Influence of Respiratory Motion on Dose Distribution in Gastric Mucosa-associated Lymphoid Tissue Lymphoma Radiotherapy.

BACKGROUND/AIM: The present study investigated the effect of respiratory motion on planned radiotherapy (RT) dose for gastric mucosa-associated lymphoid tissue (MALT) lymphoma using four-dimensional dose (4D-dose) accumulation. PATIENTS AND METHODS: 4D-computed tomography (4D-CT) images of 10 patients with gastric MALT lymphomas were divided into 10 respiratory phases. Further, the 3D-dose was calculated using 3D conformal RT (3D-CRT) and volumetric modulated arc therapy (VMAT) plans based on the average intensity projection (AIP) images. Then, both plans were recalculated according to each phase image. Moreover, the dose distributions in each phase were transferred to the AIP images using deformable image registration. The 4D-dose distribution was calculated by summing the doses of each phase, and it was compared with the dosimetric parameters of the 3D-dose distribution. RESULTS: For 3D-CRT, the D95 and D99 of the 4D-dose in the planning target volume (PTV) were significantly lower than those of the 3D-dose, with mean differences of 0.2 (p=0.009) and 0.1 Gy (p=0.021), respectively. There were no significant differences in the other PTV and organ-at-risk dosimetric parameters of 3D-CRT or in any dosimetric parameters of VMAT between the 3D- and 4D-dose distributions. CONCLUSION: The effect of respiratory motion on the planned 3D-CRT and VMAT dose distributions for gastric MALT lymphoma is minimal and clinically negligible.

Ocular blood flow evaluation by laser speckle flowgraphy in pediatric patients with anisometropia.

Purpose: To determine the differences and reproducibility of blood flow among hyperopic anisometropic, fellow, and control eyes. Methods: We retrospectively studied 38 eyes of 19 patients with hyperopic anisometropia (8.2 ± 3.0 years of age) and 13 eyes of eight control patients (6.8 ± 1.9 years). We measured the optic nerve head (ONH) and choroidal circulation using laser speckle flowgraphy (LSFG) and analyzed the choroidal mean blur rate (MBR-choroid), MBR-A (mean of all values in ONH), MBR-V (vessel mean), MBR-T (tissue mean), and sample size (sample), which are thought to reflect the ONH area ratio, area ratio of the blood stream (ARBS). We then assessed the coefficient of variation (COV) and intraclass correlation coefficient (ICC) and compared the differences among amblyopic, fellow, and control eyes in MBR, sample, and ARBS. Results: The ONH, MBR-A, MBR-T, and ARBS of amblyopic eyes were significantly higher than those of fellow eyes (P < 0.01, P < 0.05, and P < 0.05, respectively), and control eyes (MBR-A and ARBS, P < 0.05, for both comparisons). The sample-T (size of tissue component) in amblyopic eyes was significantly smaller than that in fellow and control eyes (P < 0.05). Blood flow in the choroid did not differ significantly between the eyes. The COVs of the MBR, sample, and ARBS were all ≤10%. All ICCs were ≥0.7. The COVs of pulse waveform parameter fluctuation, blowout score (BOS), blowout time (BOT), and resistivity index (RI) in the ONH and choroid were ≤10%. Conclusion: The MBR value of the LSFG in children exhibited reproducibility. Thus, this method can be used in clinical studies. The MBR values of the ONH in amblyopic eyes were significantly high. It has been suggested that measuring ONH blood flow using LSFG could detect the anisometropic amblyopic eyes.

Impact of metal artifact reduction algorithm on gross tumor volume delineation in tonsillar cancer: reducing the interobserver variation.

BACKGROUND: Patients with tonsillar cancer (TC) often have dental fillings that can significantly degrade the quality of computed tomography (CT) simulator images due to metal artifacts. We evaluated whether the use of the metal artifact reduction (MAR) algorithm reduced the interobserver variation in delineating gross tumor volume (GTV) of TC. METHODS: Eighteen patients with TC with dental fillings were enrolled in this study. Contrast-enhanced CT simulator images were reconstructed using the conventional (CTCONV) and MAR algorithm (CTMAR). Four board-certified radiation oncologists delineated the GTV of primary tumors using routine clinical data first on CTCONV image datasets (GTVCONV), followed by CTCONV and CTMAR fused image datasets (GTVMAR) at least 2 weeks apart. Intermodality differences in GTV values and Dice similarity coefficient (DSC) were compared using Wilcoxon's signed-rank test. RESULTS: GTVMAR was significantly smaller than GTVCONV for three observers. The other observer showed no significant difference between GTVCONV and GTVMAR values. For all four observers, the mean GTVCONV and GTVMAR values were 14.0 (standard deviation [SD]: 7.4) cm3 and 12.1 (SD: 6.4) cm3, respectively, with the latter significantly lower than the former (p < 0.001). The mean DSC of GTVCONV and GTVMAR was 0.74 (SD: 0.10) and 0.77 (SD: 0.10), respectively, with the latter significantly higher than that of the former (p < 0.001). CONCLUSIONS: The use of the MAR algorithm led to the delineation of smaller GTVs and reduced interobserver variations in delineating GTV of the primary tumors in patients with TC.

Risk factors for early-onset high myopia after treatment for retinopathy of prematurity.

PURPOSE: To investigate the prevalence of myopia and high myopia and the risk factors for high myopia in infants at 3 years of age with retinopathy of prematurity (ROP). STUDY DESIGN: Retrospective, observational. METHODS: We retrospectively analyzed all 89 preterm infants (178 eyes) with medical records of ROP between October 2008 and March 2018 at Toho University Medical Center Omori Hospital; these infants had a birth weight of less than 1,500 g and were followed up at least until 3 years of age. Cycloplegic autorefraction was performed to measure refractive outcomes. Multivariate analysis was performed to determine the risk factors for early-onset high myopia at 3 years of age. RESULTS: The prevalence of myopia and high myopia was significantly higher in the treated group (59.7% and 17.9%, respectively) than in the untreated group (19.7% and 0%, respectively) (p<0.001). Spherical equivalent (SE) at age 3 was more myopic in the treatment group (-1.72 ± 3.53 D) than in the untreated group (0.54 ± 1.08 D) (p<0.001). In the sub-analysis of the treatment group, there was a significant correlation between SE at age 3 and the number of laser shots (R2 = 0.36, p<0.001). Multivariate logistic analysis showed that the number of laser shots was an independent risk factor for early onset high myopia (p<0.05). CONCLUSION: The number of laser shots is an independent risk factor for early onset high myopia, and preterm infants who have undergone laser treatment for severe ROP should be considered for early optical correction with cycloplegic refractive examination.

Implementation of 99mTc-GSA SPECT Image-guided Inverse Planning into Palliative Radiotherapy for Diffuse Liver Metastases: A Novel Approach.

BACKGROUND/AIM: This is a report of the first clinical implementation of 99mTc-labeled diethylene triamine pentaacetate-galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT) image-guided inverse planning into palliative radiotherapy (RT) for diffuse liver metastases. CASE REPORT: A 48-year-old man developed chemo-refractory diffuse liver metastases from thymic carcinoma characterized by abdominal pain and distension. Palliative RT was performed with a total dose of 20 Gy in five fractions using double arc volumetric modulated arc therapy to reduce the dose to functional liver defined by 99mTc-GSA SPECT images. His symptoms were immediately relieved after RT and did not experience radiation-induced liver disease. Both Functional Assessment of Cancer Therapy (FACT)-G and FACT-Hep total scores improved after 2 weeks of RT initiation and did not become worse than baseline scores. CONCLUSION: The 99mTc-GSA SPECT image-guided palliative RT is an effective and safe treatment for patients with diffuse liver metastases.

A prospective comparison of adaptive and fixed boost plans in radiotherapy for glioblastoma.

PURPOSE: To analyze the efficacy of adaptive radiotherapy (ART) for glioblastoma. METHODS: Sixty-one glioblastoma patients who received ART were prospectively evaluated. The initial clinical target volume (CTVinitial) was represented by T2 hyperintensity on postoperative MRIs (pre-RT MRI [MRIpre])plus 10 mm. The initial planning target volume (PTVinitial) was the CTVinitial plus a 5-mm margin. The PTVinitial received 40 Gy. An MRI and a second planning CT were performed during radiotherapy (MRImid). Two types of boost CTVs (the resection cavity and residual tumor on enhanced T1-weighted MRI plus 10 mm) were created based on the MRIpre and MRImid (CTVboost-pre and -mid). The boost PTV (PTVboost) was the CTVboost plus 5 mm. Two types of boost plans (fixed and adaptive boost plans in the first and second planning CT, respectively) of 20 Gy were created. The PTV based on the post-RT MRI (PTVboost-post) was created, and the dose-volume histograms of the PTVboost-post in the fixed and adaptive boost plans were compared. Additionally, the conformity indices (CIs) of the fixed and adaptive boost plans were compared. RESULTS: The median V95 of the PTVboost-post of the fixed and adaptive boost plans (V95pre and V95mid) were 95.6% and 98.3%, respectively (P < 0.01). The median V95pre and V95mid of patients after gross total resection (GTR) were 97.4% and 98.8%, respectively (P = 0.41); in contrast, the median values of patients after non-GTR were 91.9% and 98.2%, respectively (P < 0.01). The median CIs of the fixed and adaptive boost plans in all patients were 1.45 and 1.47, respectively (P = 0.31). The median CIs of the fixed and adaptive boost plans in patients after GTR were 1.61 and 1.48, respectively (P = 0.01); in contrast, those in patients after non-GTR were 1.36 and 1.44, respectively (P = 0.13). CONCLUSION: ART for glioblastoma improved the target coverage and dose reduction for the normal brain. By analyzing the results according to the resection rate, we can expect a decrease in normal brain dose in patients with GTR and an increase in coverage in those with partial resection or biopsy.

Prevalence and risk factors of retro-styloid lymph node metastasis in oropharyngeal carcinoma.

BACKGROUND: Supporting data defining the selection criteria of level VIIb for inclusion in the target volume in radiotherapy (RT) planning are insufficient. We evaluated the prevalence of level VIIb retro-styloid lymph node metastasis (RSLNM) and associated risk factors in patients with oropharyngeal carcinoma (OPC). MATERIALS AND METHODS: We retrospectively reviewed pre-treatment [18F]-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (CT) along with contrast-enhanced thin slice CT and magnetic resonance (MR) images of 137 patients pathologically confirmed as having OPC who underwent RT. The location of lymph nodes (LNs) was confirmed on the planning CT images. Fisher's exact test and logistic regression analyses were made to determine the risk factors of RSLNM. RESULTS: RSLNM was confirmed in 18 (13%) patients. All RSLNMs were located within level VIIb on the planning CT images. No patients exhibited LNM in contralateral level VIIb. Furthermore, no patients with negative or single ipsilateral cervical LNM had RSLNM. Fisher's exact test revealed that smoking status (p=.027), multiple ipsilateral cervical LNM (p=.045) and LN ≥15 mm in the upper limit of ipsilateral level II (p<.001) were significantly associated with RSLNM. Logistic regression analyses revealed that the presence of LNs ≥15 mm in upper limit of ipsilateral level II was significantly associated with RSLNM (odds ratio: 977.297; 95% confidence interval: 57.629-16573.308; p<.001). CONCLUSIONS: RSLNM is relatively common in patients with OPC with a prevalence rate of approximately 10%. The prevalence of RSLNM in patients with negative or single ipsilateral cervical LNM and contralateral RSLNM is extremely low; therefore, level VIIb can be excluded from the target volume in such patients. LN ≥15 mm in the upper limit of ipsilateral level II is a risk factor for RSLNM. Ipsilateral level VIIb should be included in the target volume for patients with this risk factor.KEY MESSAGERetro-styloid lymph node metastasis (RSLNM) prevalence is ∼10% in oropharyngeal carcinoma.Lymph node ≥15 mm in ipsilateral level II upper limit is a risk factor for RSLNM.

Plan Quality Comparisons Between 3D-CRT, IMRT, and VMAT Based on 4D-CT for Gastric MALT Lymphoma.

BACKGROUND/AIM: We compared three-dimensional conformal RT (3D-CRT), intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT) for gastric mucosa-associated lymphoid tissue (MALT) lymphoma using four-dimensional computed tomography (4D-CT) images. PATIENTS AND METHODS: Three treatment plans of 3D-CRT, IMRT, and VMAT with 30 Gy were created based on 4D-CT images of seven patients. We calculated D95, homogeneity index (HI), and conformity index (CI) of planning target volume, and organs at risk doses. RESULTS: There was no significant difference among the three plans in D95. HI of the IMRT plan was significantly better than that of the VMAT (p=0.047) and 3D-CRT (p=0.047) plans. CIs of the IMRT and VMAT plans were significantly better than those of the 3D-CRT plan (p=0.047 and p=0.047, respectively). Dmean of the liver for 3D-CRT was significantly higher than that for the IMRT (p=0.047) and VMAT (p=0.047) plans. CONCLUSION: The IMRT plan yields the best plan quality for gastric MALT lymphoma.

Impact of four-dimensional cone-beam computed tomography on target localization for gastric mucosa-associated lymphoid tissue lymphoma radiotherapy: reducing planning target volume.

BACKGROUND: Radiotherapy of gastric mucosa-associated lymphoid tissue (MALT) lymphoma should be delivered to the entire stomach with planning target volume (PTV) that accounts for variations in stomach volume, respiratory movement, and patient set-up error. In this study, we evaluated whether the use of four-dimensional cone-beam computed tomography (4D-CBCT) reduces the PTV. METHODS: Eight patients underwent radiotherapy with 15 fractions of gastric MALT lymphoma using 4D-CBCT. PTV structures of 5-30 mm margins (5 mm intervals) from the clinical target volume (CTV) delineated based on the 4D-CT images (CTV-4D) were generated. For the target localization, we performed matching based on skin marking (skin matching), bone anatomy (bone matching), and stomach anatomy (4D soft-tissue matching) based on registration between planning CT and 4D-CBCT images from 10 phases. For each patient, we calculated the covering ratio (CR) of the stomach with variable PTV structures, based on the 4D-CBCT images, with a total of 150 phases [CR (%) = (number of covering phases/150 phases) × 100], for three target localization methods. We compared the CR values of the different target localization methods and defined the PTV with an average CR of ≥ 95% for all patients. RESULTS: The average CR for all patients increased from 17.9 to 100%, 19.6 to 99.8%, and 33.8 to 100%, in the skin, bone, and 4D soft-tissue matchings, respectively, as the PTV structures increased from 5 to 30 mm. The CR obtained by 4D soft-tissue matching was superior to that obtained by skin (P = 0.013) and bone matching (P = 0.008) for a PTV structure of 15 mm margin. The PTV required an additional margin of 20 mm (average CR: 95.2%), 25 mm (average CR: 99.1%), and 15 mm (average CR: 98.0%) to CTV-4D for the skin, bone, and 4D soft-tissue matchings, respectively. CONCLUSIONS: This study demonstrates that the use of 4D-CBCT reduces the PTV when applying 4D soft-tissue matching, compared to skin and bone matchings. Additionally, bone matching does not reduce the PTV as compared with traditional skin matching.

Hypofractionated palliative volumetric modulated arc radiotherapy with the Radiation Oncology Study Group 8502 "QUAD shot" regimen for incurable head and neck cancer.

BACKGROUND: To review a single institutional experience of the Radiation Therapy Oncology Group (RTOG) 8502 "QUAD shot" regimen using volumetric modulated arc radiotherapy (VMAT) for incurable head and neck cancer (HNC). METHODS: Thirty-four consecutive patients with HNC were treated with at least one cycle of the RTOG 8502 regimen. Treatment plans included the use of VMAT with 6 MV photons generated by a linear accelerator. Two daily fractions of 3.7 Gy were delivered with an interval of at least 6 h for 2 consecutive days, totaling 14.8 Gy over 4 fractions. This was repeated every 3-4 weeks for a total of three cycles. No concurrent systemic therapy was performed. RESULTS: The number of completed cycles was 1 in 6 (18%) patients, 2 in 5 (15%), and 3 in 23 (68%). Tumor response was achieved in 29 (85%) patients and symptom relief in 20 (77%) of 26 patients. Overall response (tumor response or symptom relief) was achieved in 32 (94%) patients. All patients who received 2 or more treatment cycles achieved overall response. Median overall survival (OS) was 5.7 months. Multivariate analysis revealed that completion of all three treatment cycles was significantly associated with better OS (P = 0.002). Grade 2 toxicity was observed in four (12%) patients, but no acute Grade ≥ 3 or late toxicity was observed. CONCLUSIONS: The RTOG 8502 "QUAD shot" regimen using VMAT is effective for incurable HNC with highly reduced toxicity. Treatment with multiple cycles is recommended for better treatment response and/or survival.

Correction to: Treatment of aggressive adult T-cell leukemia/lymphoma: a retrospective study in a hospital located in HTLV-1 highly endemic area.

In the original publication of the article, Table 5 was published with incorrect contents. The correct Table 5 is given in this correction.

Treatment of aggressive adult T-cell leukemia/lymphoma: a retrospective study in a hospital located in HTLV-1 highly endemic area.

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm associated with the human T-cell leukemia virus type-I (HTLV-1); prognosis still remains very poor. We retrospectively reviewed the treatment of 198 patients with acute-, lymphoma- and unfavorable chronic-type ATL (aggressive ATL) diagnosed from 2005 to 2014 in a hospital located in an area of Japan in which HTLV-1 is highly endemic. One-hundred forty-three, and 35 patients were treated using OPEC/MPEC and VCAP-AMP-VECP, respectively. OPEC/MPEC was mainly used until around 2010, and gradually switched to VCAP-AMP-VECP, especially for younger patients. The 2-year overall survival for patients treated by VCAP-AMP-VECP was significantly higher than that using OPEC/MPEC for patients < 70 years old (y.o.), but not for patients ≥ 70 y.o. A less intensive chemotherapy OPEC/MPEC could be performed without reducing dose intensity, even in elderly patients, and its therapeutic outcome is not inferior to that of VCAP-AMP-VECP. It is difficult to draw definite conclusion from this small retrospective study; however, OPEC/MPEC may represent an alternative option for elderly patients with aggressive ATL.

Impaired fetal growth in mothers with inadequate gestational weight gain: a retrospective study in Japanese uncomplicated pregnancy.

Introduction: The average birth weight in Japan has gradually decreased and the number of low birth weight infant has increased over the last 30 years. Japanese pregnant women are characterized with lower prevalence of obesity than those in other developed countries, and maternal underweight before pregnancy is independently associated with low birth weight. However, the association between maternal inadequate gestational weight gain (GWG) and the risk of small for gestational age (SGA) in Japanese uncomplicated pregnant women has not been fully understood. This study aimed to examine the effect of maternal inadequate GWG on the risk of SGA in Japanese uncomplicated pregnancies.Methods: We retrospectively analyzed uncomplicated Japanese singleton pregnancies that delivered at term gestation in our institution from 2006 to 2016. The association between GWG and birth weight was analyzed by multiple linear regression. Potential confounding factors included maternal age, parity, prepregnancy BMI, and neonatal sex. The association between inadequate GWG and SGA was also examined by logistic regression.Results: A total of 3837 mother-neonate dyads were analyzed. Maternal GWG was 10.1 ± 3.7 kg (mean ± SD), and 2529 (66%) had inadequate GWG. After adjusting for confounding factors, GWG significantly correlated with birth weight (standardized ß = 0.199, p < .001). Inadequate GWG increased the risk of delivering SGA neonate (adjusted odds ratio (aOR) = 1.97 [1.45-2.68], p < .001). This association was particularly pronounced in underweight (aOR = 2.95 [1.38-6.29], p = .005) and normal weight mothers (aOR = 1.79 [1.27-2.52], p = .001), and not in overweight/obese mothers (p = .115).Conclusion: Maternal GWG is associated with birth weight in Japanese women with uncomplicated singleton pregnancies. Inadequate GWG is an important risk factor of SGA, particularly in non-obese women. The present finding would potentially provide further evidence that promoting adequate gestational weight gain in Japanese underweight and normal weight mothers would reduce SGA, as well as metabolic dysfunction in later life.

Ectopic expression of a rice plasma membrane intrinsic protein (OsPIP1;3) promotes plant growth and water uptake.

Plasma membrane intrinsic proteins (PIPs) are known to be major facilitators of the movement of a number of substrates across cell membranes. From a drought-resistant cultivar of Oryza sativa (rice), we isolated an OsPIP1;3 gene single-nucleotide polymorphism (SNP) that is mostly expressed in rice roots and is strongly responsive to drought stress. Immunocytochemistry showed that OsPIP1;3 majorly accumulated on the proximal end of the endodermis and the cell surface around the xylem. Expression of GFP-OsPIP1;3 alone in Xenopus oocytes or rice protoplasts showed OsPIP1;3 mislocalization in the endoplasmic reticulum (ER)-like neighborhood, whereas co-expression of OsPIP2;2 recruited OsPIP1;3 to the plasma membrane and led to a significant enhancement of water permeability in oocytes. Moreover, reconstitution of 10×His-OsPIP1;3 in liposomes demonstrated water channel activity, as revealed by stopped-flow light scattering. Intriguingly, by patch-clamp technique, we detected significant NO3- conductance of OsPIP1;3 in mammalian cells. To investigate the physiological functions of OsPIP1;3, we ectopically expressed the OsPIP1;3 gene in Nicotiana benthamiana (tobacco). The transgenic tobacco plants exhibited higher photosynthesis rates, root hydraulic conductivity (Lpr ) and water-use efficiency, resulting in a greater biomass and a higher resistance to water deficit than the wild-type did. Further experiments suggested that heterologous expression of OsPIP1;3 in cyanobacterium altered bacterial growth under different conditions of CO2 gas supply. Overall, besides shedding light on the multiple functions played by OsPIP1;3, this work provides insights into the translational value of plant AQPs.

Gender differences in the influence of obstructive sleep apnea on optic nerve head circulation.

We investigated gender differences in the optic nerve head (ONH) microcirculation status in association with obstructive sleep apnea (OSA) by using laser speckle flowgraphy (LSFG). We evaluated 150 men (60.5 ± 11.0 yrs) and 45 women (63.0 ± 10.6 yrs) who underwent overnight polysomnography. The mean blur rate (MBR), maximum (Max) MBR, and minimum (Min) MBR were evaluated. The parameters were analyzed separately for the tissues, vessels, and throughout the ONH (All). The apnea hypopnea index (AHI: times/hr), the lowest SpO2%, and the mean SpO2% were calculated as indicators of OSA. We investigated which MBR sections are correlated with OSA parameters separately in the men and women. All MBR sections in the women were significantly positively correlated with the lowest SpO2. In the men, no MBR section was correlated with any OSA parameters. The factors contributing independently to MBR-Tissue were height (ß = 0.31) and lowest SpO2 (ß = 0.30). The lowest SpO2 in the women was significantly positively correlated with Max MBR-Tissue, Max MBR-All, and Min MBR-All. Our results confirmed a gender difference in characteristics of ONH microcirculation in association with OSA.

Influence of age and gender on the pulse waveform in optic nerve head circulation in healthy men and women.

The influences of age and gender differences on the pulse waveform in the optic nerve head (ONH) in healthy adults, using laser speckle flowgraphy (LSFG) were evaluated. We studied 908 healthy subjects (men = 701, age: 50.0 ± 9.1, women = 208, age: 49.8 ± 9.5, p = 0.76), evaluating these pulse waveform parameters: the blowout score (BOS), blowout time (BOT), acceleration time index (ATI), and the rising and falling rates. The parameters were analyzed separately for the tissue, vessels, and throughout the optic nerve head (All). All parameters were compared between genders. We investigated which independent factors for the pulse waveform in the ONH is most strongly correlated with age. All sections of the BOS, BOT, ATI, and falling rate showed a significant gender difference. A univariate regression analysis revealed that BOT-Tissue showed the strongest correlation with age (r = -0.51). The factors contributing independently to the BOT-Tissue were gender, age, heart rate, mean arterial blood pressure, pulse pressure, spherical refraction, and estimated glomerular filtration rate. Among the subjects aged >41 years, the chronological changes of BOT-Tissue in the women were significantly lower than those in the men. We concluded that the pulse waveform in the ONH has clear differences between the genders and shows chronological changes.

Safety Study of Sodium Pentosan Polysulfate for Adult Patients with Mucopolysaccharidosis Type II.

Current therapies for the mucopolysaccharidoses (MPS) do not effectively address skeletal and neurological manifestations. Pentosan polysulfate (PPS) is an alternative treatment strategy that has been shown to improve bone architecture, mobility, and neuroinflammation in MPS animals. The aims of this study were to a) primarily establish the safety of weekly PPS injections in attenuated MPS II, b) assess the efficacy of treatment on MPS pathology, and c) define appropriate clinical endpoints and biomarkers for future clinical trials. Subcutaneous injections were administered to three male Japanese patients for 12 weeks. Enzyme replacement therapy was continued in two of the patients while they received PPS and halted for two months in one patient before starting PPS. During treatment, one patient experienced an elevation of alanine transaminase, and another patient experienced convulsions; however, these incidences were non-cumulative and unrelated to PPS administration, respectively. Overall, the drug was well-tolerated in all patients, and no serious drug-related adverse events were noted. Generally, PPS treatment led to an increase in several parameters of shoulder range of motion and decrease of the inflammatory cytokines, MIF and TNF-α, which are potential clinical endpoints and biomarkers, respectively. Changes in urine and serum glycosaminoglycans were inconclusive. Overall, this study demonstrates the safety of using PPS in adults with MPS II and suggests the efficacy of PPS on MPS pathology with the identification of potential clinical endpoints and biomarkers.

The influences of gender and aging on optic nerve head microcirculation in healthy adults.

Potential differences in the nature of the influences of aging and gender on the optic nerve head (ONH) microcirculation, using laser speckle flowgraphy (LSFG) were evaluated. We studied 908 healthy subjects (men = 701, age: 50.0 ± 9.1 yrs, women = 208, 49.8 ± 9.5 yrs, p = 0.76). The average, maximum (Max), and minimum (Min) mean blur rate (MBR) in a heartbeat were evaluated. The parameters were analyzed separately for the tissue, vessels, and throughout the ONH (All). We investigated which MBR sections are correlated with gender and age by univariate and multivariate regression analyses. The Max MBR-All (r = -0.31) was most strongly correlated with gender (men = 1, women = 0). The Min MBR-All (r = -0.24) was most strongly correlated with age, followed by Min MBR-All (r = -0.20). The factors contributing independently to the Max MBR-All were gender (ß = -0.15), pulse pressure, spherical refraction, ocular perfusion pressure, and red blood cell (RBC) count. The factors contributing independently to the Min MBR-Vessel were gender (ß = -0.09), age (ß = -0.25), body mass index, heart rate, and spherical refraction. The factors contributing independently to the Min-MBR-All were age (ß = -0.22), heart rate, and RBC count. Our results revealed that gender differences influence the Max MBR, and aging influences the Min MBR. These correlations were stronger than that of average MBR.