Usefulness of the predicted percentage ventilatory efficiency for carbon dioxide output during exercise in patients with chronic heart failure.

The ventilatory efficiency for carbon dioxide output ([Formula: see text]CO2) during exercise, as measured by the minute ventilation vs. [Formula: see text]CO2 slope ([Formula: see text]E vs. [Formula: see text]CO2 slope), is a powerful prognostic index in patients with chronic heart failure (CHF). This measurement is higher in women than in men, and it increases with age. This study aimed to investigate the usefulness of the predicted value of the percentage [Formula: see text]E vs. [Formula: see text]CO2 slope (%[Formula: see text]E vs. [Formula: see text]CO2 slope) as a prognostic index in patients with CHF. A total of 320 patients with CHF and a left ventricular ejection fraction (LVEF) < 45% (male, 85.6%; mean age, 64.6 years) who underwent symptom-limited cardiopulmonary exercise tests using a cycle ergometer were included in the study. The %[Formula: see text]E vs. [Formula: see text]CO2 was calculated using predictive formulae based on age and sex. Cardiovascular-related death was defined as the primary endpoint. The mean follow-up duration was 7.5 ± 3.3 years. Of 101 patients who died during the study period, 75 experienced cardiovascular-related deaths. The average [Formula: see text]E vs. [Formula: see text]CO2 slope was 32.8 ± 8.0, and the average %[Formula: see text]E vs. [Formula: see text]CO2 slope was 119.6 ± 28.2%. The cumulative incidence of cardiovascular-related death after 10 years of follow-up were 44.7% (95% CI 34.4-54.6%) in patients with %[Formula: see text]E vs. [Formula: see text]CO2 slope > 120 and 15.0% (95% CI 9.4-21.8%) in patients with %[Formula: see text]E vs. [Formula: see text]CO2 slope ≤ 120. The multivariate Cox regression analysis indicated that a %[Formula: see text]E vs. [Formula: see text]CO2 slope > 120 was an independent predictor of cardiovascular-related death (adjusted hazard ratio, 3.24; 95% confidence interval 1.65-6.67; p < 0.01). The %[Formula: see text]E vs. [Formula: see text]CO2 slope can be used for risk stratification in patients with CHF and an LVEF < 45%.

Age- and sex-stratified normal values for circulatory and ventilatory power during ramp exercise derived from a healthy Japanese population.

Circulatory power (CP) and ventilatory power (VP), obtained by cardiopulmonary exercise testing (CPX), have been suggested to be excellent prognostic markers for heart failure. However, the normal values of these parameters in healthy Japanese populations remain unknown; thus, we aimed to investigate these values in such a population. A total of 391 healthy Japanese participants, 20-78 years of age, underwent CPX with a cycle ergometer with ramp protocols. Systolic blood pressure (SBP), heart rate, oxygen uptake ([Formula: see text]O2) at peak exercise, and the slope of minute ventilation ([Formula: see text]E) versus carbon dioxide ([Formula: see text]CO2) ([Formula: see text]E vs. [Formula: see text]CO2 slope) were measured. CP was calculated by multiplying the peak [Formula: see text]O2 and SBP values, and VP was calculated by dividing the peak SBP value by the [Formula: see text]E versus [Formula: see text]CO2 slope. For males and females, the average CP values were 6119 ± 1280 (mean ± standard deviation) and 4775 ± 914 mmHg·mL/min/kg, respectively (p < 0.001). The average VP values for males and females were 8.0 ± 1.3 and 6.9 ± 1.3 mmHg (p < 0.001). CP decreased with age in both sexes. VP increased with age in females, with no significant change in males. We calculated the normal values for CP and VP in a healthy Japanese population. The results can contribute to the evaluation of patients' CPX results as a reference.

Higher postictal parasympathetic activity following greater ictal heart rate increase in right- than left-sided seizures.

OBJECTIVES: The objectives of this study were to determine how hemispheric laterality of seizure activity influences periictal heart rate variability (HRV) and investigate the ability of HRV parameters to discriminate right- and left-sided seizures. METHODS: Long-term video electroencephalogram-electrocardiogram recordings of 54 focal seizures in 25 patients with focal epilepsy were reviewed. Using linear mixed models, we examined the effect of seizure laterality on linear (standard deviation of R-R intervals [SDNN], root mean square of successive differences [RMSSD], low frequency [LF] and high frequency [HF] power of HRV, and LF/HF) and nonlinear (standard deviation [SD]1, SD2, and SD2/SD1 derived from Poincaré plots) periictal HRV parameters, the magnitude of heart rate (HR) changes, and the onset time of increased HR. Receiver operating characteristics (ROC) were used to determine the ability of these parameters to discriminate between right- and left-sided seizures. RESULTS: Postictal SDNN, RMSSD, LF, HF, SD1, and SD2 were higher in right- than left-sided seizures. Root mean square of successive difference and HF were decreased after left- but not right-sided seizures. Standard deviation of R-R intervals, LF, and SD1 were increased after right- but not left-sided seizures. Increased ictal HR was earlier and larger in right- than left-sided seizures. Postictal HF showed the greatest area under the ROC curve (AUC) (0.87) for discriminating right- and left-sided seizures. CONCLUSIONS: Our data suggest that postictal parasympathetic activity is higher, whereas ictal HR increase is greater, in right- than left-sided seizures. Involvement of the right hemisphere may be associated with postictal autonomic instability. Postictal HRV parameters may provide useful information on hemispheric laterality of seizure activity.

Improvement of nutritional composition and antioxidant capacity of high-amylose wheat during germination.

High-amylose wheat was subjected to various germination conditions and changes in its nutritional values and antioxidant capacity were investigated. Amounts of soluble dietary fiber, total protein and free lipid of germinated high-amylose wheat increased with increased germination times, whereas no significant changes were observed for insoluble dietary fiber and free fatty acids. Total free amino acid contents of high-amylose wheat gradually increased from 129.7 to 314.4 mg/100 g of grain (db) during 48 h of germination. As compared to ungerminated wheat, essential and functional amino acids including isoleucine, leucine, phenylanaline, valine and gamma-amino butyric acid in the 48 h-germinated wheat increased by 3-10 times. Total phenolic contents of both free and bound phenolics and their antioxidant capacities significantly increased after 24 h of germination and were further improved with prolonged germination times. It appears that nutritional values and bioactive compounds of high amylose wheat significantly improved for enhanced food applications.

[A case of mucinous tubular and spindle cell carcinoma of the kidney].

Mucinous tubular and spindle cell carcinoma (MTSCC) is a distinct entity in the World Health Organization classification of kidney tumors since 2004. Herein, we report a case of a patient with MTSCC of the kidney. A 48-year-man visited our hospital with a chief complaint of occult blood in his urine, confirmed by urine occult blood reaction. Computed tomography revealed a solid tumor in the right kidney. The tumor was 40×38 mm in length and was slightly enhanced (cT1aN0M0). Therefore, we performed radical nephrectomy. On analysis of the resected specimen, we found that the number of comparatively small malignant cells had increased markedly, forming branched tubular cuboidal cells. Further more, positive results were obtained on staining the stroma with both PAS and alcian blue stains characteristic of papillary renal cell carcinoma ; however, extracellular mucinous material was found to be depleted. Therefore, we needed to differentiate between papillary renal cell carcinoma and MTSCC. Finally, on the basis of the immunohistochemical staining results-vimentin (＋), CK34ßE12 (-), and CD10 (-)-MTSCC was confirmed.

Potential plasma biomarkers for progression of knee osteoarthritis using glycoproteomic analysis coupled with a 2D-LC-MALDI system.

BACKGROUND: Although osteoarthritis (OA) is a highly prevalent joint disease, to date, no reliable biomarkers have been found for the disease. In this study, we attempted to identify factors the amounts of which significantly change in association with the progression of knee OA. METHODS: A total of 68 subjects with primary knee OA were enrolled in the study. These subjects were followed up over an 18-month period, and plasma and serum samples were obtained together with knee radiographs every 6 months, i.e., 0, 6, 12 and 18 months after the enrollment. Progressors and non-progressors were determined from the changes on radiographs, and plasma samples from those subjects were subjected to N-glycoproteomic 2D-LC-MALDI analysis. MS peaks were identified, and intensities for respective peaks were compared between the progressors and non-progressors to find the peak intensities of which differed significantly between the two groups of subjects. Proteins represented by the chosen peaks were identified by MS/MS analysis. Expression of the identified proteins was evaluated in synovial tissues from 10 OA knee joints by in situ hybridization, western blotting analysis and ELISA. RESULTS: Among the subjects involved in the study, 3 subjects were determined to be progressors, and 6 plasma and serum samples from these subjects were subjected to the analysis together with another 6 samples from the non-progressors. More than 3000 MS peaks were identified by N-glycoproteomic 2D-LC-MALDI analysis. Among them, 4 peaks were found to have significantly different peak intensities between the progressors and non-progressors. MS/MS analysis revealed that these peaks represented clusterin, hemopexin, alpha-1 acid glycoprotein-2, and macrophage stimulating protein, respectively. The expression of these genes in OA synovium was confirmed by in situ hybridization, and for clusterin and hemopexin, by western blotting analysis and ELISA as well. CONCLUSIONS: In this study, 4 potential biomarkers were identified as potential prognostic markers for knee OA through N-glycoproteomic analysis. To the best of our knowledge, this is the first report for the use of glycoproteomic technology in exploring potential biomarkers for knee OA.

Effects of germination on nutritional composition of waxy wheat.

BACKGROUND: Germination is considered to improve the nutritive value, antioxidant capacity and functional properties of grains. In this study, changes in the chemical composition, nutritive value and antioxidant capacity of waxy wheat during germination were determined. RESULTS: Over a 48 h period of germination the protein and free lipid contents of germinated waxy wheat were not significantly different from those of the control, whereas the bound lipid content decreased significantly. An increase in levels of ash and dietary fibre was clearly observed for the 48 h-germinated wheat. The total free amino acid content of the 48 h-germinated wheat was 7881 mg kg⁻¹ flour (dry basis (d.b.)), significantly higher than that of the ungerminated wheat (2207 mg kg⁻¹ flour, d.b.). In particular, γ-aminobutyric acid increased from 84 mg kg⁻¹ flour (d.b.) in the control to 155 mg kg⁻¹ flour (d.b.) in the 48 h-germinated wheat. Germination did not significantly affect the fatty acid composition of both free and bound lipids of waxy wheat, whereas free phenolic compounds increased during germination, resulting in an increase in antioxidant capacity of germinated wheat. CONCLUSION: Germinated waxy wheat had a better nutritional composition, such as higher dietary fibre, free amino acid and total phenolic compound contents, than ungerminated waxy wheat. Therefore germinated waxy wheat should be used to improve the nutritional quality of cereal-based products.

[A case of vesical endometriosis that worsened during the early pregnancy period].

We report a case of vesical endometriosis that worsened during the early pregnancy period. A 37-year old woman had been under treatment for endometriosis (including vesical endometriosis) by a gynecologist during the past 10 years. She was treated for sterility 1 year ago, and became pregnant through in vitro fertilization. In her 8th gestational week, she complained of gross hematuria at our hospital. Cystoscopic findings revealed some tumors that appeared worse than the last findings two years ago. In order to deny malignancy, transurethral resection of the bladder tumor was performed in her 12th gestational week. The pathologic diagnosis was endometriosis. She was able to stay pregnant, and delivered a girl. After delivery, cystoscopic findings revealed reduction of tumors. In most cases pregnancy cures endometriosis ; however, in this case symptoms became worse during the early stage of pregnancy. The reason for this contrary event is discussed.

Distinguishing between Cl- and O2(2-) as the bridging element between Fe3+ and Cu2+ in resting-oxidized cytochrome c oxidase.

Fully oxidized cytochrome c oxidase (CcO) under enzymatic turnover is capable of pumping protons, while fully oxidized CcO as isolated is not able to do so upon one-electron reduction. The functional difference is expected to be a consequence of structural differences: [Fe(3+)-OH(-)] under enzymatic turnover versus [Fe(3+)-O(2)(2-)-Cu(2+)] for the as-isolated CcO. However, the electron density for O(2)(2-) is equally assignable to Cl(-). An anomalous dispersion analysis was performed in order to conclusively demonstrate the absence of Cl(-) between the Fe(3+) and Cu(2+). Thus, the peroxide moiety receives electron equivalents from cytochrome c without affecting the oxidation states of the metal sites. The metal-site reduction is coupled to the proton pump.

[Efficacy and safety of imidafenacin in female patients with urge and mixed urinary incontinence].

The effect of imidafenacin for the treatment of overactive bladder (OAB), in female patients with urge and mixed urinary incontinence was examined. Prior to administration and at 1, 2, 3, 4, 6, 8, 10 and 12 weeks after administration, symptoms and quality of life were assessed using the overactive bladder symptom score (OABSS) and the international consultation on incontinence questionnaire-short form (ICIQ-SF), respectively. After administration, OABSS and ICIQ-SF scores were improved significantly when compared to baseline values. The incidence of adverse events was 7. 9% and none were serious. Imidafenacin was effective in female patients with urge and mixed urinary incontinence. In addition, imidafenacin rapidly improved incontinence one week after administration.

A novel surgical treatment for labial adhesion - The combination of Z- and Y-V-plasty: A case report.

Labial adhesion is characterised by complete or partial fusion of the labia minora. It occurs rarely in postmenopausal women. Although various methods have been proposed, there is no established treatment for postmenopausal patients with labial adhesions due to its low prevalence in this age group. Severe cases require surgical intervention, and the postoperative recurrence rate is relatively high at 14-20%. In this study, a novel therapeutic method was designed to treat labial adhesions: a combination of Z- and Y-V-plasty. An 82-year-old woman was diagnosed with severe long labial adhesion during an episode of urinary tract infection. The labia could not be separated manually; hence, Z-plasty was performed on the ventral side and Y-V-plasty on the anal side under general anaesthesia. No recurrence was noted eight months postoperatively. This method is relatively easy and produced the desired therapeutic effect with decreased risk of recurrence. This is a novel approach for postmenopausal patients with severe labial adhesion.

Paroxysmal sympathetic hyperactivity and the later development of epilepsy in a chemotherapy-associated brain damage.

BACKGROUND: Chemotherapy in childhood leukemia potentially induces brain lesions and neurological sequelae. Paroxysmal sympathetic hyperactivity (PSH) is known as a treatment-associated complication; however, the full clinical spectra of PSH remain to be elusive. CASE REPORT: A 5-year-old girl was diagnosed of acute myeloid leukemia (AML) M5. After the intensification therapy, she developed recurrent symptoms of episodic tachycardia, hypertension and perspiration lasting for several hours per day. The low-frequency-high-frequency ratio on Holter electrocardiography was rapidly increased from 0.84 to 2.24 at the onset of the paroxysmal event, whereas the video-monitoring electroencephalography (EEG) never identified ictal patterns of epileptiform discharges during the episodes. Thus, the diagnosis of PSH was given at 7 years of age. Myoclonic and generalized tonic-clonic seizures frequently appeared from 10 years of age, which poorly responded to anticonvulsants. EEG showed diffuse slow-wave bursts with multifocal spikes. Serial head magnetic resonance imaging (MRI) revealed diffuse cerebral and hippocampal atrophy, but not inflammatory lesions in the limbic system. CONCLUSION: We first demonstrate a pediatric case with PSH who developed drug-resistant epilepsy 3 years after the onset of PSH. Our data suggest the pathophysiological link of persistent PSH with chemotherapy-associated brain damage.

Ventilatory efficiency during ramp exercise in relation to age and sex in a healthy Japanese population.

BACKGROUND: The current understanding of ventilator efficiency variables during ramp exercise testing in the normal Japanese population is insufficient, and the responses of tidal volume (VT) and minute ventilation (V̇E) to the ramp exercise test in the normal Japanese population are not known. METHODS: A total of 529 healthy Japanese subjects aged 20-78 years underwent cardiopulmonary exercise testing using a cycle ergometer with ramp protocols. VT and V̇E at rest, at anaerobic threshold, and at peak exercise were determined. The slope of V̇E versus carbon dioxide (V̇CO2) (V̇E vs. V̇CO2 slope), minimum V̇E/V̇CO2, and oxygen uptake efficiency slope (OUES) were determined. RESULTS: For males and females in their 20 s, peak VT (VTpeak) was 2192 ± 376 and 1509 ± 260 mL (p < 0.001), peak V̇E (V̇Epeak) was 80.6 ± 18.7 and 57.7 ± 13.9 L/min (sex differences p < 0.001), the V̇E vs. V̇CO2 slope was 24.4 ± 3.2 and 25.7 ± 3.2 (p = 0.035), the minimum V̇E/V̇CO2 was 24.2 ± 2.3 and 27.0 ± 2.8 (p < 0.001), and the OUES was 2452 ± 519 and 1991 ± 315 (p < 0.001), respectively. VTpeak and V̇Epeak decreased with age and increased with weight and height. The V̇E vs. V̇CO2 slope and minimum V̇E/V̇CO2 increased with age, while conversely, the OUES decreased with age. CONCLUSIONS: We have established the normal range of VT and V̇E responses, the V̇E vs. V̇CO2 slope, the minimum V̇E/V̇CO2, and the OUES for a healthy Japanese population. Some of these parameters were influenced by weight, height, sex, and age. These results provide useful reference values for interpreting the results of cardiopulmonary exercise testing in cardiac patients.

Poor pregnancy outcome following assisted reproductive technology among women operated on for bilateral endometriomas.

Purpose: To determine the first line of infertility treatment for managing patients with unilateral or bilateral ovarian endometriomas. Methods: We evaluated pregnancy outcome in patients who had received ovarian surgery for unilateral (Group U, n = 47) or bilateral endometriomas (Group B, n = 38) and aspiration with or without alcohol fixation for unilateral (Group u, n = 37) or bilateral endometriomas (Group b, n = 22). Subsequently, 64 of these women, excluding 29 dropouts, underwent assisted reproductive technology. We compared the clinical pregnancy rates of the four groups. Results: The cumulative pregnancy rate after operation of Group B (18%) was significantly lower than that of a cyst-free control group (n = 143; 44%) and Group U (43%). Group B had fewer oocytes fertilized during ART than did Group b (P < 0.005) and fewer blastocysts available for transfer (P < 0.005). The cumulative pregnancy rate of Group B was also lower than in Group b (P = 0.052). Conclusions: Pregnancy outcomes of Group B were not better than for Group b. Therefore, encouraging such women to move directly to ART might help avoid ovarian damage and improve their ability to achieve a pregnancy.

[Limbic encephalitis in the course of testicular lymphoma].

The malignant tumor patient tends to develop various neuropathy by direct invasion, metastasis, secondary infectious disease of tumor, metabolic disorders, vascular damage and adverse drug reactions with a treatment, and, however, it rarely appear by mechanism of autoimmunization. Tumor tissue with paraneoplastic neurological syndrome (PNS) produces an antigen attacking nerve tissue by it's cross reaction, and many studies indicates that there are a few kinds of antineuritic antibodies occurred by the charactor of malignant diseases or the patterns of progression. There is no relationship between the symptoms and the progression of disease. We report a case of malignant testicular tumor presented the paraneoplastic limbic encephalitis which is one of paraneoplastic neurological syndrome.

Changes in oxygen uptake kinetics after exercise caused by differences in loading pattern and exercise intensity.

AIMS: The kinetics of recovery-period oxygen uptake (VO2 ) are affected by the O2 deficit generated during exercise. However, studies using ramp tests (RTs) and constant work rate tests (CT) have differently characterized VO2 responses to increased exercise intensity differently. We used these two types of loading patterns to investigate the effects of low-intensity, medium-intensity, and high-intensity exercises on the half time (T1/2 ) of recovery-period VO2 and the mechanism. METHODS AND RESULTS: Ten healthy men aged 21.2 ± 0.9 years underwent symptom-limited cardiopulmonary exercise tests with the ramp protocol to determine their anaerobic threshold. All subjects subsequently underwent three submaximal RT and CT at low, moderate, and high intensities. In all RTs, subjects began exercise by warming up (20 W). In CT, T1/2 was significantly lengthened as exercise intensity increased (CT-low: 34.0 ± 3.9 s, CT-moderate: 39.5 ± 3.5 s, CT-high:44.6 ± 4.2 s; P < 0.01, ANOVA), whereas no significant change was observed in RT, which began with the same work rate (RT-low: 46.0 ± 5.7 s, RT-moderate: 45.7 ± 4.8 s, RT-high: 44.6 ± 3.5 s, RT-max: 44.8 ± 3.2 s; P = 0.868, ANOVA). Only high-intensity exercise resulted in two components (the fast and slow components) of VO2 decay, reflecting the increased O2 deficit by anaerobic metabolism. CONCLUSIONS: The exercise intensity at the beginning of an exercise affects early recovery-period VO2 , which is a fast component. The T1/2 of recovery-period VO2 occurs during the fast component, and an increase in O2 deficit affects both the fast and slow components, lengthening the T1/2 . The T1/2 of recovery-period VO2 in CT at moderate or high intensities, even if not symptom limited, can be used to evaluate exercise intolerance and early occurrence of anaerobic metabolism. Submaximal exercise tests may be considered as convenient methods for evaluating exercise tolerance in patients with cardiac failure.

The interaction of monocytes with rheumatoid synovial cells is a key step in LIGHT-mediated inflammatory bone destruction.

Formation of osteoclasts and consequent joint destruction are hallmarks of rheumatoid arthritis (RA). Here we show that LIGHT, a member of the tumour necrosis factor (TNF) superfamily, induced the differentiation into tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) of CD14(+) monocytes cocultured with nurse-like cells isolated from RA synovium, but not of freshly isolated CD14(+) monocytes. Receptor activator of nuclear factor-kappaB ligand (RANKL) enhanced this LIGHT-induced generation of TRAP-positive MNCs. The MNCs showed the phenotypical and functional characteristics of osteoclasts; they showed the expression of osteoclast markers such as cathepsin K, actin-ring formation, and the ability to resorb bone. Moreover, the MNCs expressed both matrix metalloproteinase 9 (MMP-9) and MMP-12, but the latter was not expressed in osteoclasts induced from CD14(+) monocytes by RANKL. Immunohistochemical analysis showed that the MMP-12-producing MNCs were present in the erosive areas of joints in RA, but not in the affected joints of osteoarthritic patients. These findings suggested that LIGHT might be involved in the progression of inflammatory bone destruction in RA, and that osteoclast progenitors might become competent for LIGHT-mediated osteoclastogenesis via interactions with synoviocyte-like nurse-like cells.

Arthritis and pneumonitis produced by the same T cell clones from mice with spontaneous autoimmune arthritis.

SKG mice, a newly established model of rheumatoid arthritis (RA), spontaneously develop autoimmune arthritis accompanying extra-articular manifestations, such as interstitial pneumonitis. To examine possible roles of T cells for mediating this systemic autoimmunity, we generated T cell clones from arthritic joints of SKG mice. Two distinct CD8(+) clones were established and both showed in vitro autoreactivity by killing syngeneic synovial cells and a variety of MHC-matched cell lines. Transfer of each clone to histocompatible athymic nude mice elicited joint swelling and histologically evident synovitis accompanying the destruction of adjacent cartilage and bone. Notably, the transfer also produced diffuse severe interstitial pneumonitis. Clone-specific TCR gene messages in the inflamed joints and lungs of the recipients gradually diminished, becoming hardly detectable in 6-11 months; yet, arthritis and pneumonitis continued to progress. Thus, the same CD8(+) T cell clones from arthritic lesions of SKG mice can elicit both synovitis and pneumonitis, which chronically progress and apparently become less T cell dependent in a later phase. The results provide clues to our understanding of how self-reactive T cells cause both articular and extra-articular lesions in RA as a systemic autoimmune disease.

Liang Bua Homo floresiensis mandibles and mandibular teeth: a contribution to the comparative morphology of a new hominin species.

In 2004, a new hominin species, Homo floresiensis, was described from Late Pleistocene cave deposits at Liang Bua, Flores. H. floresiensis was remarkable for its small body-size, endocranial volume in the chimpanzee range, limb proportions and skeletal robusticity similar to Pliocene Australopithecus, and a skeletal morphology with a distinctive combination of symplesiomorphic, derived, and unique traits. Critics of H. floresiensis as a novel species have argued that the Pleistocene skeletons from Liang Bua either fall within the range of living Australomelanesians, exhibit the attributes of growth disorders found in modern humans, or a combination of both. Here we describe the morphology of the LB1, LB2, and LB6 mandibles and mandibular teeth from Liang Bua. Morphological and metrical comparisons of the mandibles demonstrate that they share a distinctive suite of traits that place them outside both the H. sapiens and H. erectus ranges of variation. While having the derived molar size of later Homo, the symphyseal, corpus, ramus, and premolar morphologies share similarities with both Australopithecus and early Homo. When the mandibles are considered with the existing evidence for cranial and postcranial anatomy, limb proportions, and the functional anatomy of the wrist and shoulder, they are in many respects closer to African early Homo or Australopithecus than to later Homo. Taken together, this evidence suggests that the ancestors of H. floresiensis left Africa before the evolution of H. erectus, as defined by the Dmanisi and East African evidence.