Insulin-like growth factor 2 mRNA-binding protein 3 enhanced melanoma migration through regulation of AKT1 and RELA expression.

IMP-3 expression is a poor prognostic factor of melanomas and it promotes melanoma cell migration and invasion by a pathway modulating HMGA2 mRNA expression. We tried to identify other putative targets of IMP-3. We identified putative IMP-3-binding RNAs, including AKT1, MAPK3, RB1 and RELA, by RNA immunoprecipitation coupled with next-generation sequencing. IMP-3 overexpression increased AKT and RELA levels in MeWo cells. siRNAs against AKT1 and RELA inhibited MeWo/Full-length IMP-3 cell migration. IMP-3 knockdown of A2058 cells decreased AKT1 and RELA expression and lowered migration ability. Co-transfection of A2058 cells with AKT1- or RELA-expressing plasmids with IMP-3 siRNA restored the inhibitory effects of IMP-3 knockdown on migration. HMGA2 did not influence AKT1 and RELA expression in melanoma cells. Human melanoma samples with high IMP-3 levels also showed high HMGA2, AKT1 and RELA expression. Our results show that IMP-3 enhances melanoma cell migration through the regulation of the AKT1 and RELA axis.

Surgical outcomes of hidradenitis suppurativa: evaluating factors influencing recurrence and complications after 284 complete excisions.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disorder associated with tunnel formation and scarring. Surgical excision is a potential curative therapy for HS. OBJECTIVES: To characterize the surgical outcomes of patients with HS undergoing complete excision and to identify the risk factors associated with postoperative recurrence. METHODS: This retrospective 16-year cohort study enrolled patients 20 years or older who underwent complete excision for HS lesions at the National Taiwan University Hospital. We assessed the rates of postsurgical recurrence and complications, and estimated the odds ratio (ORs) with 95% confidence intervals (CIs) of their association with potential risk factors using generalized estimating equations. RESULTS: In total, 136 patients with HS and the 284 corresponding complete excisions were identified. Recurrence developed in 88 (31.0%) operations, while complications occurred in 102 (35.9%). Common types of complications included wound dehiscence, hypertrophic scars, and surgical site infection. Clinical factors associated with a lower risk of recurrence were male sex (aOR, 0.48; 95% CI, 0.23-0.98), operation at atypical locations (aOR, 0.28; 95% CI, 0.08-0.99), and wound repair by split-thickness skin graft (aOR, 0.31; 95% CI, 0.12-0.77). Wound dehiscence was associated with an increased risk of recurrence (aOR, 2.55; 95% CI, 1.21-5.42). No independent factors were identified as being associated with composite postoperative complications. CONCLUSIONS: Complete excision alone is effective in curing HS in Asians. Recurrence developed in about one-third of the complete excisions performed for HS. Sex, operative locations, methods of wound repair, and wound dehiscence were major determinants for recurrence.

Optical Effects of Focused Fractional Nanosecond 1064-nm Nd:YAG Laser: Techniques of Application on Human Skin.

BACKGROUND AND OBJECTIVES: Considering the pulse widths of picosecond and nanosecond lasers used in cutaneous laser surgery differ by approximately one order of magnitude, can nanosecond lasers produce the optical effect in human skin similar to laser-induced optical breakdown (LIOB) caused by picosecond lasers? METHODS: Cutaneous changes induced by a focused fractional nanosecond 1064-nm Nd:YAG laser were evaluated by VISIA-CR imaging, histological examination, and harmonic generation microscopy (HGM). RESULTS: A focused fractional nanosecond 1064-nm Nd:YAG laser can generate epidermal vacuoles or dermal cavities similar to the phenomenon of LIOB produced by picosecond lasers. The location and extent of photodisruption can be controlled by the laser fluence and focus depth. Moreover, laser-induced shock wave propagation and thermal degeneration of papillary collagen can be observed by HGM imaging. CONCLUSION: Focused fractional nanosecond lasers can produce an optical effect on human skin similar to LIOB caused by picosecond lasers. With techniques of application, the treatment can induce epidermal and dermal repair mechanisms in a tunable fashion to improve skin texture, wrinkles, scars, and dyspigmentation, without disrupting the epidermal surface.

Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blind randomized placebo-controlled trial.

BACKGROUND: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. OBJECTIVES: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation. METHODS: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time. RESULTS: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%). CONCLUSIONS: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.

Characterization of picosecond laser-induced optical breakdown using harmonic generation microscopy.

BACKGROUND AND OBJECTIVES: By creating microinjuries usually confined to the epidermis, a fractional picosecond 1064-nm Nd:YAG laser that delivers an array of highly focused beamlets can be effectively used for facial rejuvenation or resurfacing. However, the mechanism of dermal remodeling underlying this nonablative treatment remains unclear. METHODS: Five participants having skin phototype III-IV were recruited for intervention using a fractional picosecond 1064-nm Nd:YAG laser system equipped with a holographic diffractive beam-splitting optic. The laser-induced histopathological changes on human skin were examined in vivo using a harmonic generation microscopy (HGM), visualizing second harmonic generation (SHG), and third harmonic generation (THG) contrasts dichromatically. SHG refers for collagen distribution, while THG represents for epidermal components in the HGM signal. RESULTS: Histological hematoxylin and eosin staining and in vivo HGM imaging studies revealed the presence of epidermal vacuoles below the stratum granulosum along with keratinocyte degeneration or cytolysis. In addition to the epidermal vacuoles, HGM imaging exclusively demonstrated laser-induced shock wave propagation arranged as a THG-bright concentric pattern in the epidermis and loss of SHG signals in the papillary dermis immediately beneath the epidermal vacuoles. CONCLUSIONS: Alongside generating epidermal vacuoles, the fractional picosecond 1064-nm Nd:YAG laser induced collagen changes. These collagen changes may lead to dermal remodeling and neocollagenesis underlying the fractional picosecond laser treatment.

Anatomic mapping of acral melanocytic nevi and acral lentiginous melanomas among Taiwanese patients: A retrospective cohort study.

BACKGROUND: The early diagnosis of acral lentiginous melanoma (ALM) contributes to clinical outcomes since ALM can be mistaken for acral melanocytic nevus (AMN). ALM occurrence is reported to correlate with stress-bearing areas, which may assist in differential diagnoses. Our objective is to evaluate the distribution patterns of ALMs and AMNs on the palms and soles among Taiwanese patients. METHODS: A retrospective analysis was performed by reviewing the charts of 1400 patients diagnosed with benign and malignant pigmented lesions confirmed after excisional biopsy at our institution between 2000 and 2022 in Taiwan. Correlations between lesions and clinicopathological factors were analyzed. RESULTS: 309 AMNs and 177 ALMs were included. Mechanical stress was significantly associated with plantar ALMs (weight-bearing area: 92.65 %, arch: 7.35 %, P < 0.001). Significant differences in the distribution patterns were observed for plantar ALMs compared with all AMNs (P < 0.001) and non-atypical AMNs (P < 0.001), but were not observed between palmar AMNs and ALMs. CONCLUSION: Plantar ALMs were most commonly observed on the weight-bearing areas of the soles, distinct from the distribution of all AMNs and of non-atypical AMNs. The distribution features and anatomic mapping of ALMs may facilitate the early clinical diagnosis of ALM.

Taiwanese Dermatological Association (TDA) consensus recommendations for the definition, classification, diagnosis, and management of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory follicular disease characterized by painful, recurrent, inflamed lesions most commonly occurring in the axillary, inguinal, and anogenital regions. HS can inflict immense physical and psychological impact on patients who suffer from this distressing disease. Management of HS generally requires combining various medical and procedural treatment modalities; however, the disease is often recalcitrant to conventional treatments. In light of recent evidence supporting the effectiveness of biologic agents in the treatment of HS, the Taiwanese Dermatological Association established an expert panel of nine dermatologists to develop consensus statements aimed to provide up-to-date evidence-based guidance in optimizing HS patient management in Taiwan. The recommendations described in the statements were summarized in a management algorithm in terms of general care, topical treatment, systemic treatment, and procedural treatment.

Clinicopathological characteristics and prognosis in significantly thick acral lentiginous melanoma in Taiwan.

This retrospective cohort study enrolled 385 patients diagnosed with cutaneous melanoma from 1980 to 2021 in National Taiwan University Hospital (NTUH). The aim of this study was to investigate the relationship between thickness of primary melanoma lesions and disease outcome of melanoma patients, in particular, those diagnosed with acral lentiginous melanoma (ALM). The association between important clinicopathological characteristics other than tumor thickness and disease outcome was also analyzed. Survival analyses with the Kaplan-Meier method were utilized to investigate the prognoses of patients with different lesion thickness. The male-to-female ratio was 1.12:1. The median age at diagnosis was 63 years old (mean: 62.2 years). There were 283 cases (73.5%) of acral lentiginous melanoma (ALM) with a male-to-female ratio of 1.04:1. Between patients with primary ALM lesions 4.1 millimeters (mm) to 8.0 mm thick and those with lesions over 8.0 mm thick, significant differences in prognostic outcomes including incidence of second recurrences within 1 year (raw p = 0.003, Bonferroni corrected p = 0.009) and distant metastases within 1 year (raw p = 0.003, Bonferroni corrected p = 0.008), were observed. Significantly worse 1-year (raw p = 0.01, Bonferroni corrected p=0.03) and 2-year survival (raw p = 0.006, Bonferroni corrected p = 0.02) were found in ALM patients with lesions of over 8 mm thick than those with lesions 4.1 mm to 8.0 mm at diagnosis. Vigilant short-term follow-up is warranted in ALM patients with lesions of over 8.0 mm thick at diagnosis due to higher risks of adverse outcome.

Risk factors for lymphatic and hematogenous metastasis after diagnosis of cutaneous Melanoma in Taiwan.

BACKGROUND: Risk factors of lymphatic and hematogenous metastasis in cutaneous melanoma remained unclear in Asian population. This study aimed to identify clinical and histopathological factors to predict metastatic pathways in cutaneous melanoma in Taiwan. METHODS: A total of 247 patients diagnosed as stage I and II melanoma, followed at National Taiwan University Hospital were included in this retrospective study from 1980 to 2020. Kaplan-Meier curves and Cox proportional hazards regression were utilized to identify risk factors. RESULTS: During a median follow-up of 143 months, 48 (19.4%) and 62 (25.1%) patients developed lymphatic and hematogenous metastasis respectively. In the univariate analysis, age> 70 years, greater Breslow thickness, ulceration, neurotropism, and NRAS mutation were significant risk factors for lymphatic metastasis in all subtypes of melanoma. Age >70 years, head and neck location, thickness, ulceration, higher mitotic rate, neurotropism, and NRAS mutation were significant predictors of hematogenous metastasis in all subtypes. In the multivariate analysis, greater thickness (HR for 2.0-4.0 mm, 4.5; p = .009 and HR for >4.0 mm, 5.7; p = .003) retained its significance as an independent risk factor for lymphatic metastasis in all subtypes of melanoma. Thickness (HR for >4.0 mm, 5.7; p < .001) and ulceration (HR, 2.5; p = .001) were independent risk factors for hematogenous metastasis. CONCLUSION: Risk factors of metastasis not only differ between lymphatic and hematogenous pathways, but also differ between ethnics and melanoma subtypes. Better understanding the behavior of cutaneous melanoma may help guide further treatments and follow-up plans.

The additive efficacy of therapeutic low-intensity pulsed ultrasound in the treatment of vitiligo: A randomized, left-right comparison clinical trial.

Repigmentation of vitiligo relies on the proliferation and migration of melanoblasts from hair follicles to the epidermis to replenish epidermal melanin. Our previous study has demonstrated low-intensity pulsed ultrasound (LIPUS) can stimulate melanoblast migration in vitro. We sought to evaluate the potential additive efficacy and safety of LIPUS for repigmentation of vitiligo. Twenty-seven adult patients with stable generalized vitiligo on the face or trunk were recruited in this randomized, open, left-right comparison study. In each patient, two symmetric lesional sites were randomly selected; one was assigned as the target lesion, which was treated with add-on LIPUS twice weekly for 24 weeks, and the other as the control lesion, which was administrated with sham sonification. The primary outcome was the difference of repigmentation degree between the target and control lesions at week 24, based on the 7-point physician global assessment score. At the end of study, 23 patients with vitiligo on the face (n = 10) or trunk (n = 13) completed the 24-week treatment course. Enhanced repigmentation for vitiligo receiving LIPUS as compared to sham sonification was observed in 38.5% (5/13) of the patients with truncal vitiligo, but none of those with facial vitiligo. Truncal vitiligo (P = .046) and higher intensity of LIPUS administered (P = .01) were statistically significantly associated with the effectiveness of additive LIPUS treatment. The LIPUS treatment was well-tolerated without remarkable adverse effects. This pilot study showed that LIPUS could provide therapeutic benefits and could be considered as a treatment adjunct for truncal vitiligo.

Presence of intralesional melanocytes as a histopathological feature of actinic keratosis based on in vivo harmonic generation microscopy in Asians.

BACKGROUND: Most patients with actinic keratosis (AK) present with more than one lesion. Although histopathological examination is the gold standard for diagnosing this condition, performing an invasive skin biopsy for each AK is impractical. Thus, this study aimed to identify AK's morphological characteristics based on harmonic generation microscopy (HGM). Moreover, the correlation between features observed using HGM and histopathological grading of AK was examined. METHODS: Lesions of seven patients were examined using HGM (n = 1, ex vivo and n = 6, in vivo), and histopathological examinations of the biopsy specimens were also performed. The features of each AK, based on HGM, were assessed and compared with corresponding standard histopathological findings. RESULTS: Using the histopathological findings as a standard reference, HGM's accuracy in detecting features of AK lesions, such as hyperkeratosis, epidermal thinning, abnormal architecture, and atypical honeycomb pattern, was 100%. Approximately five (72%) patients had similar histopathological grades. Moreover, based on HGM, except for one patient with grade 1 AK, six (85.71%) patients had lesions with intraepidermal dendritic cell-like cells, representing melanocytes. CONCLUSION: Harmonic generation microscopy can be used in vivo to provide critical diagnostic information with a resolution comparable to histopathological examination. In addition, intralesional melanocytes in AK, which may be correlated with disease severity, can be specifically enhanced using HGM.

Pulmonary hospitalizations and ischemic heart disease events in patients with peripheral artery disease.

The prognostic significance of acute pulmonary events in people with lower extremity peripheral artery disease (PAD) is unknown. We hypothesized that an acute pulmonary event (hospitalization for pneumonia and/or chronic lower respiratory disease (CLRD) exacerbation) would be associated with a higher rate of subsequent ischemic heart disease (IHD) events in PAD. A total of 569 PAD participants were systematically identified from among patients in Chicago medical practices and followed longitudinally. Hospitalizations after enrollment were evaluated and adjudicated for pulmonary events. The primary outcome was adjudicated myocardial infarctions, unstable angina, and IHD death. Of 569 PAD participants, 34 (6.0%) were hospitalized for a pulmonary event (11 CLRD exacerbation and 23 pneumonia) during a mean follow-up of 1.52 years±0.80. Participants hospitalized for a pulmonary event had a higher rate of subsequent IHD events than those not hospitalized for a pulmonary event (10/34 (29%) vs 38/535 (7.1%), p<0.001). After adjusting for age, sex, race, comorbidities, and other confounders, a pulmonary hospitalization was associated with an increased risk of a subsequent IHD event (hazard ratio (HR) = 12.42, 95% confidence interval (CI) = 5.35 to 28.86, p<0.001). Non-pulmonary hospitalizations were also associated with IHD events (HR = 3.39, 95% CI = 1.78 to 6.44, p<0.001), but this association was less strong compared to pulmonary hospitalizations and IHD events ( p = 0.011 for difference in the strength of association). In conclusion, hospitalization for an acute pulmonary event was associated with higher risk for subsequent IHD events in PAD. Future study should examine whether hospitalization for pulmonary events warrants increased surveillance or potential intervention to prevent IHD events in PAD.

Longitudinal Melanonychia: Differences in Etiology Are Associated with Patient Age at Diagnosis.

BACKGROUND: Longitudinal melanonychia (LM) may occur as a result of nail apparatus melanoma. Knowledge of etiology plays an important role in the management of LM. OBJECTIVES: The study is aimed to compare the diagnosis of LM in different age groups. METHODS: We collected 63 cases (45 adults and 18 children) with LM who underwent nail matrix biopsy or excision in a 21-year cohort and assessed their clinicopathological features. RESULTS: Melanomas in adults and children were 40% and none, while nevi accounted for 15.6% in adults and 94.4% in children. There was a statistically significant difference between the average age at diagnosis for melanoma (54.5 ± 13.3 years) and nevus (15.2 ± 18.5 years). Logistic regression related the occurrence of melanoma to older ages with a relative risk of 1.2 compared to nevus, but no cutoffs between age groups could be defined between LM-associated nevus and melanoma. CONCLUSION: The adult group has a significantly higher risk of melanoma, while children with LM show mostly nonmelanoma etiologies. Tissue proof is more warranted in adult cases, and it is needed in selected cases of children with LM.

Community walking speed, sedentary or lying down time, and mortality in peripheral artery disease.

We studied whether slower community walking speed and whether greater time spent lying down or sleeping were associated with higher mortality in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 0.90 were identified from Chicago medical centers. At baseline, participants reported their usual walking speed outside their home and the number of hours they spent lying down or sleeping per day. Cause of death was adjudicated using death certificates and medical record review. Analyses were adjusted for age, sex, race, comorbidities, ABI, and other confounders. Of 1314 PAD participants, 189 (14.4%) died, including 63 cardiovascular disease (CVD) deaths. Mean follow-up was 34.9 months ± 18.1. Relative to average or normal pace (2-3 miles/hour), slower walking speed was associated with greater CVD mortality: no walking at all: hazard ratio (HR) = 4.17, 95% confidence interval (CI) = 1.46-11.89; casual strolling (0-2 miles/hour): HR = 2.24, 95% CI = 1.16-4.32; brisk or striding (>3 miles/hour): HR = 0.55, 95% CI = 0.07-4.30. These associations were not significant after additional adjustment for the six-minute walk. Relative to sleeping or lying down for 8-9 hours, fewer or greater hours sleeping or lying down were associated with higher CVD mortality: 4-7 hours: HR = 2.08, 95% CI = 1.06-4.05; 10-11 hours: HR = 4.07, 95% CI = 1.86-8.89; ⩾ 12 hours: HR = 3.75, 95% CI = 1.47-9.62. These associations were maintained after adjustment for the six-minute walk. In conclusion, slower walking speed outside the home and less than 8 hours or more than 9 hours lying down per day are potentially modifiable behaviors associated with increased CVD mortality in patients with PAD.

Changes in D-dimer and inflammatory biomarkers before ischemic events in patients with peripheral artery disease: The BRAVO Study.

Whether circulating biomarker levels increase shortly before an ischemic heart disease (IHD) event is unknown. We studied whether levels of D-dimer, C-reactive protein (CRP), and serum amyloid A (SAA) are higher within 2 months of an IHD event compared to time periods more than 2 months before the IHD event. We assembled 595 participants with peripheral artery disease (PAD) and followed them for up to 3 years. Blood samples were obtained every 2 months. The primary outcome was IHD events: myocardial infarctions, unstable angina, or IHD death. We used a nested case-control design. Fifty participants (cases) had events and were each matched by age, sex, duration in the study, and number of blood draws to two controls without events. Among cases, the mean D-dimer value of 1.105 obtained within 2 months of the event was higher than values obtained 10 months (0.68 mg/L, p<0.001), 12 months (0.71 mg/L, p=0.001), 16 months (0.65 mg/L, p=0.008), 20 months (p=0.032), 22 months (p=0.033), 26 months (p=0.038), and 32 months (p=0.04) before the event. Compared to controls, median D-dimer levels in cases were higher 4 months (p=0.017), 6 months (p=0.005), and 8 months (p=0.028) before the event. Values of CRP and SAA obtained within two months of an IHD event not consistently higher than values obtained during the prior months. In PAD participants with an IHD event, D-dimer was higher within 2 months of the event, compared to most values obtained 10 to 32 months previously. D-dimer was also higher in cases as compared to controls during most visits within 8 months of the IHD event.

Prevalence of BRAF and NRAS mutations in cutaneous melanoma patients in Taiwan.

BACKGROUND/PURPOSE: BRAF and NRAS mutations have been described in melanomas among Caucasians and some Asian populations. However, few large-scale studies have investigated the status and clinical significance of BRAF and NRAS mutations in a Taiwanese population. METHODS: Melanoma samples (n = 119) were analyzed for mutations in exons 11 and 15 of the BRAF gene, and in exons 1 and 2 of the NRAS gene. The samples were studied in genomic DNA, using polymerase chain reaction amplification and Sanger sequencing. Mutations of the BRAF and NRAS genes were then correlated with clinicopathological features and patients' prognosis. RESULTS: The incidence of somatic mutations within the BRAF and NRAS genes was 14.3% (17/119 patients) and 10.1% (12/119 patients), respectively. Among the 17 patients with BRAF mutations, 15 (88.2%) had V600E mutations. BRAF mutation was frequently detected in younger patients (p = 0.0035), in thin melanomas (p = 0.0181), and in melanomas with less ulceration (p = 0.0089). NRAS mutation was more often seen in patients with lymph node metastasis (p = 0.0332). Both BRAF and NRAS mutations were not significantly correlated with overall survival and disease-free survival. CONCLUSION: As BRAF and NRAS mutations are rare in Taiwan, BRAF- or NRAS-targeted therapies may be effective only for selected Taiwanese melanoma patients.

Ischemia-related changes in circulating stem and progenitor cells and associated clinical characteristics in peripheral artery disease.

The extent and clinical significance of stem and progenitor cell (SPC) increases in response to lower-extremity ischemia in people with peripheral artery disease (PAD) are unclear. We compared changes in SPC levels immediately following a treadmill exercise test between individuals with and without PAD. Among participants with PAD, we determined whether more severe PAD was associated with greater increases in SPCs following treadmill exercise-induced lower-extremity ischemia. We measured SPC levels in 25 participants with PAD and 20 without PAD before and immediately after a treadmill exercise test. Participants with PAD, compared to participants without PAD, had greater increases in CD34(+)CD45(dim) (+0.08±0.03 vs -0.06±0.04, p=0.008), CD34(+)CD45(dim)CD133(+) (+0.08±0.05 vs -0.08±0.04, p=0.014), CD34(+)CD45(dim)CD31(+) (+0.10±0.03 vs -0.07±0.04, p=0.002), and CD34(+)CD45(dim)ALDH(+) SPCs (+0.18±0.07 vs -0.05±0.08, p=0.054) measured as a percentage of all white blood cells. Among participants with PAD, those with any increases in the percent of SPCs immediately after the treadmill exercise test compared to those with no change or a decrease in SPCs had lower baseline ankle-brachial index values (0.65±0.17 vs 0.90±0.19, p=0.004) and shorter treadmill times to onset of ischemic leg symptoms (2.17±1.54 vs 5.25±3.72 minutes, p=0.012). In conclusion, treadmill exercise-induced lower-extremity ischemia is associated with acute increases in circulating SPCs among people with PAD. More severe PAD is associated with a higher prevalence of SPC increases in response to lower-extremity ischemia. Further prospective study is needed to establish the prognostic significance of ischemia-related increases in SPCs among patients with PAD.

Wall morphology, blood flow and wall shear stress: MR findings in patients with peripheral artery disease.

OBJECTIVES: To investigate the influence of atherosclerotic plaques on femoral haemodynamics assessed by two-dimensional (2D) phase-contrast (PC) magnetic resonance imaging (MRI) with three-directional velocity encoding. METHODS: During 1 year, patients with peripheral artery disease and an ankle brachial index <1.00 were enrolled. After institutional review board approval and written informed consent, 44 patients (age, 70 ± 12 years) underwent common femoral artery MRI. Patients with contra-indications for MRI were excluded. Sequences included 2D time-of-flight, proton-density, T1-weighted and T2-weighted MRI. Electrocardiogram (ECG)-gated 2D PC-MRI with 3D velocity encoding was acquired. A radiologist classified images in five categories. Blood flow, velocity and wall shear stress (WSS) along the vessel circumference were quantified from the PC-MRI data. RESULTS: The acquired images were of good quality for interpretation. There were no image quality problems related to poor ECG-gating or slice positioning. Velocities, oscillatory shear stress and total flow were similar between patients with normal arteries and wall thickening/plaque. Patients with plaques demonstrated regionally increased peak systolic WSS and enhanced WSS eccentricity. CONCLUSIONS: Combined multi-contrast morphological imaging of the peripheral arterial wall with PC-MRI with three-directional velocity encoding is a feasible technique. Further study is needed to determine whether flow is an appropriate marker for altered endothelial cell function, vascular remodelling and plaque progression. KEY POINTS: • Femoral plaques are associated with altered dynamics of peripheral blood flow. • Multi-contrast MRI can investigate the presence and type of atherosclerotic plaques. • Three-dimensional velocity-encoding phase-contrast MRI can investigate flow and wall shear stress. • Atherosclerotic peripheral arteries demonstrate increased systolic velocities and wall shear stress.

Associations of diabetes mellitus and other cardiovascular disease risk factors with decline in the ankle-brachial index.

We compared the associations of diabetes mellitus (DM) and other cardiovascular disease (CVD) risk factors with decline in the ankle-brachial index (ABI) over 4 years in participants with and without peripheral artery disease (PAD). A total of 566 participants, 300 with PAD, were followed prospectively for 4 years. Mean (SD) baseline ABI values were 0.70 (0.13) for participants with both PAD and DM, 0.67 (0.14) for participants with only PAD, 1.10 (0.13) for participants with only DM, and 1.10 (0.10) for participants with neither PAD nor DM. After adjusting for age, sex, and baseline ABI, the corresponding ABI change from baseline to 4-year follow-up were -0.02, -0.04, +0.05, and +0.05, respectively. Compared to participants with neither PAD nor DM, participants with only PAD showed significantly more ABI decline (p <0.01), while the decline in participants with both PAD and DM was borderline non-significant (p = 0.06). After adjustments for baseline ABI, age, sex, African American ethnicity, and other CVD risk factors, independent factors associated with ABI decline in participants with PAD in the lower ABI leg were older age and elevated D-dimer. DM was not related to ABI decline. Despite being an important risk factor for PAD, DM was not independently associated with ABI decline. This could reflect the effect of DM promoting both PAD and lower-extremity arterial stiffness, resulting in a small decline in the ABI over time. In conclusion, ABI change over time in persons with diabetes may not accurately reflect underlying atherosclerosis.