Dynamics of iron metabolism in patients with bloodstream infections: a time-course clinical study.

The close relationship between infectious diseases and iron metabolism is well known, but a more detailed understanding based on current knowledge may provide new insights into the diagnosis and treatment of infectious diseases, considering the growing threat of antibiotic-resistant bacteria. This study investigated adult patients with bloodstream infections, temporal changes, and relationships between blood levels of iron and related markers, including hepcidin and lipocalin-2 (LCN2). We included 144 samples from 48 patients (mean age 72 years, 50% male), with 30 diagnosed with sepsis. During the acute phase of infection, blood levels of hepcidin and LCN2 increased rapidly, whereas iron levels decreased, with values in 95.8% of cases below the normal range (40-188 µg/dL). Later, hepcidin and LCN2 decreased significantly during the recovery phase, and the decreased iron concentrations were restored. In the case of persistent inflammation, iron remained decreased. Acute LCN2 levels were significantly higher in patients with sepsis (p < 0.01). Hypoferremia induced by increased hepcidin would reduce iron in the environment of extracellular pathogens, and the increased LCN2 would inhibit siderophores, resulting in the prevention of the pathogen's iron acquisition in each manner during the acute phase of bloodstream infection.

Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome.

Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS. Clinical data from four Japanese patients with WS revealed significant associations between the decrease of areas of subcutaneous fat and increased insulin resistance measured by the glucose clamp. Adipose-derived stem cells from the stromal vascular fraction derived from WS subcutaneous adipose tissues (WSVF) showed early replicative senescence and a significant increase in the expression of senescence-associated secretory phenotype (SASP) markers. Additionally, adipogenesis and insulin signaling were suppressed in WSVF, and the expression of adipogenesis suppressor genes and SASP-related genes was increased. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of C. elegans. To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.

Quality of life in Werner syndrome and associated subjective foot/ankle symptoms: A cross-sectional survey.

AIM: The aims of this study were to assess the general quality of life and foot/ankle health-related quality of life among subjects with Werner syndrome (WS) and to determine subjective foot/ankle symptoms associated with quality of life. METHODS: Using a questionnaire survey, patients were asked to provide information on age, sex and presence of subjective symptoms and complete both the 36-Item Short Form Health Survey (SF-36) questionnaire and the Self-Administered Foot Evaluation Questionnaire (SAFE-Q). Statistical analyses were performed using Student's t-test, the Mann-Whitney U test, Fisher's exact test and Spearman's rank correlation. RESULTS: Data from 12 patients with an average age of 54 ± 8.6 years were analyzed. The mean SF-36 score for the domain of physical functioning was 21.2; for role-physical function, 32.6; for bodily pain, 38.5; for general health, 34.4; for vitality, 44.8; for social function, 38.5; for role-emotional function and for mental health, 46.7. The mean mental component summary was as high as the national standard, but it was low in men. The mean SAFE-Q scores were also low. Patients with ulcers had significantly more pain and low general health perception. As compared with the national standard, the role/social component score was not low, and there was a correlation in most domains of the SAFE-Q. CONCLUSION: In WS, the general health-related quality of life was low overall in the physical domain and low only in men for the mental domain, whereas it was low in the social domain when foot/ankle health-related quality of life was low. Geriatr Gerontol Int 2023; 23: 188-193.

Factors associated with cytomegalovirus antigenemia in patients with rheumatic disease: A retrospective study.

INTRODUCTION: This study aimed to examine the factors associated with cytomegalovirus (CMV) antigenemia and the time of onset of CMV antigenemia among patients with rheumatic diseases. METHODS: A single-center, retrospective, observational study was conducted in our institution from January 2009 to December 2017. This study included patients with rheumatic diseases who had at least one CMV antigen measurement. Multivariate analysis and receiver operating characteristic analysis was performed. RESULTS: A total of 249 patients underwent CMV antigenemia assay, and 84 (33.7%) patients tested positive. When the association between CMV antigenemia and possible associated factors was investigated, multivariate analysis showed that daily steroid dose increased the odds of having CMV [odds ratio 16.25, 95% confidence interval (CI), 5.360-49.253]. In this study, the cutoff value of daily steroid dose found in this study (0.45 mg/kg/day) was reasonable in clinical practice, and the area under the curve of the steroid dose was 0.838 [95% CI 0.781-0.882], which was the largest of the known indicators. Moreover, the median time from the start of immunosuppressive therapy to the onset of CMV antigenemia was 30 (interquartile range, 21-44) days, and most of the daily steroid users (85.7%) developed CMV antigenemia within 60 days. CONCLUSIONS: The daily steroid dose is the most important factor associated with CMV antigenemia. Therefore, monitoring and treatment strategies based on the steroid dose, especially in the initial 2 months, are important.

The usefulness of a free thinned deep inferior epigastric artery perforator flap and measurement of the vascular pedicle length: A thin flap with a long pedicle.

BACKGROUND: The thinned deep inferior epigastric perforator (DIEP) flap branching from the main trunk to the superolateral direction may be useful because of its long vascular pedicle. DIEP flap is used as an axial-pattern adipose flap. The vascular pedicle length of the thinned DIEP flap was investigated using originally developed software. The clinical application of the thinned DIEP flap was verified in a case series. METHODS: In 40 patients with enhanced computed tomography (CT) data, the vascular pedicle length of the longest thinned DIEP flap was simulated using the software. A free thinned DIEP flap was used in 10 clinical cases of facial or breast reconstruction. RESULTS: In all simulated cases, the vascular pedicle of the DIEP branching to the superolateral direction was the longest, and the vascular pedicle could be lengthened up to 34.8% by dissecting the vessels on the fascia as a vascular pedicle. In all the clinical cases, the reconstruction of a complex form defect or reconstruction requiring a long vascular pedicle could be achieved in one stage without any perioperative complications. The intraclass correlation coefficient between simulated pedicle length and dissected pedicle length was 0.99. CONCLUSION: Thinned DIEP flaps with long vascular pedicles could be elevated safely. Multiple adipose or muscle flaps could be combined without complications. The length of the winding vascular pedicle could be measured using imaging data using the software first developed in the present study. This software would be useful in the planning of a thinned DIEP flap and other free flaps.

Comparison of Vectra three-dimensional stereophotogrammetry measurement and tape measurement in the evaluation of perioperative volume change of the lower abdomen in association with lymphatic microsurgery.

BACKGROUND: Although microsurgical treatment for lower extremity lymphedema (LEL) can improve lower abdominal morphology, methods to evaluate the volume change of the lower abdomen have yet to be established. This study aimed to determine the accuracy and reproducibility of three-dimensional stereophotogrammetry (3DSM) in measuring the volume change in the lower abdomen. METHODS: The perioperative volume changes in the lower abdomen were estimated using tape measurement (TM) and 3DSM in 26 patients with LEL. Thirteen patients with suprapubic lymphedema underwent abdominoplasty simultaneously. Each of them underwent multiple lymphaticovenular anastomoses (LVAs), and five of them underwent vascularized lymph node transfer, simultaneously. Thirteen patients with pelvic lymphatic fluid underwent multiple LVAs. Two patients underwent this surgery twice. When assessed on the Internal Society of Lymphology scale, eight patients were Stage I, 10 patients were Stage II, four patients were late Stage II, and four patients were Stage III. The difference between the two measurement methods and reproducibility of each method were analyzed. RESULTS: During a mean follow-up period of 6 months, all patients had no postoperative complications and their chief complaint improved. The calculated reduction volume between TM and 3DSM showed a high correlation (p < .0001, r = .84). The reduction volume based on TM was significantly larger than 3DSM (991.1 ± 460.3 ml vs. 862.3 ± 333.5 ml, p = .02). The interrater ICC was 0.94 and 0.98 based on TM and 3DSM, respectively. CONCLUSION: 3DSM may be a useful method for assessment of the lower abdominal morphology due to its high accuracy and reproducibility.

Calcification in Werner syndrome associated with lymphatic vessels aging.

In addition to the symptoms of aging, the main symptoms in Werner syndrome (WS), a hereditary premature aging disease, include calcification of subcutaneous tissue with solid pain and refractory skin ulcers. However, the mechanism of calcification in WS remains unclear. In this study, the histological analysis of the skin around the ulcer with calcification revealed an accumulation of calcium phosphate in the lymphatic vessels. Moreover, the morphological comparison with the lymphatic vessels in PAD patients with chronic skin ulcers demonstrated the ongoing lymphatic remodeling in WS patients because of the narrow luminal cross-sectional area (LA) of the lymphatic vessels but the increment of lymphatic microvessels density (MLVD). Additionally, fluorescence immunohistochemical analysis presented the cytoplasmic distribution and the accumulation of WRN proteins in endothelial cells on remodeling lymphatic vessels. In summary, these results point out a relationship between calcification in lymphatic vessels and the remodeling of lymphatic vessels and suggest the significance of the accumulation of WRN mutant proteins as an age-related change in WS patients. Thus, cytoplasmic accumulation of WRN protein can be an indicator of the decreasing drainage function of the lymphatic vessels and the increased risk of skin ulcers and calcification in the lymphatic vessels.

Eyelid Crease Height Affects the Evaluation of Age-related Changes in the Eyelids.

Although the functional and anatomical differences between the left and right eyelids are important in the evaluation of age-related changes in the eyelids, they have not been described clearly as indications for surgical treatments. This study aimed to investigate how laterality of the eyelids affects evaluation of age-related changes. METHODS: Photographs of either one or both eyelids of 100 people were evaluated in four stages by 10 plastic surgeons. To investigate the consistency of the results between evaluations, surgeons evaluated the single-eyelid photographs (group U) or two-eyelid photographs (group B). It was investigated whether the difference in margin reflex distance 1, height of the upper eyelid crease, height of eyebrow, and levator contractile function were associated with mismatched evaluations. RESULTS: The weighted kappa coefficient for groups B and U was 0.77 (substantial agreement). One-point difference in scores was observed in 23 cases. In the multiple logistic regression analysis, only the laterality the height of the eyelid crease was significantly different between patients whose evaluations were matched and those whose evaluations were mismatched (0.9 ± 0.1 mm versus 1.7 ± 0.2 mm; OR = 1.06, 95%CI: 1.01-1.10; P = 0.01). CONCLUSIONS: Besides the structure and function of each eyelid, the laterality of the height of the eyelid crease was important in the evaluation of the age-related changes in the eyelids. This factor may be important in evaluating the aesthetic and visual impressions of age-related changes in the eyelids.

Efficacy of the new ß-D-glucan measurement kit for diagnosing invasive fungal infections, as compared with that of four conventional kits.

BACKGROUND: Each of the currently available (1→3)-ß-D-glucan (BDG) measurement kits follows a different measurement method and cut-off value. Comparisons of diagnostic performance for invasive fungal infections (IFIs) are desirable. Additionally, ecological considerations are becoming increasingly important in the development of new measurement kits. METHODS: The plasma BDG levels in clinical samples were measured using the following currently available kits: the Fungitec G test MKII, the Fungitec G test ES, Fungitell, the ß-Glucan test Wako, and the newly developed Wako kit (Wako-Eu). Wako-Eu uses a pre-treatment solution that conforms to European regulations for the registration, evaluation, authorisation, and restriction of chemicals. The values obtained for the samples using each kit were studied and compared. RESULTS: Of the 165 patients evaluated, 12 had IFIs, including pneumocystis pneumonia, aspergillosis, and candidiasis. BDG values obtained using the kits were moderately correlated with each other. Clinical diagnoses of the evaluated cases indicated that 21 false positives were diagnosed by at least one kit. The sensitivity of the Fungitell kit was relatively low, but those of the other four were over 90%. The specificity was above 90% for all kits. For positive predictive value, the Wako and the Wako-Eu methods were superior to the others owing to fewer false positive results. CONCLUSIONS: The newly developed Wako-Eu method, which considers ecological concerns, shows diagnostic performance equivalent to that of its predecessor. To improve the diagnostic accuracy of IFIs, it is necessary to interpret the results carefully, giving due consideration to the characteristics of each measurement kit.

Epigenetic modifications underlie the differential adipogenic potential of preadipocytes derived from human subcutaneous fat tissue.

Ceiling culture-derived preadipocytes (ccdPAs) and adipose-derived stem cells (ASCs) can be harvested from human subcutaneous fat tissue using the specific gravity method. Both cell types possess a similar spindle shape without lipid droplets. We previously reported that ccdPAs have a higher adipogenic potential than ASCs, even after a 7-wk culture. We performed a genome-wide epigenetic analysis to examine the mechanisms contributing to the adipogenic potential differences between ccdPAs and ASCs. Methylation analysis of cytosines followed by guanine (CpG) using a 450-K BeadChip was performed on human ccdPAs and ASCs isolated from three metabolically healthy females. Chromatin immunoprecipitation sequencing was performed to evaluate trimethylation at lysine 4 of histone 3 (H3K4me3). Unsupervised machine learning using t-distributed stochastic neighbor embedding to interpret 450,000-dimensional methylation assay data showed that the cells were divided into ASC and ccdPA groups. In Kyoto Encyclopedia of Genes and Genomes pathway analysis of 1,543 genes with differential promoter CpG methylation, the peroxisome proliferator-activated receptor (PPAR) and adipocytokine signaling pathways ranked in the top 10 pathways. In the PPARγ gene, H3K4me3 peak levels were higher in ccdPAs than in ASCs, whereas promoter CpG methylation levels were significantly lower in ccdPAs than in ASCs. Similar differences in promoter CpG methylation were also seen in the fatty acid-binding protein 4 and leptin genes. In conclusion, we analyzed the epigenetic status of adipogenesis-related genes as a potential mechanism underlying the differences in adipogenic differentiation capability between ASCs and ccdPAs.

Where does subcutaneous lymph from the chest wall flow into after mastectomy?

BACKGROUND: Changes of the lymph flow from the chest wall after mastectomy and sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (Ax) has yet to be understood. This study aimed to investigate the effect of axillary surgery on lymphatic flow from the chest wall in patients who have undergone mastectomy, including those have undergone breast reconstruction and vascularized lymph node transfer (VLNT). METHODS: Following mastectomy in 100 breasts, the directions of lymph flow from the chest wall was compared between the SLNB omission, SLNB, Ax, and Ax followed by VLNT groups using indocyanine green (ICG) lymphography in cross-sectional study. Lymph flow on the deep epigastric artery perforator (DIEP) flap was also investigated. RESULTS: Lymph flow directing to the ipsilateral axilla was observed more frequently after SLNB than Ax (48% vs. 12.5%; p = 0.005); however, no significant difference was observed in the frequency of contralateral axillary route adoption between them (8% vs. 15%; p = 0.65). In the VLNT group, lymph flow to the ipsilateral axilla was not observed at a significantly higher frequency than in the Ax group (12.5% vs. 12.5%, p = 1.00). On the transferred DIEP flap, the lymph flowed anterograde or retrograde parallel to the anatomic course of the lymphatic vessels. CONCLUSION: To visualize the direction of lymph flow of the chest following mastectomy, ICG lymphography may be useful to discern the direction in which malignant neoplasms, including lymphoma, are transported and to plan for lymph flow restoration.

Fibroblasts from different body parts exhibit distinct phenotypes in adult progeria Werner syndrome.

Werner syndrome (WS), also known as adult progeria, is characterized by accelerated aging symptoms from a young age. Patients with WS experience painful intractable skin ulcers with calcifications in their extremities, subcutaneous lipoatrophy, and sarcopenia. However, there is no significant abnormality in the trunk skin, where the subcutaneous fat relatively accumulates. The cause of such differences between the limbs and trunk is unknown. To investigate the underlying mechanism behind these phenomena, we established and analyzed dermal fibroblasts from the foot and trunk of two WS patients. As a result, WS foot-derived fibroblasts showed decreased proliferative potential compared to that from the trunk, which correlated with the telomere shortening. Transcriptome analysis showed increased expression of genes involved in osteogenesis in the foot fibroblasts, while adipogenic and chondrogenic genes were downregulated in comparison with the trunk. Consistent with these findings, the adipogenic and chondrogenic differentiation capacity was significantly decreased in the foot fibroblasts in vitro. On the other hand, the osteogenic potential was mutually maintained and comparable in the foot and trunk fibroblasts. These distinct phenotypes in the foot and trunk fibroblasts are consistent with the clinical symptoms of WS and may partially explain the underlying mechanism of this disease phenotype.

Correlation of the changes in physical activity and clinical results following lymphatic microsurgery.

BACKGROUND: The physical activity (PA) of patients may change after microsurgical treatment for lower extremity lymphedema (LEL). We investigated whether PA changes perioperatively and whether it influences the treatment result. PATIENTS AND METHODS: Sixty patients with unilateral LEL (56 secondary and 4 primary) underwent lymphatic microsurgeries. Patients were divided into two groups based on improvement in International Physical Activity Questionnaire Short Form (IPAQ-SF) categories; the outcomes were compared. RESULTS: Fifty-three patients in whom linear pattern could be partially observed in indocyanine green lymphography or lymphoscintigraphy underwent lymphaticovenular anastomosis (LVA); seven patients in whom no linear pattern was observed underwent simultaneous LVA and vascularized lymph node transfer. No surgical complication was observed. The median IPAQ-SF score significantly improved from 990 (interquartile range: 231-2,376) to 1,386 (interquartile range: 940.5-4,158; p < .0001). The IPAQ-SF category improved in 22 patients (33.7%), who were categorized into the IPAQ-improved group. Improvement in excess limb volume was significantly larger in the IPAQ-improved group than that in the unimproved group (8.0 ± 4.2 vs. 3.5 ± 2.4%; p < .0001). CONCLUSION: The PA of patients may change after surgical treatment for unilateral LEL. Perioperative improvement in PA significantly correlated with the perioperative change in the excess limb volume. The change in PA is an important factor that might affect the outcome of surgical treatment for LEL. In evaluating the results of microsurgery for lymphedema, it may be necessary to consider changes in PA to avoid bias.

Prevention of venous reflux with full utilization of venoplasty in lymphaticovenular anastomosis.

BACKGROUND: Intraoperative retrograde blood flow from the vein to the lymphatic vessels in lymphaticovenular anastomosis (LVA) for lower extremity lymphedema (LEL) leads to poor results. This study aimed to establish a treatment strategy to control venous reflux in LVA. METHODS: A unified strategy to prevent venous reflux was used in 95 limbs (study group). Dilated perforating veins were ligated, and LVA at the small branch of the ligated vein was considered. External valvuloplasty in the small vein was performed to eliminate venous reflux pre- and post-LVA. A Y-shaped venoplasty for the relatively large vein was considered in cases without adequate-sized vein stump with a functional valve. The results were compared with the 34 limbs undergoing conventional multiple LVAs (control group). RESULTS: Intraoperative venous reflux and postoperative ecchymosis significantly decreased in the study group (0/462 anastomosis vs. 15/148 anastomosis, p < 0.0001 and 0/81 patients vs. 3/25 patients, p = 0.01, respectively). The average frequency of cellulitis during a year following LVA was significantly smaller in the study group than in the control group (0.05 ±â€¯0.03 vs 0.20 ±â€¯0.06, p = 0.04).The amount of improvement in the LEL index a year after LVA was significantly larger in the study group than in the control group (22.2 ±â€¯9.6 vs. 18.3 ±â€¯9.8, p = 0.04). CONCLUSION: Using the new strategy developed in this study, venous reflux could be completely prevented, and stable clinical results were obtained in patients with LEL. Prevention of venous reflux with full utilization of venoplasty might improve the LVA result.

The beneficial effect of traditional Japanese herbal (Kampo) medicine, Hochu-ekki-to (Bu-Zhong-Yi-Qi-Tang), for patients with chronic wounds refractory to conventional therapies: A prospective, randomized trial.

Hochu-ekki-to (HET) is a traditional Japanese herbal (Kampo) medicine for the treatment of severe weakness, loss of appetite, and indigestion in elderly patients and for the prevention of opportunistic infections. The impact of HET on patients with chronic wounds refractory to conventional therapies was investigated in a prospective, randomized trial, including 18 patients divided into medication (7.5 g oral HET per day, n = 9) and control (n = 9) groups. Wound healing during the 12-week study period was scored based on depth, exudate, size, inflammation/infection, granulation tissue, necrotic tissue, and pocket size. At 12 weeks, wound healing progressed in all nine patients in the medication group, whereas wound healing progressed in only three patients in the control group (significant difference, p < 0.01; relative risk: 3.00). In the medication group, the total score decreased significantly at 8 weeks and later. To the best of our knowledge, this study was the first to show that HET promoted the healing of chronic wounds resistant to conventional treatments. HET may be a choice as an adjunctive therapy for chronic wounds, particularly for patients with malnutrition. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000031620).

Intraoperative Detection of Efferent Lymphatic Vessels Emerging from Lymph Node during Lymphatic Microsurgery.

BACKGROUND: Although the usefulness of efferent lymphaticovenular anastomosis (ELVA) in lymphatic microsurgery has been reported, the optimal method to distinguish efferent from afferent lymphatics is not yet established. We propose a novel technique to detect efferent lymphatics appropriate for anastomosis. METHODS: In total, 62 groin lymph nodes (LNs) of 46 limbs were divided into four groups based on the findings of indocyanine green lymphography: n = 15 in normal, 15 in dermal backflow stage 0, 18 in stage I, and 14 in stage II groups. The target LN and afferent lymphatic connecting it were preoperatively detected using ultrasonography. Intraoperatively, 0.05 mL patent blue dye was slowly manually injected from the afferent lymphatic; the lymphatic(s) subsequently stained was diagnosed as the efferent lymphatic(s) emerging from the node. The success rates of efferent lymphatic detection, sizes of LN, and diameter of efferent lymphatics were compared among the groups. RESULTS: Both LN size and diameter of efferent lymphatic were significantly larger in the stage 0 and I groups than the other groups (p < 0.01). Efferent lymphatic could be stained in 13, 13, 18, and 9 LNs in the normal and stage 0, I, and II groups, respectively. A significant difference was observed between the stage I and II groups regarding the success rate of efferent lymphatic detection (p = 0.04). CONCLUSION: Efferent lymphatics could be detected using patent blue dye in 85.5% of the cases. The patients in early-stage lymphostasis might be the most appropriate candidates for ELVA.