP evaluation at week 1. The primary endpoint was the change in IOP from baseline to week 1 and the secondary endpoint was the proportion of patients with an improvement of ≥ 1 grade of neovascularization of the angle (NVA) from baseline to week 1. RESULTS: Sixteen patients received treatment (full analysis set); the per-protocol set comprised 15 patients. The mean IOP decreased from 34.1 mmHg at baseline to 25.8 mmHg at week 1 (mean change, -8.3 mmHg [95% confidence interval; CI -12.2 to -4.4; P = 0.0004]). At week 1, 81.3% of patients had an improvement in the grade of neovascularization of the iris (NVI) and 50.0% of patients had an improvement in NVA grade. The proportion of patients with controlled IOP (≤ 21 mmHg) was 43.8% (95% CI 19.8-70.1) at week 1, and increased to 56.3% at week 2 and 86.7% at week 5. The most common ocular treatment-emergent adverse event was eye pain, which occurred in 4 patients (25.0%). CONCLUSIONS: IVT-AFL was associated with statistically significant and clinically meaningful IOP reductions, without concomitant use of systemic IOP-lowering drugs or PRP. The safety profile was consistent with the known safety profile of IVT-AFL. These findings supplement those from the previous VEGA study, and suggest that IVT-AFL may be a potential treatment option for patients with neovascular glaucoma. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT03639675.

Controlling Nutritional Status (CONUT) Score is Associated with Overall Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Cohort Study.

We aimed to investigate the impact of the controlling nutritional status (CONUT) score, an immuno-nutritional biomarker, on the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). This retrospective study enrolled 164 patients with HCC and treated with LEN (median age 73 years, Barcelona Clinic Liver Cancer (BCLC) stage B/C 93/71). Factors associated with overall survival (OS) were evaluated using multivariate and decision tree analyses. OS was calculated using the Kaplan-Meier method and analyzed using the log-rank test. Independent factors for OS were albumin-bilirubin grade 1, BCLC stage B, and CONUT score <5 (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.58-5.31, p < 0.001). The CONUT score was the most important variable for OS, with OS rates of 70.0% and 29.0% in the low and high CONUT groups, respectively. Additionally, the median survival time was longer in the low CONUT group than in the high CONUT group (median survival time not reached vs. 11.3 months, p < 0.001). The CONUT score was the most important prognostic variable, rather than albumin-bilirubin grade and BCLC stage, in patients with HCC treated with LEN. Accordingly, immuno-nutritional status may be an important factor in the management of patients with HCC treated with LEN.

Lenvatinib prolongs the progression-free survival time of patients with intermediate-stage hepatocellular carcinoma refractory to transarterial chemoembolization: A multicenter cohort study using data mining analysis.

Tyrosine kinase inhibitors are considered for use in patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). The aim of the present retrospective study was to identify factors associated with progression-free survival (PFS) and to evaluate the indications for lenvatinib treatment in patients with intermediate-stage HCC refractory to TACE using a data-mining analysis. A total of 171 patients with intermediate-stage HCC refractory to TACE were included. All patients were classified into three groups according to their HCC treatment: Lenvatinib (n=45), sorafenib (n=53) and TACE (n=73) groups. PFS time was calculated using the Kaplan-Meier method and analyzed using a log-rank test. Factors associated with PFS time were evaluated using multivariate and decision-tree analyses. The median PFS time was 5.8, 3.2 and 2.4 months in the lenvatinib, sorafenib and TACE groups, respectively (P<0.001). In the Cox regression analysis, lenvatinib treatment and being within the up-to-seven criteria were identified as independent factors for PFS (lenvatinib, P<0.0001; within up-to-seven, P=0.001). The decision-tree analysis revealed that patients beyond the up-to-seven criteria, treated with lenvatinib and with albumin-bilirubin (ALBI) grade 1 had a longer PFS time (245.2±107.9 days) than patients beyond the up-to-seven criteria, treated with lenvatinib and with ALBI grade 2 (147.1±78.6 days). Additionally, lenvatinib was independently associated with longer PFS time in patients with intermediate-stage HCC refractory to TACE. Therefore, lenvatinib may be recommended for patients who have intermediate-stage HCC refractory to TACE, ALBI grade 1 and who are within the up-to-seven criteria.

Fibrotic disorders in the eye: targets of gene therapy.

Fibrotic diseases, e.g., cutaneous and corneal scarring, keloids, and liver and lung fibrosis, etc., are characterized by appearance of myofibroblasts, the key player of the fibrogenic reaction, and excess accumulation of extracellular matrix with resultant tissue contraction and impaired functions. Inflammatory/fibrogenic growth factors/cytokines produced by injured tissues play a pivotal role in fibrotic tissue formation. Ocular tissues are also susceptible to fibrotic diseases. In this article, the pathogenesis of such fibrotic disorders in the eye, i.e., scarring in the cornea and conjunctiva, post-cataract surgery fibrosis of the lens capsule and proliferative vitreoretinopathy are reviewed. Focus is put on the roles of myofibroblast and signals activated by the fibrogenic cytokine, transforming growth factor beta. Modulation of signal transduction molecules, e.g., Smad and mitogen-activated protein kinases, by gene transfer and other technology is beneficial and can be an important treatment regiment to overcome (prevent or treat) these diseases.

Corneal wound healing in an osteopontin-deficient mouse.

PURPOSE: To investigate the effects of loss of osteopontin (OPN) in the healing of the injured cornea in mice. Cell culture study was also conducted to clarify the effects of OPN in fibroblast behaviors. METHODS: Ocular fibroblasts from wild-type (WT) and OPN-null (KO) mice were used to study the role of OPN on cell behavior. The effect of the lack of OPN on corneal wound healing was evaluated in mice. RESULTS: In cell culture, OPN is involved in cell adhesion and in the migration of ocular fibroblasts. Adhesion of the corneal epithelial cell line was not affected by exogenous OPN. OPN was upregulated in a healing, injured mouse cornea. Loss of OPN did not affect epithelial healing after simple epithelial debridement. Healing of an incision injury in cornea was delayed, with less appearance of myofibroblasts and transforming growth factor beta1 expression in a KO mouse than in a WT mouse. The absence of OPN promoted tissue destruction after an alkali burn, resulting in a higher incidence of corneal perforation in KO mice than in WT mice. CONCLUSIONS: OPN modulates wound healing-related fibroblast behavior and is required to restore the physiological structure of the cornea after wound healing.

Connective tissue growth factor modulates extracellular matrix production in human subconjunctival fibroblasts and their proliferation and migration in vitro.

PURPOSE: We examined the role of connective tissue growth factor (CTGF) in transforming growth factor beta1 (TGFbeta1)-related behavior in cultured human subconjunctival fibroblasts (SCFs), protein production, mRNA expression of CTGF and type I collagen alpha1 chain (colIA1), and cell proliferation and migration. TGFbeta1 is the major factor involved in bleb scarring following filtration surgery. METHODS: An antisense deoxynucleotide (antisense) (5 microM) for CTGF mRNA was used to block endogenous CTGF expression. Effects of antisense on extracellular matrix (ECM) production and immunolocalization, mRNA expression, and cell proliferation and migration were examined in human SCF cultures with or without TGFbeta1 (5 ng/ml). Cell migration was examined in an in vitro wound model of monolayer fibroblast cultures. RESULTS: CTGF antisense reduced mRNA expression of CTGF and colIA1 and production of the ECM components type I collagen, and fibronectin much more markedly in cells treated with TGFbeta1 compared with control fibroblasts, and it inhibited the proliferation of cultured SCFs to 71.9% of that of controls after 13 days of culture. CTGF antisense also delayed defect closure in monolayer cell sheets. In the culture, the defect was closed by TGFbeta1 by 36 h, whereas 7.0% of the defect remained at 48 h in the antisense-treated culture. CONCLUSIONS: These findings indicate that CTGF is involved in ECM production in SCFs activated by exogenous TGFbeta1 in vitro. Inhibition of CTGF expression may be effective in preventing undesirable scar formation during healing following filtration surgery.

Fetal intraventricular bleeding possibly due to maternal vitamin K deficiency.

We report a rare case of fetal intraventricular bleeding possibly due to maternal vitamin K deficiency. A 20-year-old woman was admitted to our hospital due to impending premature delivery and loss of dietary intake at 28 weeks of gestation. Her blood examination showed metabolic alkalosis, prolonged prothrombin time, and extremely high level of plasma des-gamma-carboxyprothrombin (protein induced by vitamin K absence, PIVKA-II). Intraventricular hemorrhage was demonstrated by ultrasonography 6 days after admission. She delivered a 2,288-gram girl infant at 40 weeks of gestation. Cranial computerized tomography and magnetic resonance images obtained postnatally demonstrated a reduced cerebral parenchyma adjacent to the interior side of the right lateral ventricle and the deficit of left cerebellum. The infant's head control was insufficient and central impaired hearing was noted at 6 months of life.