Immune checkpoint inhibitors for metastatic uveal melanoma: a meta-analysis.

Several studies have evaluated immune checkpoint inhibitors (ICIs) for metastatic uveal melanoma; however, the efficacy of ICIs in the previous studies varied greatly. In this systematic review, we searched for prospective or retrospective studies on single or dual-ICIs for metastatic uveal melanoma treatment. A random-effect model meta-analysis with generic inverse-variance was conducted, and 36 articles representing 41 cohorts of 1414 patients with metastatic uveal melanoma were included. The pooled outcomes were as follows: objective response rate (ORR) was 5.6% (95% confidence interval [95%CI] 3.7-7.5%; I2, 36%), disease control rate (DCR) was 32.5% (95% CI 27.2-37.7%; I2, 73%), median progression-free survival was 2.8 months (95% CI 2.7-2.9 months; I2, 26%), and median overall survival (OS) was 11.2 months (95% CI 9.6-13.2 months; I2, 74%). Compared to single-agent ICI, dual ICI led to better ORR (single-agent: 3.4% [95% CI 1.8-5.1]; dual-agent: 12.4% [95% CI 8.0-16.9]; P < 0.001), DCR (single-agent: 29.3%, [95% CI 23.4-35.2]; dual-agent: 44.3% [95% CI 31.7-56.8]; P = 0.03), and OS (single-agent: 9.8 months [95% CI 8.0-12.2]; dual-agent: 16.3 months [95% CI 13.5-19.7]; P < 0.001). Our analysis provided treatment outcomes as described above. Dual-ICIs appear better than single-agent ICIs for the treatment of metastatic uveal melanoma.

HLA-DRB1*04:05 is involved in the development of Vogt-Koyanagi-Harada disease-like immune-related adverse events in patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) activate anti-tumor activity by inhibiting immune checkpoint molecules that suppress inflammatory T-cell activity. However, ICIs can initiate excessive immune responses, thereby causing immune-related adverse events (irAEs). ICI-associated uveitis (ICIU) is an irAE that affects the eyes. Although Vogt-Koyanagi-Harada disease (VKH)-like uveitis is a common form of ICIU, it is unclear which factors determine the ICIU form. We retrospectively reviewed the medical records of nine ICIU cases treated with ICIs for malignancies. We also performed HLA typing in seven cases to investigate the association between HLA and disease type. Fisher's exact test was used for the statistical analysis. Five of the ICIU cases were VKH-like ICIUs, and four were non-VKH-like ICIUs. No association was found between mean age, sex, primary disease, ICI, time to onset, and disease type. Four patients with VKH-like uveitis underwent HLA genotyping and were all positive for HLA-DRB1*04:05. All 3 patients with non-VKH-like uveitis were negative for HLA-DRB1*04:05. Statistical analysis showed that HLA-DRB1*04:05 was significantly associated with developing VKH-like ICIU (P = 0.029). In ICIU, HLA-DRB1*04:05 was associated with the pathogenesis of VKH-like uveitis, suggesting that ICI-associated VKH-like uveitis has a similar pathogenesis to VKH.

Genetic polymorphisms in CYP19A1 and ESR1 are associated with serum CK activity after prolonged running in men.

This study aimed to clarify 1) the influence of genetic polymorphisms in the cytochrome P450 aromatase gene (CYP19A1) on circulating estradiol levels in men and 2) whether estrogen-related genetic polymorphisms, such as the CYP19A1 rs936306 and estrogen receptor-α (ESR1) rs2234693 polymorphisms, predict exercise-induced serum creatine kinase (CK) activity, which is an index of skeletal muscle membrane disruption. Serum estradiol levels were examined in young men (n = 167). In a different cohort, serum CK activity was analyzed in a 2-day ultramarathon race: baseline, after the first day, and after the second day (114 males and 25 females). Genetic polymorphisms in CYP19A1 rs936306 C/T and ESR1 rs2234693 T/C were analyzed using the TaqMan SNP Genotyping Assay. Male subjects with the TT genotype of the CYP19A1 polymorphism exhibited significantly higher serum estradiol levels than the C allele carriers. Male runners had significantly higher postrace serum CK activity than female runners. The change in the CK activity during the ultramarathon race was significantly lower in male subjects with the CYP19A1 TT genotype than in those with the CC + CT genotypes and was correlated with the number of C alleles in ESR1 rs2234693 in male subjects. Furthermore, the genotype scores of these two polymorphisms were significantly correlated with changes in serum CK activity during race (r = -0.279, P = 0.003). The results of this study suggest that genetic polymorphisms in CYP19A1 rs936306 influence serum estradiol levels in men, and genetic polymorphisms in CYP19A1 and ESR1 are associated with serum CK activity in men.NEW & NOTEWORTHY Men with the TT genotype of the CYP19A1 polymorphism exhibited higher circulating estradiol levels than the TC + CC genotype. The TT genotype in the CYP19A1 polymorphism and the C allele of the ESR1 polymorphism, an allele increasing ESR1 expression, were associated with low serum CK activity after the ultramarathon. A combination of these polymorphisms was correlated with changes in the serum CK activity. Therefore, estrogen-related genetic polymorphisms partially predict exercise-induced muscle damage, that is, skeletal muscle membrane disruption.

One-year limb outcome and mortality in patients undergoing revascularization therapy for acute limb ischemia: short-term results of the Edo registry.

The present study aimed to clarify the current status, therapeutic strategy, and 1-year outcome in acute limb ischemia (ALI) patients in Japan. The EnDOvascular treatment (Edo) registry database includes 324 patients from 10 institutes who were registered between November 2011 and October 2013. A total of 70 ALI patients (mean age 74.0 years) from the Edo registry database were enrolled in this study. Of the 70 included patients, 72.9% were male and 35.7% had embolism. Of patients, 38.6%, 42.9%, and 18.6% underwent EVT, surgery, and hybrid thrombectomy, respectively, in primary revascularization strategy. Limb ischemia was categorized into four classes at initial evaluation: SVS/ISCVS class I (n = 13, 18.6%), SVS/ISCVS class IIa (n = 36, 51.4%), SVS/ISCVS class IIb (n = 21, 30%), and SVS/ISCVS class III (n = 0, 0%). Three patients with SVS/ISCVS class IIb limb ischemia developed myonephropathic metabolic syndrome. No catheter-directed thrombolysis was employed as a primary revascularization strategy. The 1-year rates of all-cause death, major amputation, and a composite of perioperative death or major adverse limb event were 28.6%, 5.7%, and 40.0%, respectively. Lower age, male sex, dyslipidemia, high estimated glomerular filtration rate, high albumin level, and low C-reactive protein level were independent positive predictors of all-cause death. In this registry, SVS/ISCVS class IIa ALI was predominant. Approximately 40% of primary revascularization strategy was surgery and EVT, followed by hybrid therapy. All-cause death and major amputation rates at 1 year were less than 30% and 6%, respectively.

Bacterial Detection Rate and Surgical Outcome in Povidone-Iodine Irrigation After Nasolacrimal Duct Intubation.

PURPOSE: In various ophthalmic surgical procedures, 0.25% povidone-iodine (PI) solution is used to prevent infections. This study examined the bacterial colonisation before and after endoscopic nasolacrimal duct intubation irrigated with PI solution and investigated the relationship between bacterial detection and surgical failure. METHODS: A retrospective study at Saitama Medical University Hospital. We enrolled 113 patients (33 men, 80 women) who underwent lacrimal intubation surgery between April 2016 and December 2018. Preoperatively, the lacrimal pathways were washed with normal saline solution, which was subsequently cultured. The sites of obstruction in the lacrimal pathway were endoscopically determined, perforated, and intubated. The tubes were afterward either irrigated with 0.25% PI or normal saline every 2 weeks. After 8 weeks, a piece of the removed lacrimal tube was cultured. We characterized the pre- and postoperative bacterial cultures. RESULTS: We enrolled 54 and 52 patients in PI and saline groups (mean age: 69.1±9.2 and 73.2±7.2 years), respectively. In the PI group, Staphylococcus epidermidis was less frequently detected postoperatively than preoperatively. S. oralis and Candida parapsilosis were identified more often postoperatively (P=0.02, P=0.01, respectively). The PI group had significantly lower bacterial detection rate than the saline group (P=0.01). However, the surgical failure rates did not differ between groups. In surgical failure patients, the postoperative rate of Pseudomonas aeruginosa was very high (75%). CONCLUSION: PI reduces the bacterial detection rate but does not improve the surgical success rate. P. aeruginosa is associated with an increased risk of surgical failure.

Iris Posterior Synechiae After Descemet Membrane Endothelial Keratoplasty in Asian Eyes: Prevention and Management of Posterior Synechiae.

OBJECTIVES: To evaluate the efficacy of a mydriatic agent for posterior synechiae after phacoemulsification and intraocular lens (IOL) implantation followed by Descemet membrane endothelial keratoplasty (staged DMEK). METHODS: In this prospective study, the outcomes of DMEK with or without mydriasis (0.5% tropicamide and 0.5% phenylephrine hydrochloride [Mydrin-P; Santen, Osaka, Japan]) after the DMEK procedure were analyzed. Patients underwent IOL implantation approximately 4 weeks before DMEK. Six months after DMEK, the iris posterior synechiae severity score was evaluated based on the extent of posterior synechiae affecting the eight areas (45° each) of the pupillary rim (posterior synechiae score; grades 0-8). Best spectacle-corrected visual acuity, central corneal thickness, endothelial cell density, axial length, and the amount of air at the end of the surgery were also evaluated. RESULTS: Fifteen eyes of 15 patients (mydriatic: n=8, control: n=7) were eligible for inclusion. Iris posterior synechiae were detected in all seven eyes (100.0%) in the control group, whereas they were noted in two eyes in the mydriatic group (25%). The mean iris posterior synechiae score was 0.69±1.20 in the mydriatic group and was significantly lower than that in the control group (4.57±0.90; P<0.001). There was no significant difference in other clinical factors. Although the incidence and scores of posterior synechiae in the control group were higher, the incidence was significantly reduced with the use of a mydriatic agent (in the mydriatic group). CONCLUSIONS: Use of a mydriatic agent is an effective measure to prevent postoperative synechiae after DMEK.

Efficacy of Strip Meniscometry for Detecting Lacrimal Obstructive Diseases Among Patients With Epiphora.

PURPOSE: Strip meniscometry (SM) is a new technique for evaluating tear film volume. The aim of the present study was to evaluate the efficacy of SM in detecting lacrimal obstructive diseases (LODs) in patients with epiphora retrospectively. METHODS: One-hundred sixty-six patients (53 men, 113 women; mean age: 72.4 ± 8.0 years) who were referred to Saitama Medical University Hospital with epiphora as their chief complaint were enrolled; finally, 72 patients with and 89 patients without LOD were examined. We assessed tear volume using SM, tear meniscus height (TMH), tear meniscus area (TMA), and Schirmer-1 test values. Patients with LOD underwent lacrimal intubation surgery to treat their epiphora; their SM scores were assessed before and 8 weeks after surgery. RESULTS: SM, TMH, TMA, and Schirmer-1 values were significantly higher in the LOD group (10.80 ± 3.63 mm, 0.49 ± 0.24 mm, 0.06 ± 0.06 mm2, 18.46 ± 8.00 mm, respectively) than in the non-LOD group (5.44 ± 3.20 mm, 0.30 ± 0.18 mm, 0.03 ± 0.04 mm2, 11.84 ± 7.16 mm). The area under the receiver operating characteristic curve (AUC) for SM was 0.88, the sensitivity and specificity were 82% and 84%. The AUC was significantly larger for SM than for the Schirmer-1 test and TMA. The SM scores significantly improved after surgery (5.30 ± 2.20 mm) compared with those before (10.69 ± 3.20 mm). CONCLUSIONS: SM was significantly better than the Schirmer-1 test, TMH, and TMA for detecting LOD and evaluating the effect of lacrimal surgery. TRANSLATIONAL RELEVANCE: SM, widely used for dry eye, is also useful for using epiphora.

Outcomes of Descemet Membrane Endothelial Keratoplasty for Vitrectomized Eyes with Sutured Posterior Chamber Intraocular Lens.

PURPOSE: To evaluate the clinical outcomes of Descemet membrane endothelial keratoplasty (DMEK) for vitrectomized eyes that underwent pars plana vitrectomy (PPV) and transscleral-sutured intraocular lens (IOL) implantation. METHODS: In this retrospective study, DMEK cases were reviewed from medical records and divided into two groups: the eyes after PPV and transscleral-sutured IOL implantation (vitrectomized group) and the eyes with in-the-bag IOL implantation (control group) prior to DMEK. The main outcome measures included time of graft unfolding during surgery and best spectacle-corrected visual acuity (BSCVA), central corneal thickness (CCT), and endothelial cell density (ECD) at 1, 3, and 6 months after the DMEK. RESULTS: Twenty-three eyes (vitrectomized group, n = 8; control group, n = 15) in 23 patients were included in this study. The unfolding time was significantly longer in the vitrectomized group than in the control group (P < 0.001). Postoperative BSCVA was worse in the vitrectomized group (0.16 ± 0.15) than in the control group (-0.06 ± 0.06; P = 0.017). The improvement in BSCVA was negatively correlated with the patients' age and frequency of previous surgeries. CONCLUSIONS: Despite the longer graft unfolding time and limited visual recovery, DMEK should be applicable to vitrectomized eyes with transscleral-sutured IOL implantation.

Creating a Full-thickness Choroidal Incision: An Ex Vivo Analysis of Human and Porcine Tissue Contraction Dynamics.

PURPOSE: We hypothesized that the elastic nature of the choroid leads to tissue contraction following a full-thickness, sharp incision. Furthermore, we sought to quantify, measure, and compare tissue contraction in ex vivo porcine globes and human globes of various ages using predetermined variables. METHOD: A full-thickness, ex vivo choroidal incision was performed in either pig (n = 97) or human (n = 30) specimens. Variables included trephine diameter (1.5, 2.0, or 2.5 mm) versus a straight surgical blade, and temperature (1.7 °-4.4° vs. 36.6°F). Central centripetal and surround centrifugal tissue contractions were measured. Mean percentage tissue contraction was assessed as a ratio of trephine diameter to final tissue contraction measured immediately following each incision using a standardized device. RESULTS: For trephination in pig specimens, centripetal contraction ranged from 38% to 50% with a mean of 44%. Centrifugal contraction was approximately 15%. Human choroidal contraction was 39% and 15%, respectively, with a statistically significant inverse relationship to age (R2 = 0.35, P ≤ 0.01). Asymmetric contraction was noted when incisions were closer to choroidal attachment sites to the sclera, such as near vortex ampullae. Linear incisions resulted in contraction that correlated with incision length (R2 = 0.35, P ≤ 0.001). CONCLUSIONS: A full-thickness choroidal incision results in significant tissue contraction. For circular incisions, the centripetal contraction approaches 50% of the original incision size. For linear incisions, the contraction corresponds directly with incision length. In human specimens, there is less contraction with advancing age. TRANSLATIONAL RELEVANCE: Our findings have clinical relevance for choroidal biopsy, traumatic injury, and choroidal translocation surgery.

Use of four asymmetric marks to orient the donor graft during Descemet's membrane endothelial keratoplasty.

INTRODUCTION: Maintaining the correct orientation of the donor graft is important during Descemet's membrane endothelial keratoplasty (DMEK). We describe a new method of marking the donor graft prior to DMEK. METHODS: Twelve eyes of 10 patients with bullous keratopathy who underwent DMEK were retrospectively analysed. Donor discs were created by stripping the endothelium-Descemet's membrane layer from corneoscleral buttons. Four semicircular marks, two 1.0 mm and two 1.5 mm in diameter, were created at the edge of the donor disc. The small and large marks were paired. Each donor graft was inserted into the anterior chamber, unfolded and attached to the posterior corneal stroma with an air bubble. RESULTS: The inserted grafts were all appropriately orientated when attached to the back surfaces of the corneas. The two pairs of asymmetric marks afforded valuable guidance. Even when the graft was partially folded or decentred, and one pair of marks was obscured, the other pair was always visible to indicate graft orientation. Best spectacle-corrected visual acuity improved significantly in all patients (p<0.001). Compared with the preoperative endothelial cell density of the donor graft, that of the corneal endothelium had decreased 44.0%±10.0% by 6 months after surgery. CONCLUSIONS: Two pairs of asymmetrical semicircular marks placed on the edge of the donor graft allowed appropriate graft orientation during DMEK.

Routes for Drug Delivery to the Retina: Topical, Transscleral, Suprachoroidal and Intravitreal Gas Phase Delivery.

Local drug delivery to the posterior segment, particularly the macula, represents a significant challenge. In this chapter, we review current challenges, barriers and limitations. Due to the local drug delivery to the retina and macula, systemic side effects are limited. In this chapter, we also discuss the historical approaches, key aspects of ideal drug delivery systems, the use of animal models to study pharmacokinetics, and the principles of transscleral, suprachoroidal and gas phase drug delivery.

A convenient route to synthetic analogues of the oxidized form of high-potential iron-sulfur proteins.

An amide-bound [Fe4S4](3+) cluster, [Fe4S4{N(SiMe3)2}4](-) (1), was found to serve as a convenient precursor for synthetic analogues of the oxidized form of high-potential iron-sulfur proteins. Treatment of 1 with 4 equiv of bulky thiols led to replacement of the amide ligands with thiolates, giving rise to a series of [Fe4S4(SR)4](-) clusters (R = Dmp (2a), Tbt (2b), Eind (2c), Dxp (2d), Dpp (2e); Dmp = 2,6-di(mesityl)phenyl, Tbt = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl, Eind = 1,1,3,3,5,5,7,7-octaethyl-s-hydrindacen-4-yl, Dxp = 2,6-di(m-xylyl)phenyl, Dpp = 2,6-diphenylphenyl). These clusters were characterized by the mass spectrum, the EPR spectrum, and X-ray crystallography. The redox potentials of the [Fe4S4](3+/2+) couple, -0.82 V (2a), -0.86 V (2b), -0.84 V (2c), -0.74 V (2d), and -0.63 V (2e) vs Ag/Ag(+) in THF, are significantly more negative than that of [Fe4S4(SPh)4](-/2-) (-0.21 V).

Cluster of diffuse alveolar hemorrhage cases after the 2011 Tohoku Region Pacific Coast Earthquake.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a clinical syndrome that presents with progressively hemorrhagic bronchoalveolar lavage fluid (BALF) in serial samples and generally has a poor prognosis. The South Miyagi Medical Center, located on the inland side of southern Miyagi Prefecture, documented an increase in the number of patients with DAH after the 2011 Tohoku Region Pacific Coast Earthquake. METHODS: We describe the clinical features of post-earthquake DAH in comparison to pre-earthquake DAH. We analyzed the data of the DAH patients we have been able to follow for at least 6 months since we started performing bronchoscopy and bronchoalveolar lavage (BAL) for all patients with interstitial lung disease in August 2009 until September 2011, and separated these patients into pre- and post-earthquake groups according to the earthquake date of March 11, 2011. RESULTS: Post-earthquake DAH patients tended to test positive for infectious agents and showed higher serum IgE titers, with BALF that exhibited a tendency to higher silica concentrations. Post-earthquake DAH generally had a better prognosis than pre-earthquake DAH. CONCLUSIONS: In describing the clinical features of post-earthquake cases of DAH, this report documents the possibility of an infection- and/or dust-induced, partially allergic, and relatively benign form of DAH.

Genetic variation in the hypoxia-inducible factor-1alpha gene is associated with type 2 diabetes in Japanese.

CONTEXT AND OBJECTIVE: Vascular endothelial growth factor plays a critical role both in neovascularization of proliferative diabetic retinopathy and in angiogenesis of islets in the pancreatic developmental stage in determining beta-cell mass and properties. Vascular endothelial growth factor mRNA levels increase as a result of increased transcriptional activation, mediated predominantly by hypoxia-inducible factor-1 alpha (HIF-1alpha) in response to hypoxia. DESIGN AND PATIENTS: In this study, we examined all regions of the HIF-1alpha to detect single-nucleotide polymorphisms (SNPs), evaluated the pattern of linkage disequilibrium to analyze haplotypes, and performed association studies in Japanese type 2 diabetes patients with or without retinopathy. RESULTS: A total of 35 SNPs were found in the gene, 27 of which were reported previously and eight of which were novel. Three of the 35 SNPs were located in coding regions, one in exon 2 (S28Y), and the others in exon 12 (P582S, A588T). The P582S HIF-1alpha mutation was associated with type 2 diabetes (P = 0.0028) by a consistently higher level of transcriptional activity than wild type, especially under hypoxic condition (P = 0.012), but no association with retinopathy was detected. CONCLUSION: This is the first report that HIF-1alpha is associated with the occurrence of type 2 diabetes and suggests that the P582S HIF-1alpha mutation should be assessed in larger studies as a risk factor for type 2 diabetes.

Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population.

Variation in the gene encoding the cysteine protease calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and > or =50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis > or =50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.

Tomographic features and surgical outcomes of vitreomacular traction syndrome.

PURPOSE: To study the relation between preoperative macular changes and surgical outcomes in vitreomacular traction syndrome. DESIGN: Prospective study. METHODS: We prospectively examined 14 eyes of 13 patients (aged 48 to 82 years; mean 66.1) with vitreomacular traction syndrome using optical coherence tomography (OCT) before and after vitreous surgery. RESULTS: OCT demonstrated two types of partial posterior vitreous detachment: incomplete V-shaped detachment in 10 eyes (group 1) and partial detachment temporal to the fovea but attached nasally in 4 eyes (group 2). Preoperative OCT showed foveal retinal detachment in all eyes in group 1; the detached retina was intact in 2 eyes and edematous with (6 eyes) or without (2 eyes) cystic changes. After surgery, these 10 eyes had a normal foveal configuration accompanied by visual improvement. In group 2, 3 of the 4 eyes had prominent cystoid macular edema (CME) without foveal retinal detachment before surgery. After surgery, 2 eyes developed a full-thickness macular hole, 1 had persistent CME, and 1 developed macular atrophy. The visual acuity decreased in 2 eyes and remained the same in 2 eyes. CONCLUSIONS: Two types of vitreous traction develop in vitreomacular traction syndrome: an incomplete V-shaped posterior vitreous detachment that leads to foveal retinal detachment, the surgical outcome of which is favorable, and partial posterior vitreous detachment temporal to the fovea in which prominent CME developed, which may result in a macular hole or macular atrophy postoperatively.

Leucine fastener formation mechanism between peptide beta-sheets in a monolayer studied by infrared multiple-angle incidence resolution spectroscopy.

A leucine zipper and a leucine fastener formed between peptide molecules have been hypothetical models of a molecular association via interdigitation. As a molecular interaction mechanism, a "leucine zipper" with the aid of an alpha-helix backbone in biological peptides is believed to play an important role in the molecular association, but no experimental evidence to prove the zipping has been reported thus far. In the same fashion, a "leucine fastener" built on the structure of peptide beta-sheets has never been experimentally captured either. In the present study, very fine changes of molecular stress and orientation in monolayers of a synthesized tetraleucine-containing amphiphile before and after the molecular interdigitation have readily been detected by infrared multiple-angle incidence resolution spectroscopy, which was recently developed for the analysis of structural anisotropy in thin materials. It has been suggested that the conventional molecular orientation model of the leucine fastener should be modified, and the backbone structure (parallel beta-sheet in the present study) plays a necessary role for the interlock of the leucine fastener.

Anthropometric, lifestyle and biomarker assessment of Japanese non-professional ultra-marathon runners.

BACKGROUND: Anthropometric characteristics, lifestyle, and baseline biological markers of Japanese non-professional ultra-marathon runners have not been fully assessed. METHODS: We evaluated anthropometric characteristics, lifestyle, and baseline biological markers of 180 Japanese amateur ultra-marathon runners (144 males [mean age: 50.5 +/- 9.4 (standard deviation) years] and 36 females [48.9 +/- 6.9]), and compared them with those of participants in a community heath check-up program and with the figures in the literature. We furthermore evaluated baseline blood indices according to monthly running distance with analysis of variance adjusted for age, body mass index, smoking and alcohol drinking habits. RESULTS: The ultra-marathon runners demonstrated more favorable values for body mass index and bone density, and the proportion of smoking, and undertaking physical activity (for both sexes), eating breakfast (for males), and having daily bowel movements (for females), while greater proportion of alcohol drinking habit (for both sexes), than the comparison group. Average monthly running distances and standard deviations (km) were 257.2 +/- 128.9 for males and 209.0 +/- 86.2 for females. Male runners possessed beneficial markers, including lowered triglyceride and elevated high-density lipoprotein cholesterol, and their values showed hockey-stick (or inverse hockey-stick) patterns depending on their monthly running distance. Some subjects running more than 300 km/month exhibited signs of an over-reaching/training syndrome, including somewhat lowered hemoglobin, ferritin and white blood cell count, and elevated creatine kinase and lactate dehydrogenase. CONCLUSIONS: Together with a desirable lifestyle, Japanese non-professional ultra-marathon runners with vigorous exercise habit demonstrated a preferable health status according to biological indices.