Bleach activates a redox-regulated chaperone by oxidative protein unfolding.

Hypochlorous acid (HOCl), the active ingredient in household bleach, is an effective antimicrobial produced by the mammalian host defense to kill invading microorganisms. Despite the widespread use of HOCl, surprisingly little is known about its mode of action. In this study, we demonstrate that low molar ratios of HOCl to protein cause oxidative protein unfolding in vitro and target thermolabile proteins for irreversible aggregation in vivo. As a defense mechanism, bacteria use the redox-regulated chaperone Hsp33, which responds to bleach treatment with the reversible oxidative unfolding of its C-terminal redox switch domain. HOCl-mediated unfolding turns inactive Hsp33 into a highly active chaperone holdase, which protects essential Escherichia coli proteins against HOCl-induced aggregation and increases bacterial HOCl resistance. Our results substantially improve our molecular understanding about HOCl's functional mechanism. They suggest that the antimicrobial effects of bleach are largely based on HOCl's ability to cause aggregation of essential bacterial proteins.

Zoon vulvitis - a rare form of chronic inflammation of the vulva.

OBJECTIVE: Description of finding out rare disease Zoon vullvitis. Desing: Case report and differential diagnosis. SETTING: Department of Obstetric and Gynecology, University Hospital Ostrava. CASE REPORT: Zoon vulvitis or plasma cell vulvitis (PCV) belongs to extremely rare and often misdiagnosed inflammatory disease of the vulva. Lesions may look like shiny, sharply bordered , erythematosus patches or macular lesions. Less than 50 cases have been reported. This article is devoted to clinical findings, differential diagnosis and treatment of PCV. We present one clinical case with typical clinical and histopathological manifestations. Risk of dysplasia exists and long-term follow-up is desirable.

Reversible 2D Phase Transition Driven By an Electric Field: Visualization and Control on the Atomic Scale.

We report on a reversible structural phase transition of a two-dimensional system that can be locally induced by an external electric field. Two different structural configurations may coexist within a CO monolayer on Cu(111). The balance between the two phases can be shifted by an external electric field, causing the domain boundaries to move, increasing the area of the favored phase controllable both in location and size. If the field is further enhanced new domains nucleate. The arrangement of the CO molecules on the Cu surface is observed in real time and real space with atomic resolution while the electric field driving the phase transition is easily varied over a broad range. Together with the well-known molecular manipulation of CO adlayers, our findings open exciting prospects for combining spontaneous long-range order with man-made CO structures such as "molecule cascades" or "molecular graphene". Our new manipulation mode permits us to bridge the gap between fundamental concepts and the fabrication of arbitrary atomic patterns in large scale, by providing unprecedented insight into the physics of structural phase transitions on the atomic scale.

Prognostic significance of low volume sentinel lymph node disease in early-stage cervical cancer.

OBJECTIVE: Evaluate prognostic significance of low volume disease detected in sentinel nodes (SN) of patients with early stages cervical cancer. Although pathologic ultrastaging of SN allows for identification of low volume disease, including micro-metastasis and isolated tumor cells (ITC), in up to 15% of cases, prognostic significance of these findings is unknown. METHODS: A total of 645 records from 8 centers were retrospectively reviewed. Enrolled in our study were patients with early-stage cervical cancer who had undergone surgical treatment including SN biopsy followed by pelvic lymphadenectomy and pathologic ultrastaging of SN. RESULTS: Macrometastasis, micrometastasis, and ITC were detected by SN ultrastaging in 14.7%, 10.1%, and 4.5% patients respectively. False negativity of SN ultrastaging reached 2.8%. The presence of ITC was not associated with significant risk, both for recurrence free survival and overall survival. Overall survival was significantly reduced in patients with macrometastasis and micrometastasis; hazard ratio for overall survival reached 6.85 (95% CI, 2.59-18.05) and 6.86 (95% CI, 2.09-22.61) respectively. Presence of micrometastasis was an independent prognostic factor for overall survival in a multivariable model. CONCLUSION: Presence of micrometastasis in SN in patients with early stage cervical cancer was associated with significant reduction of overall survival, which was equivalent to patients with macrometastasis. No prognostic significance was found for ITC. These data highlight the importance of SN biopsy and pathologic ultrastaging for the management of cervical cancer.

A novel type of silver nanoparticles and their advantages in toxicity testing in cell culture systems.

Silver nanoparticles (SNPs) are among the most commercialized nanoparticles worldwide. Often SNP are used because of their antibacterial properties. Besides that they possess unique optic and catalytic features, making them highly interesting for the creation of novel and advanced functional materials. Despite its widespread use only little data exist in terms of possible adverse effects of SNP on human health. Conventional synthesis routes usually yield products of varying quality and property. It thus may become puzzling to compare biological data from different studies due to the great variety in sizes, coatings or shapes of the particles applied. Here, we applied a novel synthesis approach to obtain SNP of well-defined colloidal and structural properties. Being stabilized by a covalently linked small peptide, these particles are nicely homogenous, with narrow size distribution, and form monodisperse suspensions in aqueous solutions. We applied these peptide-coated SNP in two different sizes of 20 or 40 nm (Ag20Pep and Ag40Pep) and analyzed responses of THP-1-derived human macrophages while being exposed against these particles. Gold nanoparticles of similar size and coating (Au20Pep) were used for comparison. The cytotoxicity of particles was assessed by WST-1 and LDH assays, and the uptake into the cells was confirmed via transmission electron microscopy. In summary, our data demonstrate that this novel type of SNP is well suited to serve as model system for nanoparticles to be tested in toxicological studies in vitro.

Simulating amnesic symptoms in normal subjects.

Patients with organic brain damage resulting in anterograde amnesia cannot recall a list of words, but when given the first three letters of each word, they complete these word stems with words from the list. We simulated this phenomenon in normal subjects who examined the list words for vowels while ignoring their semantic component. The subjects produced the list words when completing the word stems although they could not recall the words.

[Lymphatic mapping in cervical cancer]. / Lymfatické mapování u karcinomu cípku delozního.

BACKGROUND AND AIMS: The aim of the study is to analyze the feasibility of intraoperative sentinel lymph nodes (SLN) detection using gamma detection probe and blue dye in patients with cervical cancer. DESIGN AND SUBJECTS: Prospective clinical study. 106 patients with cervical cancer were included into the study in the period from May 2004 to November 2006. METHODS AND RESULTS: Patients were divided into three groups according to the tumor volume. Lymphoscintigraphy was performed following an injection of 99m Tc-labeled nanocolloid and intraoperatively the SLN were identified visually after marking of lymphatic vessels with blue dye and further detected using a handheld gamma detection probe. The SLN were histologically and immunohistochemically analyzed. Total number of 309 SLN with an average of 2.9 per patient were identified. The SLN detection rate was 94.3% per patient, 84.4 % per side, and depended on the tumor volume. Metastatic disease was detected in 39 patients (36.8%) and micrometastatic disease in 15 patients (14.2%). Sensitivity and negative predictive value calculated were 93.9% and 98.0%, false negative rate reached 5.1. CONCLUSIONS: Intraoperative detection of SLN using combination of technecium-99-labeled nanocolloid and blue dye represents a feasible, safe and accurate technique to identify lymphatic spreading in stages IA2-IB1 of cervical cancer.

Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea pigs.

To study the roles of substance P and endogenous neutral endopeptidase in mediating cough, we measured cough responses in awake guinea pigs in response to exogenous substance P and capsaicin aerosols in the presence and absence of the neutral endopeptidase inhibitors leucine-thiorphan and phosphoramidon. Substance P stimulated cough in very low concentrations (10(-17)-10(-16) M). In a second study where the investigator did not know whether substance P or diluent alone was aerosolized, substance P (10(-16) M) caused cough. Leucine-thiorphan (10(-5) M) and phosphoramidon (10(-5) M) potentiated substance P-induced cough; NEP inhibitors also potentiated capsaicin-induced cough significantly. These findings suggest that substance P is a potent stimulator of cough responses, that capsaicin-induced cough is mediated by substance P or another similar neuropeptide, and that cough responses are modulated by endogenous neutral endopeptidase.

Mast cell chymase potentiates histamine-induced wheal formation in the skin of ragweed-allergic dogs.

Skin mast cells release the neutral protease chymase along with histamine during degranulation. To test the hypothesis that chymase modulates histamine-induced plasma extravasation, we measured wheal formation following intradermal injection of purified mast cell chymase and histamine into the skin of ragweed-allergic dogs. We found that chymase greatly augments histamine-induced wheal formation. The magnitude of the potentiating effect increases with increasing doses of chymase and becomes maximal approximately 30 min after administration. Injection of chymase without histamine does not evoke wheal formation. The chymase potentiation of histamine-induced skin responses is prevented completely by pretreatment with the H1-receptor antagonist pyrilamine, and is prevented by inactivation of chymase with soybean trypsin inhibitor, suggesting that both histamine and preserved catalytic activity are required for the effects of chymase. To examine the effects of histamine and chymase released in situ in further experiments, we measured wheal size following local degranulation of mast cells by intradermal injection of ragweed antigen or compound 48/80. We found that pretreatment with either soybean trypsin inhibitor or pyrilamine markedly reduces ragweed antigen- or 48/80-induced wheal formation, supporting the results obtained by injection of exogenous chymase and histamine. These findings suggest a novel and important proinflammatory role for chymase in modulating the effects of histamine on vascular permeability during mast cell activation.

Impaired cortical inhibition in adult ADHD patients: a study with transcranial magnetic stimulation.

The aim of this study was to analyze motor inhibition and facilitation of adult ADHD patients using double pulse transcranial magnetic stimulation (TMS). Twenty-six right handed adult ADHD patients according to DSM-IV were investigated and compared to 26 age and sex-matched controls. In the left hemisphere, mean motor inhibition was 0.53 +/- 0.33 (mean +/- SD) in ADHD patients and 0.34 +/- 0.16 (mean +/- SD) in controls (p = 0.012). There were no significant differences in motor excitability concerning facilitation or in the right hemisphere. Decreased motor inhibition correlated with a higher symptom score derived from the Wender Reimherr Interview (WRI) (p = 0.28; p = 0.04) and also with self rated hyperactivity/impulsivity symptoms (p = 0.30; p = 0.03). In conclusion, decreased motor inhibition in adult ADHD corroborate similar findings in children with ADHD (Moll et al., 2000) and reflect disturbed impulsivity and hyperactivity on a neurophysiological level.

[The City of Munich's preparations for an influenza pandemic]. / Vorbereitungen der Stadt München auf eine Influenzapandemie.

The publication of the German National Influenza Pandemic Plan initiated many public health activities at state and regional levels to get prepared for an influenza pandemic. Because of their population densities, urban areas will likely be affected earlier und more extensively. Therefore, the City of Munich started its preparations for a crisis situation early. The Division of Health and Environment of the City of Munich is the public health office responsible for putting plans into action. The main responsibilities are coordination and communication. Common measures to prevent and control infections on the basis of the Infectious Disease Control Act have to be implemented in a pandemic situation. The surveillance of influenza including laboratory diagnosis is highly sophisticated in Bavaria. Therapeutic means have developed significantly compared with the last pandemic in 1968. Nevertheless, at the peak of a pandemic, a shortage of personnel, hospital beds, vaccines and medications is expected. Priorities in the distribution of health resources should be defined in advance to help with decision making during the pandemic. Adequate communication with the public and all partners will be critical in order to reduce fear and unforeseen social disruption.

[Sentinel node detection in early stage of cervical carcinoma using 99mTc-nanocolloid and blue dye]. / Detekce sentinelové uzliny u casných stadií cervikálního karcinomu kombinovanou metodou s uzitím nanokoloidu technecia Tc99 a patentní modri.

OBJECTIVE: The aim of the study was to analyse the feasibility of intraoperative sentinel lymph nodes (SLN) detection using gamma detection probe and blue dye in patients undergoing radical hysterectomy for treatment of early stage of cervical cancer. DESIGN: Prospective case observational study. METHODS: In the period from May 2004 to February 2006 77 patients with early stage of cervical cancer who underwent a radical surgery were included into the study. Patients were divided into three groups according to the tumour volume. First group consists of patients FIGO IA2 and FIGO IB1 with tumour diameter less than 2 cm, second group tumours FIGO IB1 with tumour diameter more than 2 cm and third group stadium IB2. SLN was detected by blue dye and Tc99. Preoperative lymphoscintigraphy was done after Tc99 colloid injection, intraoperative detection was performed by visual observation and by hand-held gamma-detection probe. SLN were histologically and immunohistochemically analysed. RESULTS: A total number of 2764 lymph nodes with an average 36 and 202 SLN with an average 2.6 were identified. The SLN detection rate was 94.8% per patient and 85.1% for the side of dissection and depends on the tumor volume. SLN were identified in obturator area in 48%, in external iliac area in 15%, in common iliac and internal iliac both in 9%, in interiliac region in 8%, in praesacral region in 6% and in parametrial area in 5%. Metastatic disease was detected in 31 patients (40.2%), metastatic involvement of SLN only in 12 patients (15.6%). False negative rate was 2.6%, sensitivity and negative predictive value calculated by patient were 923% and 95.7%. CONCLUSIONS: Intraoperative lymphatic mapping using combination of technecium-99-labeled nanocolloid and blue dye are feasible, safe and accurate techniques to identified SLN in early stage of cervical cancer.

[Computer assisted orthopedics surgery]. / L'expérience de la navigation chirurgicale dans l'ouest.

Computer-assisted surgery has become commonplace in orthopedic surgery. The number of applications grows steadily as does the number of patients benefiting from these new techniques. The hearty debates heard when these techniques were first introduced have now given way to more evidence-based evaluation. Our objective here is to continue this approach by presenting our six-year experience with navigation. We will not discuss the theoretical background of these technologies nor attempt to present an exhaustive review of the literature but rather focus attention on surgical skills acquired by a group of surgeons working in a wide range of areas. The common point is that all have now integrated computer-assisted navigation into their routine surgical practices including: a) first-intention and revision knee arthroplasty; b) hip arthroplasty; c) anterior cruciate ligament surgery; d) proximal tibial osteotomy; e) shoulder arthroplasty. We will terminate this round table with a presentation of future technological advances and propose our advice for an increasingly widespread use of these new techniques.

Absorption characteristics of EC-MPS--an enteric-coated formulation of mycophenolic sodium.

UNLABELLED: Enteric-coated mycophenolate sodium is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying MPA release until the small intestine. OBJECTIVE: Two studies were undertaken to identify the absolute bioavailability and dose-proportionality of enteric-coated mycophenolate sodium in stable renal transplant patients receiving cyclosporine. METHODS: Study 1: The mean MPA AUC(0-t) was shown to be greater after MPA infusion than after oral enteric-coated mycophenolate sodium (42.1 vs. 28.9 microg x h/ml). Mean absolute bioavailability was 0.71 +/- 0.21 (SD). Study 2: The AUC(0-t) and C(max) for MPA were proportional to the dose of enteric-coated mycophenolate sodium, similarly mean AUC(0-infinity) and C(max) for MPA glucuronide were proportional to dose administered. RESULTS AND CONCLUSIONS: In patients receiving cyclosporine the absolute bioavailability of MPA provided by enteric-coated mycophenolate sodium is equivalent to that provided by mycophenolate mofetil when administered in combination with cyclosporine, and exhibits dose-proportionality. Enteric-coated mycophenolate sodium was well tolerated from 180 - 2,160 mg with no serious adverse events reported.

[Lymphatic mapping and detection of sentinel node in early stages of cervical carcinoma]. / Lymfatické mapováni a detekce sentinelové uzliny u casných stadií cervikálního karcinomu.

OBJECTIVE: The aim of the study was to analyse two methods of intraoperative sentinel node detection using blue dye and blue dye with Tc99 labeled tracer in early stage of the cervical cancer. DESIGN: Prospective case observational study. SETTING: Department of Obstetrics and Gynecology, University Hospital Ostrava. METHODS: From May 2004 to September 2005, 49 patients with cervical cancer who underwent a radical surgery were included into the study. Sentinel lymph node was detected using blue dye in the first group of 23 patients and by blue dye with Tc99 in the second group of 26 patients. Intraoperative sentinel node detection was performed by visual aspection in the first group, and by visual aspection and by hand-held gamma-probe in the second group. RESULTS: Patients were divided according to stage of the disease into three subgroups FIGO IA2, FIGO IB1 and FIGO IB2. A total number of 1561 lymph node with an average 32 and 94 SLN with an average 1.9 were identified. The specific detection rate per site was 63% in the first group and 80.8% in the second group respectively. Metastatic disease was detected in 26 patients (41%) and metastatic involvement of SLN only in 11 patients (17.4%). Sensitivity and negative predictive value were 100% in both groups, false negativity was 0%. CONCLUSION: Detection of SLN by combination of blue dye and Tc99 labeled tracer has a higher detection rate of SLN than detection by blue dye alone.

Radiographic outcomes in the coronal plane with iASSIST™ versus optical navigation for total knee arthroplasty: A preliminary case-control study.

BACKGROUND: The new navigation system iASSIST™ for total knee arthroplasty (TKA) relies on accelerometers and gyroscopes. The objective of this prospective study was to compare the accuracy of iASSIST™ to that of the conventional optical navigation system Navitrack™ by determining the rate of mechanical axis restoration (±3°), postoperative mean mechanical alignment, rate of adequate femoral and tibial component positioning, mean operative time, and occurrence of navigation-related adverse events. HYPOTHESIS: The rate of mechanical axis restoration (±3°) is not lower with iASSIST™ than with the conventional navigation system Navitrack™. MATERIAL AND METHODS: Of 40 patients who underwent primary TKA between October 2013 and March 2014, 20 had navigation using iASSIST™ and 20 using Navitrack™. Six months after TKA, an independent observer measured three parameters on coronal radiographs: the hip-knee-ankle angle (HKA), the mechanical lateral distal femoral angle (mLDFA), and the mechanical medial proximal tibial angle (mMPTA). RESULTS: The two groups showed no significant differences for the rates of HKA restoration (P=0.3), adequate coronal positioning of the femoral component (P=0.12) and tibial component (P=0.12), or optimal success (P=0.09). Significant differences in favour of iASSIST™ were demonstrated for the values and angular deviations of the HKA (P=0.02) and mMPTA (P=0.01), whereas no significant difference was found for mLDFA. There were no significant differences regarding the mean operative time (P=0.06) or the occurrence of navigation-related adverse events (P=0.18). DISCUSSION: The iASSIST™ system provides a neutral mechanical axis and optimal component position in the coronal plane in 95% of cases, indicating that it is as accurate as the optical navigation system Navitrack™. LEVEL OF EVIDENCE: III, prospective case-control study.

Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C.

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses > or = 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve (0-24 hours) and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 micromol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.

Use of liquid crystal thermography in the evaluation of the diabetic foot.

Liquid crystal thermography (LCT) was used to determine temperature variations on the plantar surface of feet. The purpose was to identify thermal emission patterns associated with diabetic foot ulcers. Three population groups were screened: group I, 16 nondiabetic controls; group II, 21 diabetic patients with no history of pedal ulcers; and group III, 28 diabetic patients with active pedal ulceration or history of foot ulcerations. The results demonstrate a generalized increase in plantar foot temperature in group III compared with groups I and II. Temperature readings under metatarsal heads 1-5, great toe, heel, and lateral band were significantly increased (P less than .01) in group III. Additionally, the warm lateral surface displayed by group III patients was not significantly different in temperature from the medial arch of the foot. In groups I and II, the lateral band was significantly cooler (P less than .01) than the medial arch. In group III patients with active ulceration on only one foot, no significant difference in temperature was found between the foot with active ulceration compared with the contralateral nonulcerated foot. When patients with active pedal ulceration were compared with patients with a history of foot ulcers, no significant difference in temperature was seen at five of seven sites tested. A warm concentric color band surrounding active plantar ulcers was identified in group III. This pattern extended from the center of the ulcer to a distance of 8 mm. A significant change in temperature (P less than .01) was noted at 6- and 8-mm distances from the center of the ulcer. In addition, a mottled thermographic pattern was observed more frequently in group III patients than in groups I and II.(ABSTRACT TRUNCATED AT 250 WORDS)

Mobile-bearing versus fixed-bearing total knee implants. Results of a series of 100 randomised cases after 9 years follow-up.

HYPOTHESIS: Mobile-bearing total knee arthroplasty (TKA) implants were developed as an alternative to fixed-bearing implants because of their theoretical advantages related to wear and range of motion. For all that, none of the short-term and medium-term studies published so far have reported a significant clinical improvement related to these mobile bearings. The goal of this study was to compare the outcomes of fixed and mobile bearings in the same type of TKA model after a longer follow-up. MATERIAL AND METHODS: This series initially comprised 100 patients with a mean age of 73 years who were operated by a single surgeon. The patients were randomised to receive either a fixed bearing TKA implant or a mobile one; their outcomes evaluated after a mean of 9 years (7.2-12.2) follow-up. Twenty-two patients died before the final review, 15 were lost to follow-up and 2 were excluded. This resulted in 30 patients with a mobile-bearing knee and 31 with a fixed-bearing knee being available for analysis. RESULTS: There were no significant clinical differences between the groups receiving a fixed or mobile bearing in terms of the range of motion, subjective outcomes or validated outcomes measured, such as the self-reported Oxford or the IKS. Conversely, there was a significantly higher rate of osteolysis in the fixed-bearing group, but it was not clinically relevant. CONCLUSION: This study, which has the longest published follow-up, confirms the results found in the seven randomised studies published up to now: there are no significant differences in the clinical outcomes between fixed-bearing and mobile-bearing inserts of the same TKA model. Although the mobile bearing knees had a better radiographic appearance, this did not translate to better clinical outcomes. In practice, the superiority of mobile bearings is solely theoretical. LEVEL OF EVIDENCE II: Prospective randomised study.