Effect of Early Rehabilitation on Walking Independence and Health-Related Quality of Life in Patients With Chronic Foot Wounds: A Multicenter Randomized Clinical Trial.

Rehabilitation is usually provided to patients with chronic foot wounds (CFWs) after surgery. This study aimed to assess whether early postoperative rehabilitation could maintain walking independence in hospitalized patients with CFWs. This single-blind, randomized clinical trial was performed between September 10, 2018 and March 2019, involving 60 patients who underwent both surgical procedures and rehabilitation. Participants were randomly allocated into the early rehabilitation (EG, n = 30) or the control (CG, n = 30) groups. EG received early rehabilitation immediately after surgery, while CG received late rehabilitation after wound closure. Both groups received rehabilitation sessions 5 times per week until discharge. The primary outcome was walking independence, measured via Functional Independence Measure (FIM)-gait scores. Secondary outcomes included health-related quality of life (HRQoL) using EuroQol 5 dimensions 5-level (EQ-5D-5L) and the presence of rehabilitation-related adverse events, including dehiscence of wounds and falls. Differences in intervention timing effects were analyzed using nonparametric split-plot factorial design analysis, including Fisher's exact test, Mann-Whitney U test, and Wilcoxon signed-rank test (P < .05). Out of the 60 participants, 53 patients completed the discharge follow up. Three participants (10.0%) from the EG and 4 (13.3%) from the CG dropped out due to postoperative complications unrelated to rehabilitation intervention. No rehabilitation-related adverse events were found. Participants in the EG maintained greater FIM-gait scores during hospitalization than the CG (difference, -1; P = .0001), with a difference of 0 (P = .109) at discharge. EQ-5D-5L significantly improved in both groups (EG: difference, 0.13 [P = .014], CG: difference, 0.17 [P = .0074]). The EG intervention was associated more with maintaining walking independence at discharge than CG intervention. Postoperative rehabilitation improved HRQoL without adverse events, indicating that clinicians should recommend early rehabilitation for patients with CFW to enhance walking independence.

Effect of Partial Foot Amputation Level on Gait Independence in Patients With Chronic Lower Extremity Wounds: A Retrospective Analysis of a Japanese Multicenter Database.

Partial foot amputation (PFA) is generally planned to minimize the amputation level; nonetheless, the effect of PFA levels on gait independence in amputees remains unclear. This study aimed to investigate the impact of PFA levels of the forefoot on gait independence in patients with chronic lower extremity (LE) wounds. This multicenter retrospective cohort study included 232 hospitalized Japanese patients treated and rehabilitated for chronic LE wounds. A multivariate analysis based on PFA levels was conducted for gait independence at discharge, with age and comorbidities as independent variables. Patients with Lisfranc amputation had significantly less independent gait than patients with more distal amputation and those without amputation (<22% vs >40%; P = .027; Fisher's exact test). Logistic regression analysis revealed that Lisfranc amputation (odds ratio [OR]: 0.257, P = .047), age (OR: 0.559, P = .043), and chronic limb-threatening ischemia (OR: 0.450, P = .010) were independent factors associated with gait independence. Additionally, the regression model confirmed discrimination performance using the C index (0.691, P < .001) with receiver operating characteristic analysis. In patients with chronic LE wounds undergoing PFA, Lisfranc amputation was negatively associated with gait independence.

Effects of streptozotocin-induced diabetes on leg muscle contractile properties and motor neuron morphology in rats.

Skeletal muscle fiber subtypes are differentially sensitive to diabetes-related pathology; For example, fast-twitch muscles exhibit severe decreases in contraction force while slow-twitch muscles demonstrate prolonged half-relaxation time. However, such alterations have only been examined after a relatively short period following diabetes onset, with no information available regarding muscle damage caused by longer disease periods (>20 weeks). This study examined alterations in the contractile properties of the medial gastrocnemius (fast-twitch) and soleus (slow-twitch) muscles, as well as morphological changes in their motor neurons 12 and 22 weeks after diabetes onset. Adult male Wistar rats were divided into diabetic (12- or 22-week post-streptozotocin injection) and age-matched control groups. Electrically evoked maximum twitch and tetanic tension were recorded from leg muscles. Additionally, motor neuron number and cell body size were examined. At 12 weeks after diabetes onset, decreases in twitch force were observed predominantly in medial gastrocnemius muscles, while soleus muscles exhibited prolonged half-relaxation time. However, these differences became ambiguous at 22 weeks, with decreased twitch force and prolonged half-relaxation time observed in both muscles. On the other hand, reduction in soleus motor neurons was observed 12 weeks after diabetes onset, while medial gastrocnemius motor neurons were diminished at 22 weeks. These data indicate that experimental diabetes induces differential damage to medial gastrocnemius and soleus muscles as well as motor neurons. These diabetes-induced differences may partly underlie the differential deficits observed in gastrocnemius and soleus.

Validation of the Risk Score of the Mortality and Lower Limb Loss Considering Ambulatory Status after Surgical Revascularization in Maintaining Patients with Dialysis.

Surgical revascularization is performed to preserve limb and to maintain functional status of patients with critical limb ischemia (CLI). The PREVENT III risk score helps to predict the postoperative course of CLI. However, this score is not available to estimate the risk of amputation or death properly in patients with hemodialysis (HD) and tissue loss (HD: 4 points, Tissue loss: 3 points), because they are classified as a high-risk group. Therefore, we investigated 213 patients with revascularized HD for CLI and proposed prognosis amputation or death for patients with HD risk score (PAD for HD risk score). PAD for HD risk score (non-ambulation: 3 points, ulcer/gangrene: 2 points, GNRI<92: 2 points, CRP>0.3 mg/dl: 1 point, Age≥75: 1 point) is more accurate for the prediction of amputation or death than the PREVENT III risk score (area under the curve [AUC]: 0.79 [95% confidence interval: CI: 0.71-0.87], p<0.01 vs. AUC: 0.63 [95%CI: 0.56-0.71]). The patients were stratified into three groups by total score in ascending order. The rate of 1-year amputation-free survival and independent ambulatory status were significantly different among three groups. PAD for HD risk score is useful for rehabilitation planning in patients with HD and CLI. (This is a translation of J Jpn Coll Angiol 2016; 56: 85-91.).

Passive ankle movement increases cerebral blood oxygenation in the elderly: an experimental study.

BACKGROUND: Ankle exercise has been proven to be an effective intervention to increase venous velocity. However, the efficacy of ankle exercise for improving cerebral circulation has not been determined. We hypothesized that ankle exercise in the supine position would be able to increase oxyhemoglobin levels measured at the forehead. METHODS: Seventeen community-dwelling elderly women participated in this study. We recorded blood pressure, heart rate (HR), and oxyhemoglobin (OxyHb) levels from the participants in the supine position. Participants repeated ankle plantar flexion and dorsiflexion movements for 1 min. Two types of exercise were used: active movement and passive movement. We used two-way analysis of variance to assess the differences in mean arterial blood pressure (MAP), HR, and OxyHb between different exercises (active and passive) and times (before and after exercise). RESULTS: The HR and MAP increased during active exercise but not during passive exercise. On the other hand, the levels of OxyHb measured at the forehead were elevated during both active and passive exercises. This increase lasted at least 1 min after exercise. There was no significant difference between active and passive exercise with regard to OxyHb; however, a significant difference was observed between before and after exercise (p < 0.05, η(2) G = 0.153). CONCLUSIONS: The physiological response of OxyHb to ankle exercise was different from that of the other cardiovascular functions. Both active and passive ankle exercises were able to increase cerebral blood oxygenation, whereas the other cardiovascular functions did not respond to passive exercise.

A retrospective cohort study evaluating efficacy in high-risk patients with chronic lower extremity ulcers treated with negative pressure wound therapy.

The purpose of this study was to evaluate the efficacy of negative pressure wound therapy (NPWT) compared with standard of care on wound healing in high-risk patients with multiple significant comorbidities and chronic lower extremity ulcers (LEUs) across the continuum of care settings. A retrospective cohort study of 'real-world' high-risk patients was conducted using Boston University Medical Center electronic medical records, along with chart abstraction to capture detailed medical history, comorbidities, healing outcomes and ulcer characteristics. A total of 342 patients, 171 NPWT patients with LEUs were matched with 171 non-NPWT patients with respect to age and gender, were included in this cohort from 2002 to 2010. The hazard ratios (HRs) were estimated by COX proportional hazard models after adjusting for potential confounders. The NPWT patients were 2·63 times (95% CI = 1·87-3·70) more likely to achieve wound closure compared with non-NPWT patients. Moreover, incidence of wound closure in NPWT patients were increased in diabetic ulcers (HR = 3·26, 95% CI = 2·21-4·83), arterial ulcers (HR = 2·27, CI = 1·56-3·78) and venous ulcers (HR = 6·31, 95% CI = 1·49-26·6) compared with non-NPWT patients. In addition, wound healing appeared to be positively affected by the timing of NPWT application. Compared with later NPWT users (1 year or later after ulcer onset), early NPWT users (within 3 months after ulcer onset) and intermediate NPWT users (4-12 months after ulcer onset) were 3·38 and 2·18 times more likely to achieve wound healing, respectively. This study showed that despite the greater significant comorbidities, patients receiving NPWT healed faster. Early use of NPWT demonstrated better healing. The longer the interval before intervention is with NPWT, the higher the correlation is with poor outcome.

A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers.

Non-contact low-frequency ultrasound (NCLF-US) devices have been increasingly used for the treatment of chronic non-healing wounds. The appropriate dose for NCLF-US is still in debate. The aims of this pilot study were to evaluate the relationship between dose and duration of treatment for subjects with non-healing diabetic foot ulcers (DFUs) and to explore the correlation between wound healing and change of cytokine/proteinase/growth factor profile. This was a prospective randomised clinical study designed to evaluate subjects with non-healing DFUs for 5 weeks receiving standard of care and/or NCLF-US treatment. Subjects were randomly assigned to one of the three groups: application of NCLF-US thrice per week (Group 1), NCLF-US once per week (Group 2) and the control (Group 3) that received no NCLF-US. All subjects received standard wound care plus offloading for a total of 4 weeks. Percent area reduction (PAR) of each wound compared with baseline was evaluated weekly. Profiles of cytokines/proteinase/growth factors in wound fluid and biopsied tissue were quantified to explore the correlation between wound healing and cytokines/growth factor expression. Twelve DFU patients, 2 (16·7%) type 1 and 10 (83·3%) type 2 diabetics, with an average age of 58 ± 10 years and a total of 12 foot ulcers were enrolled. Average ulcer duration was 36·44 ± 24·78 weeks and the average ABI was 0·91 ± 0·06. Group 1 showed significant wound area reduction at weeks 3, 4 and 5 compared with baseline, with the greatest PAR, 86% (P < 0·05); Groups 2 and 3 showed 25% PAR and 39% PAR, respectively, but there were no statistically significant differences between Groups 2 and 3 over time. Biochemical and histological analyses indicated a trend towards reduction of pro-inflammatory cytokines (IL-6, IL-8, IL-1ß, TNF-α and GM-CSF), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and macrophages in response to NCLF-US consistent with wound reduction, when compared with control group subjects. This proof-of-concept pilot study demonstrates that NCLF-US is effective in treating neuropathic diabetic foot ulcers through, at least in part, inhibiting pro-inflammatory cytokines in chronic wound and improving tissue regeneration. Therapeutic application of NFLU, thrice (3) per week, renders the best wound area reduction.

BNIP-3: a novel candidate for an intrinsic depression-related factor found in NG108-15 cells treated with Hochu-ekki-to, a traditional oriental medicine, or typical antidepressants.

Wakan-yaku is a type of Japanese and Sino traditional, systematized medical care that has been practiced for hundreds of years. To search for novel intrinsic factors related to the action of antidepressants, we used Hochu-ekki-to (HET), a Wakan-yaku medicine with antidepressive effects. First, we verified the quality of the HET by three-dimensional high-performance liquid chromatography and a cytotoxicity check in NG108-15 cells. We performed a DNA microarray analysis of the gene expression in cells treated with 50 micro/ml HET for more than 20 days. HET enhanced the expression of 125 (2.9%) genes and decreased the expression of 255 (6.0%) genes among the 4277 genes that were tested. The concentration-dependent increase in the expression of BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP-3) mRNA was particularly remarkable. A concentration-dependent increase in the expression of BNIP-3 mRNA was also observed when cells were treated with imipramine, mianserin, or milnacipran. These results suggest that BNIP-3 is a candidate for an intrinsic factor related to antidepressive effects and that Wakan-yaku theory may be useful for the identification of other intrinsic functional molecules.

Immersing Feet in Carbon Dioxide-enriched Water Prevents Expansion and Formation of Ischemic Ulcers after Surgical Revascularization in Diabetic Patients with Critical Limb Ischemia.

OBJECTIVE: We investigated the effect of immersion of feet in CO2-enriched water for preventing expansion and formation of ischemic ulcer in critical limb ischemia of diabetic patients after surgical revascularization. MATERIALS AND METHODS: Eligible patients were allocated CO2 group (CO2 immersion plus standard care) or control group (standard care alone) and were followed up for 3 months after surgical revascularization. The end point is defined as an expansion of a target ulcer (more than 101% of original size) or the formation of new ulcers during the follow-up period. RESULTS: Fifty-nine patients out of originally enrolled 66 patients with type II diabetes were included in intention-to-treat population. The cumulative prevention rate for ischemic ulcer after 3 months was 97.1% in the CO2 group, while, in the control group, it was 77.8%, i.e., significantly lower than the CO2 group (P = 0.012, log-rank test). The transcutaneous oxygen pressure increased significantly only in the CO2 group, from 56 ± 14 to 63 ± 15 mmHg (P < 0.01, Wilcoxon signed rank test), in 3 months. CONCLUSION: These results suggest that addition of CO2 immersion to standard care of critical limb ischemia in diabetic patients improves early postoperative outcome after vascular surgery.

The effects of Choto-san on the mRNA expression of Alzheimer's disease related factors in the permanent ischemic rat brain.

Choto-san is a Kampo medicines that has been used clinically for the treatment of dementia. We measured the mRNA expressions of some factors related to Alzheimer's disease in a dementia model rat brain. The expressions of beta-amyloid precursor protein, gamma-secretase, alpha7 nicotinic acetylcholine receptor, neprilysin, and insulin degrading enzyme (IDE) were significantly increased on day 4 after permanent occlusion of the bilateral common carotid arteries (2VO). Choto-san inhibited the enhancement of IDE expression caused by 2VO, although it failed to show any effects on the expressions of the other molecules. These results suggest that Choto-san may produce a state in which it is not necessary to induce IDE expression to demonstrate the anti-dementia effects.

Depletion of lymphocytes, but not neutrophils, via apoptosis in a murine model of Vibrio vulnificus infection.

Vibrio vulnificus causes severe sepsis in humans. There are several reports about the relationship between host immunity and bacterial growth in V. vulnificus infection. However, the effect on leukocytes of V. vulnificus infection in vivo has not been elucidated. A murine model of V. vulnificus infection was used to investigate its effects on leukocytes in this study. Bacteria were recovered from the blood of mice 3 h after subcutaneous injection in the right lower flank. They were detected in 87.5 % (n = 7/8) of mice at 6 h, but this value decreased to 12.5 % (n = 1/8) at 12 h. In contrast, the number of lymphocytes in peripheral blood had already started to decrease at 3 h, and reached a minimum at 6-9 h post-inoculation. Typical DNA laddering, a hallmark of apoptosis, was also detected in thymocytes and splenocytes at 6 and 9 h, and showed a tendency to disappear by 12 h. Although the number of lymphocytes decreased in the model, the numbers of neutrophils did not. These results suggested that V. vulnificus has selective cytotoxicity for lymphocytes in peripheral blood in vivo, and the lymphocyte depletion was probably associated with apoptosis in vivo.

Expression changes of the mRNA of Alzheimer's disease related factors in the permanent ischemic rat brain.

The rat with permanent occlusion of the bilateral common carotid arteries (2VO) is useful model for the study of dementia. The expression changes of amyloid precursor protein (APP), secretase, alpha7 nicotinic acetylcholine receptor (alpha7NicR) and acetylcholine esterase (AChE), which are involved in Alzheimer's disease, were examined by quantitative RT/PCR in this model rat brain. The expression of APP, alpha7NicR and secretase were increased 4 d after 2VO. The alpha7NicR level at 2 d after operation already tended to increase. These result suggest that alpha7NicR expression was enhanced at early stage of brain ischemia. Using this model to find drugs which regulate the alpha7NicR expression will be useful to assay the materials with anti-dementive effect.

Vibrio vulnificus induces macrophage apoptosis in vitro and in vivo.

In this study, we compared the apoptotic activities of clinical and environmental isolates of Vibrio vulnificus toward macrophages in vitro and in vivo. The clinical isolates induced apoptosis in macrophage-like cells in vitro and in macrophages in vivo. This suggests that macrophage apoptosis may be important for the clinical virulence of V. vulnificus.