A multi center real world observation to evaluate the efficacy of cryotherapy versus local hyperthermia for the treatment of plane warts.

Most plane warts are recalcitrant to treatment. Both cryotherapy and local hyperthermia have been applied to treat plane warts. However, no direct comparative study on their respective efficacy and safety has ever been performed. To assess the efficacy and safety of local hyperthermia at 43 ± 1°C versus liquid nitrogen cryotherapy for plane warts. Sequential patients with plane warts entered the study, either receiving cryotherapy or local hyperthermia therapy at the discretion of the patients and the recommendations of consultants. Cryotherapy with liquid nitrogen was delivered in two sessions 2 weeks apart, while local hyperthermia was delivered on three consecutive days, plus two similar treatments 10 ± 3 days later. The temperature over the treated skin surface was set at 43 ± 1°C for 30 min in each session. The primary outcome was the clearance rates of the lesions 6 months after treatment. Among the 194 participants enrolled, 183 were included in the analysis at 6 months. Local hyperthermia and cryotherapy achieved clearance rates of 35.56% (48/135) and 31.25% (15/48), respectively (p = 0.724); recurrence rates of 16.67% (8/48) and 53.33% (8/15) (p = 0.01); and adverse events rates of 20.74% (28/135) and 83.33% (40/48), respectively (p < 0.001). Cryotherapy had a higher pain score (p < 0.001) and a longer healing time (p < 0.001). Local hyperthermia at 43°C and cryotherapy had similar efficacy for plane warts. Local hyperthermia had a safer profile than cryotherapy but it required more treatment visits during a treatment course. More patients preferred local hyperthermia due to its treatment friendly nature.

Local Hyperthermia Versus Cryotherapy for Treatment of Plantar Warts: A Prospective Multi-centre Non-randomized Concurrent Controlled Clinical Trial.

Cryotherapy is one of the most common treatments for warts; however, pain during treatment and relatively high recurrence rates limit its use. Local hyperthermia has also been used successfully in the treatment of plantar warts. The aim of this study was to compare the clinical effectiveness of local hyperthermia vs cryotherapy for the treatment of plantar warts. This multi- centre, open, 2-arm, non-randomized concurrent controlled trial included 1,027 patients, who received either cryotherapy or local hyperthermia treatment. Three months after treatment, local hyperthermia and cryotherapy achieved complete clearance rates of 50.9% and 54.3%, respectively. Recurrence rates were 0.8% and 12%, respectively. Pain scores during local hyperthermia were significantly lower than for cryotherapy. Both local hyperthermia and cryotherapy demonstrated similar efficacy for clearance of plantar warts; while local hyperthermia had a lower recurrence rate and lower pain sensation during treatment.

Local Hyperthermia at 44°C Is Effective in Clearing Cervical High-Risk Human Papillomaviruses: A Proof-of-Concept, Randomized Controlled Clinical Trial.

BACKGROUND: Persistent infection by high-risk human papillomavirus (HPV) is the leading cause of cervical intraepithelial neoplasia and cervical carcinoma. Local hyperthermia at 44ºC has been proven efficacious to clear cutaneous or anogenital warts caused by HPV infection. This study aims to assess the effect of hyperthermia at 44ºC on the clearance of high-risk HPV. METHODS: A randomized, patient-blind, sham treatment-controlled trial was conducted in 4 medical centers. We enrolled patients with positive high-risk HPVs and normal or insignificant cytological findings (negative/atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion). Participants were randomly assigned (1:1) to receive either hyperthermia at 44ºC or 37ºC, for 30 minutes in each session. Patients in both groups received treatment once a day for 3 consecutive days, plus 2 more sessions 10 ±â€…3 days later. The primary outcome was clearance rate of HPV 3 months after treatment. RESULTS: After a 3-month follow-up, hyperthermia treatment at 44ºC and 37ºC achieved HPV clearance rates of 85.19% (23/27) and 50% (13/26), respectively (P = .014). There was no significant difference of treatment response between patients with single and multiple type of HPV by 44ºC hyperthermia treatment. There were no significant adverse events recorded during the treatment period in both groups. CONCLUSIONS: Local hyperthermia at 44ºC safely and significantly aids in clearing cervical high-risk HPVs, the effect of which helps halt the progression of cervical transformation and transmission of the virus. CLINICAL TRIALS REGISTRATION: NCT03436251.

Mesenchymal stem cells-derived exosomal microRNA-21-5p downregulates PDCD4 and ameliorates erectile dysfunction in a rat model of diabetes mellitus.

Erectile dysfunction (ED) is a common comorbidity in males with diabetes mellitus (DM), whose pathogenesis might be induced by dysregulation of corpus cavernosum smooth muscle cells (CCSMCs). Gene Expression Omnibus repository-based analysis identified the differentially expressed PDCD4 in DM rats. PDCD4 has also been determined as a putative gene under the regulatory control of microRNA-21-5p (miR-21-5p). This study aimed to further determine the functional role of miR-21-5p in CCSMCs in a rat model of diabetes mellitus-induced erectile dysfunction (DMED). CCSMCs were isolated from penile cavernous tissue and cultured in high glucose (HG) medium. The expression of miR-21-5p and/or PDCD4 was altered in CCSMCs, as directly or indirectly measured by CCK-8 assay, flow cytometry, and TUNEL assays. Furthermore, exosomes were isolated from mesenchymal stem cells (MSCs) transfected with miR-21-5p mimic or miR-21-5p inhibitor and co-cultured with CCSMCs. DMED rats were injected with lentivirus carrying PDCD4/siRNA-PDCD4 plasmids, or exosomes from MSCs containing miR-21-5p-agomir to explore their roles in vivo. The experimental data validated that PDCD4 was upregulated in cavernous tissue of DMED rats. miR-21-5p targeted and inhibited PDCD4. miR-21-5p was enriched in MSC-exosomes. Moreover, PDCD4 downregulation, miR-21-5p elevation or MSC-derived exosomal miR-21-5p reduced apoptosis and enhanced proliferation of CCSMCs cultured in HG medium. PDCD4 silencing or miR-21-5p-containing MSC-exosomes improved erectile function and smooth muscle density in DMED rats. Collectively, our findings suggested that MSC-derived exosomal miR-21-5p suppressed PDCD4 expression and ED in rats with DM.

Epigenetic silencing of microRNA-874-3p implicates in erectile dysfunction in diabetic rats by activating the Nupr1/Chop-mediated pathway.

Diabetes is a global medical problem that causes many deaths every year. Complications caused by diabetes are serious and affect patients' quality of life. Diabetes mellitus erectile dysfunction (DMED) affects more than half of male diabetes patients. In this study, we determined the role of microRNA-874-3p (miR-874-3p) and nuclear protein-1 (Nupr1) in streptozocin-induced DMED rats. Control rats received equal amount of vehicle. These rats were also injected with lentiviral vector or agomir to silence or overexpress miR-874-3p or Nupr1. Apomorphine (100 µg/kg, s.c.) was used to induce erection and time of erection was recorded. Intracavernosal and mean arterial pressure ratio (ICP/MAP) were also recorded. O2- level and concentration of thiobarbituric acid reactive substances (TBARs) were detected using lucigenin-derived chemiluminescence method and Colorimetry. Rat cavernosum tissues were collected for subsequent experiments. Cavernosum smooth muscle cells (CSMCs) were also used for in vitro experiments. Nupr1 was found highly expressed (by RT-qPCR and Western blot analysis) in cavernosum tissues from DMED rats. Nupr1 silencing improved the ICP/MAP ratio and erection time. Nupr1 silencing also reduced CSMC apoptosis (by TUNEL assay) as well as decreased O2- level and TBAR concentration. Nupr1 was targeted and inhibited by miR-874-3p (by luciferase activity and RNA immunoprecipitation assays), which was downregulated in DMED. miR-874-3p downregulation was due to increased methylation at the promoter region (methylation-specific PCR). miR-874-3p overexpression improved erection time and reduced apoptosis. In summary, miR-874-3p was downregulated which led to increased apoptosis and erectile dysfunction in DMED rats, through inhibition of Nupr1-mediated pathway. This study may also provide a new therapeutic direction for the treatment of DMED.

MicroRNA-495 alleviates ulcerative interstitial cystitis via inactivating the JAK-STAT signaling pathway by inhibiting JAK3.

INTRODUCTION AND HYPOTHESIS: As a notable chronic disorder, the incidence of interstitial cystitis (IC) has been documented to have increased among the female population with activity in microRNA-495 (miR-495) implicated in this disease. The current study was aimed at elucidating the effects associated with miR-495 on the inflammatory response and bladder fibrosis in rats with ulcerative IC via the JAK-STAT pathway by targeting JAK3. METHODS: Ulcerative IC rat models were established. The targeting relationship between JAK3 and miR-495 was evaluated using luciferase reporter assay. After gain- or loss-of-function assays, mast-cell infiltration was assessed using toluidine blue staining, bladder fibrosis using Masson staining, and NO content using nitrate reductase method. JAK3 protein expression was detected by immunohistochemistry, JAK3, STAT1, STAT3, TGFß-1, Col-I, Col-III, JAK1, JAK2, p-STAT1, and p-STAT3 expression by RT-qPCR and Western blot analysis, and serum IL-6, IL-8, IL-10, IL-17, and TNF-α levels in rats by ELISA. RESULTS: Following transfection of overexpressed miR-495 or siRNA-JAK3, a diminished degree of mast-cell infiltration, number of mast cells, bladder fibrosis, NO content, JAK3-positive expression, mRNA expression of JAK3, STAT1, STAT3, TGFß-1, Col-I, Col-III, protein expression of JAK1, JAK2, JAK3, p-STAT1, p-STAT3, and expression of IL-6, IL-8, IL-10, IL-17, and TNF-α were identified. CONCLUSIONS: Collectively, our key findings provide evidence supporting the notion that the overexpression of miR-495 ameliorates inflammatory response and bladder fibrosis in ulcerative IC rat models via inactivation of the JAK-STAT signaling pathway by inhibiting JAK3.

Mitosis-specific MRN complex promotes a mitotic signaling cascade to regulate spindle dynamics and chromosome segregation.

The MRE11-RAD50-NBS1 (MRN) complex is well known for participating in DNA damage response pathways in all phases of cell cycle. Here, we show that MRN constitutes a mitosis-specific complex, named mMRN, with a protein, MMAP. MMAP directly interacts with MRE11 and is required for optimal stability of the MRN complex during mitosis. MMAP colocalizes with MRN in mitotic spindles, and MMAP-deficient cells display abnormal spindle dynamics and chromosome segregation similar to MRN-deficient cells. Mechanistically, both MMAP and MRE11 are hyperphosphorylated by the mitotic kinase, PLK1; and the phosphorylation is required for assembly of the mMRN complex. The assembled mMRN complex enables PLK1 to interact with and activate the microtubule depolymerase, KIF2A, leading to spindle turnover and chromosome segregation. Our study identifies a mitosis-specific version of the MRN complex that acts in the PLK1-KIF2A signaling cascade to regulate spindle dynamics and chromosome distribution.

THBS4 silencing regulates the cancer stem cell-like properties in prostate cancer via blocking the PI3K/Akt pathway.

BACKGROUND: Although thrombospondins 4 (THBS4) participates in controlling the biology of prostate cancer (PCa), the mechanism underlying this regulation remains unknown. Hence, this study aims to identify the regulatory effects of THBS4 on the PCa stem cell-like properties and the potential mechanism associated with the phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (Akt) pathway. METHODS: PCa stem cells were sorted and identified using flow cytometry and THBS4 expression in the identified PCa stem cells was measured using Western blot assay. THBS4 was overexpressed or silenced in PCa stem cells, following which, self-renewal, proliferation, cell cycle distribution, and apoptosis of PCa stem cells were assessed as well as tumorigenicity in vivo was evaluated. PI3K/Akt pathway inhibitor was applied to identify its involvement in the regulatory roles of THBS4 in PCa stem cells. RESULTS: THBS4 was expressed at a higher level in PCa stem cells than in PCa cells. The overexpression of THBS4 promoted the self-renewal and proliferation, curbed the apoptosis of PCa stem cells, and enhanced the in vivo tumorigenicity, which was achieved by activating the PI3K/Akt pathway. On the contrary, short-hairpin RNA-mediated silencing of THBS4 exhibited suppressive effects on those cancer stem cell (CSC)-like properties and promotive effects on their apoptosis. CONCLUSION: THBS4 silencing can impede the CSC-like properties in PCa via blockade of the PI3K/Akt pathway, which provides patients with PCa a new therapeutic target.

Long non-coding RNA FER1L4 inhibits prostate cancer progression via sponging miR-92a-3p and upregulation of FBXW7.

BACKGROUND: Dysregulation of long non-coding RNAs (lncRNAs) is involved in development of prostate cancer. However, the molecular mechanisms of many lncRNAs in prostate cancer have not been studied yet. METHODS: The lncRNA Fer-1-like protein 4 (FER1L4) expression was explored in prostate tumors and normal prostate tissues by RT-qPCR and bioinformatic analysis. Overexpression of FER1L4 was performed to evaluate its role in prostate cancer cell proliferation and survival. The molecular mechanism of FER1L4 was investigated by dual luciferase reporter assay, RNA pull down assay, western blotting and RT-qPCR. RESULTS: It was found that FER1L4 was lower in prostate cancer tissues than normal tissues. Higher expression of FER1L4 was associated with prostate cancer tissues of early stage (AJCC stage I/II). Overexpression of FER1L4 inhibited cell proliferation and promoted cell apoptosis in prostate cancer cells. Bioinformatic analysis, RT-qPCR, RNA pull down assay and dual luciferase assay showed that FER1L4 upregulated F-box/WD repeat-containing protein 7 (FBXW7) tumor suppressor via sponging miR-92a-3p. Silencing of FBXW7 reversed the cell phenotypes caused by FER1L4 overexpression in prostate cancer cells. CONCLUSION: The data demonstrated that FER1L4, a downregulated lncRNA in prostate cancer, was pivotal for cell proliferation and survival of prostate cancer. The study provided new sights into understanding of the signaling network in prostate cancer and implied that FER1L4 might be a biomarker for patients with prostate cancer.

Benefit-risk assessment of commonly consumed fish species from South China Sea based on methyl mercury and DHA.

Even though a growing number of reports indicated favorable health effects with fish consumption, kinds of hazardous substances in fish were detected in fish and to be exceeded advisory limitation. Benefit-risk assessment of commonly consumed fish is urgently needed. We conducted fish consumption survey and fish sampling in the coast of South China Sea to assess benefit-risk effect of commonly consumed fish species. For local residents, weekly methyl mercury (MeHg) exposures from commonly consumed fish species ranged from 0.12 to 2.11 µg/kg bw. Apart from Muraenesox cinereus and Acanthopagrus latus, the rest of 92% (23/25) fish species were at low risk of MeHg exposure. Daily docosahexaenoic acid intakes via consuming specific fish were between 42.18 and 1687.04 mg/day. A total of 72% (18/25) fish species could provide 200 mg/day of DNA for local residents. Benefit-risk assessment assuming intelligence quotient (IQ) score model showed net IQ point gains between 1.53 and 5.65 points with consuming various fish species, indicative of large distinction of health benefit from various fish species. This study suggests commonly consumed fish species from China South Sea could bring much more positive effect than negative effect. Species-specific fish should be considered when providing recommendations of fish consumption. Muraenesox cinereus and Acanthopagrus latus should be minded with risk of MeHg exposure in taking large amounts.

Efficacy of protein extracts from medium of Adipose-derived stem cells via microneedles on Asian skin.

OBJECTIVES: To explore efficacy of protein extracts from medium of Adipose-derived stem cells (ADSCs) via microneedles on Asian skin in a double-blind, split-face, randomized, control study. METHODS: Thirty volunteers received the treatment, left-side and right-side of their face were randomly assigned to test side and control side. The protein extracts from medium of ADSCs were applied via microneedles into the test side and ultrapure water was applied into the control side. The only person who knew what was being used by each subject on each side of the face was the therapist. Clinical evaluation including instrument test and self-questionnaire was performed by independent observers before and after the treatment, which lasted for 3 months. RESULTS: All subjects completed the study. Compared to ultrapure water, the protein extracts from medium of ADSCs showed a statistically significant improvement for melanin index, skin brightness, gloss, skin roughness, elasticity, and wrinkles (p < 0.05). More than 70% of the participants described that all wrinkles, firmness, elasticity, hydration, whitening, and radiance were strongly improved in the test side. CONCLUSIONS: Protein extracts from medium of ADSCs presented anti-aging and whitening efficacy via microneedles on Asian skin without skin adverse side.

Health Risk Assessment for Local Residents from the South China Sea Based on Mercury Concentrations in Marine Fish.

The offshore area of the South China Sea is an important fishing ground in China. We used a food frequency questionnaire to determine marine fish consumption by local residents, and we detected mercury concentrations in commonly consumed marine fish species. In total, 127.9 g/day of the marine fish consumed was identified in 178 local residents. THg and MeHg concentrations in 209 samples of 22 fish species ranged from 11.3 to 215.0 µg/kg wt and 2.0 to 160.0 µg/kg wt, respectively. The mean MeHg exposure from marine fish to local residents was 0.099 µg/kg bw, accounting for 43.0% of the provisional tolerated weekly intake (PTWI) (1.6 µg/kg bw/week), suggesting a low health risk. However, a potentially high health risk (202.2% of PTWI) was identified in those with 97.5% MeHg exposure.

Ewing Tumor-associated Antigen 1 Interacts with Replication Protein A to Promote Restart of Stalled Replication Forks.

The replication protein A (RPA) complex binds single-stranded DNA generated at stalled replication forks and recruits other DNA repair proteins to promote recovery of these forks. Here, we identify Ewing tumor-associated antigen 1 (ETAA1), which has been linked to susceptibility to pancreatic cancer, as a new repair protein that is recruited to stalled forks by RPA. We demonstrate that ETAA1 interacts with RPA through two regions, each of which resembles two previously identified RPA-binding domains, RPA70N-binding motif and RPA32C-binding motif, respectively. In response to replication stress, ETAA1 is recruited to stalled forks where it colocalizes with RPA, and this recruitment is diminished when RPA is depleted. Notably, inactivation of the ETAA1 gene increases the collapse level of the stalled replication forks and decreases the recovery efficiency of these forks. Moreover, epistasis analysis shows that ETAA1 stabilizes stalled replication forks in an ataxia telangiectasia and Rad3-related protein (ATR)-independent manner. Thus, our results reveal that ETAA1 is a novel RPA-interacting protein that promotes restart of stalled replication forks.

Transforming Growth Factor ß Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer.

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo In addition, we demonstrate for the first time that TGFß mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFß signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFß pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFß/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.

In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model.

Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven Klebsiella pneumoniae isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with K. pneumoniae and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The Emax Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log10 or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentration-time curve over 24 h (AUC0-24)/MIC ratio was the PD index most closely linked to efficacy (R2 = 0.96). The mean free-drug AUC0-24/MIC ratios required to achieve net bacterial stasis, a 1-log10 kill, and a 2-log10 kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving K. pneumoniae.

Complete Nucleotide Sequence of an IncI2 Plasmid Coharboring blaCTX-M-55 and mcr-1.

We report the complete nucleotide sequence of a plasmid, pA31-12, carrying blaCTX-M-55 and mcr-1 from a chicken Escherichia coli isolate. pA31-12 has an IncI2 replicon that displays extensive sequence similarity with pHN1122-1-borne blaCTX-M-55 and pHNSHP45-borne mcr-1 Insertion sequences ISEcp1 and ISApl1 are responsible for the mobilization of blaCTX-M-55 and mcr-1, respectively. The colocalization of mcr-1 with an extended-spectrum ß-lactamase gene on a conjugative plasmid may accelerate the dissemination of both genes by coselection.

One stone, two birds: managing multiple common warts on hands and face by local hyperthermia.

A man developed with multiple warts on his hands and the inner canthus of his left eye. We applied local hyperthermia on a single target lesion on his hand at a surface temperature of 44 °C for 30 minutes on Days 1, 2, 3, 17, and 18. All the lesions treated with or without heat cleared 8 weeks after the last treatment. Treatment of a target lesion resolved all other untreated lesions, a fact suggestive that local hyperthermia could induce activation of specific immunity against human papillomavirus on the lesional skin, which lead to resolution of all the warts.

Intensive local thermotherapy cleared extensive viral warts in a patient with systemic lupus erythematosus.

PURPOSE: A variety of medications and procedures are available for the treatment of warts, but it appeared the treatment response in systemic lupus erythematosus (SLE) patients is poor. It is necessary to investigate the feasibility, safety and efficacy of local thermotherapy for extensive viral warts. MATERIALS AND METHODS: A SLE patient on systemic steroid developed extensive viral warts on both her hands and feet for months. She had a high score of SLE Disease Activity Index (SLEDAI), up to 30, and was extensively treated with high and prolonged dosage of corticosteroid and intermittent use of cyclophosphamide. We applied local hyperthermia at 44 °C on a target lesion for 30 min on days 1, 2, 3, 17, 18, a protocol which has been successfully used in treating viral warts. There was no sign of clinical response in a 3-month follow-up. Then we treated the patient on a once-a-week protocol. RESULT: All the lesions cleared in ten weeks and there was no sign of recurrence. CONCLUSION: This observation suggests that more intensive local hyperthermia is required for clearing viral warts in SLE.

[De-noising of Impedance Cardiography Differential Signal and Detection of the Feature Points Based on Wavelet Transformation].

Calculation of cardiac hemodynamic parameters is based on accurate detection of feature points in impedance cardiogram. According to these parameters, doctors can determine heart conditions, so it is very important to accurately detect the feature point of impedance differential signals. This article presents a process in which we used wavelet threshold method to de-noise signals, and then detected the feature points after six layers wavelet decomposition by using bior3. 7. The experimental data were collected from healthy persons in our laboratory and twenty two clinical patients in Chongqing Daping Hospital by using KF_ICG instrument. The results indicated that this method could precisely detect feature points whether it was from healthy people or clinical patients. This helps to achieve the application of noninvasive detection cardiac hemodynamic parameters in clinical treatments by using impedance method.