Local Well-Posedness to the Cauchy Problem for an Equation of the Nagumo Type.

In this paper, we show the local well-posedness for the Cauchy problem for the equation of the Nagumo type in this equation (1) in the Sobolev spaces H s (ℝ). If D > 0, the local well-posedness is given for s > 1/2 and for s > 3/2 if D=0.

IEC 62304 Ed. 2: Software Life Cycle Standard for Health Software.

The quality of software is high in medical devices due to the strict regulatory requirements and their implementation in the software development processes through the use of the IEC 62304 standard. The goal of this standard revision project was to extend the scope of the standard to all health software and also to bring the requirements of the 12 year old standard back to the state-of-the-art including provisions for cybersecurity. The joint IEC/SC62A and ISO/TC215 project team revised the standard and adapted its risk management, usability, and security requirements to serve both the medical device industry and the overall health software industry. The resulting second version of the standard has gone through a multistage global voting process to achieve a consensus of the requirements to serve both these communities. The resulting standard has potential to have a major impact on the quality of software used in health care globally.

Sevoflurane and renal function: a meta-analysis of randomized trials.

OBJECTIVE: This study aims to describe the overall cumulative effect of sevoflurane on kidney function in healthy patients in terms of mean plasma creatinine, blood urea nitrogen (BUN), creatinine clearance, urinary protein, and glucose excretion at 24 and 72 hours post-anesthesia. DATA RETRIEVAL: A systematic literature search using MEDLINE and EMBASE as primary search engines was conducted. Articles, relevant abstracts, and citations dated January 1, 1995 to June 30, 2016 were retrieved. DATA SELECTION: Search terms included the pharmacological generic name sevoflurane. Search was expanded using the terms "renal function" OR "kidney" function AND "creatinine" OR "blood urea nitrogen" OR "creatinine clearance" OR "proteinuria" OR "glucosuria" OR "nephrotoxicity." Limitations included randomized controlled trial, humans, and ages 19 and above, to include English and non-English text formats. All bibliographic indices for the relevant journals identified were also searched and collated according to relevance. MAIN OUTCOME MEASURES: Changes in serum/plasma creatinine, BUN, urinary protein, and glucose excretion of sevoflurane at 24 and 72-hours were determined. RESULTS: Six relevant studies were qualified by both the inclusion criteria and inclusion dates. This review consists of 873 patients, 65% are males and 35% are females, with mean age of 56 ± 3 years. Sevoflurane was compared to isoflurane with regard to its nephrotoxic potential. Analyses on the effects of sevoflurane were performed on serum/plasma creatinine, BUN, urinary protein, and glucose excretion at 24 and 72 hours which showed no statistical difference between sevoflurane and isoflurane. CONCLUSION: In an apparently healthy adult without coexisting renal disorder, sevoflurane does not produce elevations in creatinine and BUN above the established upper limit of the reference range.

A comparison of renal responses to sevoflurane and isoflurane in patients undergoing donor nephrectomy: a randomized controlled trial.

Sevoflurane and isoflurane are volatile halogenated ether widely used in anesthesia. Both have comparable potency and easy titratability but sevoflurane has lower pungency and results in faster patient recovery. Isoflurane, however, is more affordable. The nephrotoxicity of sevoflurane is undisputed but studies on isoflurane nephrotoxicity are lacking. The objective of this paper is to determine the overall nephrotoxicity profile of sevoflurane and isoflurane in donor nephrectomy patients using the renal function markers - nuclear glomerular filtration rate (GFR), serum creatinine, urine protein-to-creatinine ratio, proteinuria, and glucosuria. A randomized comparative study of postoperative renal functions in donor nephrectomy patients who had received either low-flow (< 1 L/min) sevoflurane or isoflurane were analyzed. The renal parameters were repeated 72 hours post anesthesia. Forty-seven subjects (46%) were randomized to receive isoflurane while fifty-five received sevoflurane (54%). Between the two anesthetic groups, there was no significant difference in terms of serum creatinine, total GFR, or nuclear GFR. There was a statistically higher proportion of patients with urine protein-to-creatinine ratios of 0.2 and above in the isoflurane group (64% vs. 38%), while more patients in the sevoflurane group had ratios above 0.2 (62% vs. 36%, P < 0.05). The type of anesthetic agent was not an independent predictor of increasing serum creatinine, total GFR and urine protein-to-creatinine ratio and nuclear GFR. In conclusion, the overall nephrotoxicity profile of sevoflurane and isoflurane-treated donor nephrectomy patients is minimal.

Large 14C excursion in 5480 BC indicates an abnormal sun in the mid-Holocene.

Radiocarbon content in tree rings can be an excellent proxy of the past incoming cosmic ray intensities to Earth. Although such past cosmic ray variations have been studied by measurements of 14C contents in tree rings with ≥10-y time resolution for the Holocene, there are few annual 14C data. There is a little understanding about annual 14C variations in the past, with the exception of a few periods including the AD 774-775 14C excursion where annual measurements have been performed. Here, we report the result of 14C measurements using the bristlecone pine tree rings for the period from 5490 BC to 5411 BC with 1- to 2-y resolution, and a finding of an extraordinarily large 14C increase (20‰) from 5481 BC to 5471 BC (the 5480 BC event). The 14C increase rate of this event is much larger than that of the normal grand solar minima. We propose the possible causes of this event are an unknown phase of grand solar minimum, or a combination of successive solar proton events and a normal grand solar minimum.

Cox1 mutation abrogates need for Cox23 in cytochrome c oxidase biogenesis.

Cox23 is a known conserved assembly factor for cytochrome c oxidase, although its role in cytochrome c oxidase (CcO) biogenesis remains unresolved. To gain additional insights into its role, we isolated spontaneous suppressors of the respiratory growth defect in cox23∆ yeast cells. We recovered independent colonies that propagated on glycerol/lactate medium for cox23∆ cells at 37°C. We mapped these mutations to the mitochondrial genome and specifically to COX1 yielding an I101F substitution. The I101F Cox1 allele is a gain-of-function mutation enabling yeast to respire in the absence of Cox23. CcO subunit steady-state levels were restored with the I101F Cox1 suppressor mutation and oxygen consumption and CcO activity were likewise restored. Cells harboring the mitochondrial genome encoding I101F Cox1 were used to delete genes for other CcO assembly factors to test the specificity of the Cox1 mutation as a suppressor of cox23∆ cells. The Cox1 mutant allele fails to support respiratory growth in yeast lacking Cox17, Cox19, Coa1, Coa2, Cox14 or Shy1, demonstrating its specific suppressor activity for cox23∆ cells.

Folding mechanism of the metastable serpin α1-antitrypsin.

The misfolding of serpins is linked to several genetic disorders including emphysema, thrombosis, and dementia. During folding, inhibitory serpins are kinetically trapped in a metastable state in which a stretch of residues near the C terminus of the molecule are exposed to solvent as a flexible loop (the reactive center loop). When they inhibit target proteases, serpins transition to a stable state in which the reactive center loop forms part of a six-stranded ß-sheet. Here, we use hydrogen-deuterium exchange mass spectrometry to monitor region-specific folding of the canonical serpin human α(1)-antitrypsin (α(1)-AT). We find large differences in the folding kinetics of different regions. A key region in the metastable → stable transition, ß-strand 5A, shows a lag phase of nearly 350 s. In contrast, the "B-C barrel" region shows no lag phase and the incorporation of the C-terminal residues into ß-sheets B and C is largely complete before the center of ß-sheet A begins to fold. We propose this as the mechanism for trapping α(1)-AT in a metastable form. Additionally, this separation of timescales in the folding of different regions suggests a mechanism by which α(1)-AT avoids polymerization during folding.

Progress in myeloma stem cells.

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and affects about 4 in 100,000 Americans. Even though much progress has been made in MM therapy, MM remains an incurable disease for the vast majority of patients. The existence of MM stem cell is considered one of the major causes of MM drug-resistance, leading to relapse. This highlights the importance and urgency of developing approaches to target MM stem cells. However, very little is known about the molecular characteristics of the MM stem cells, which makes it difficult to target MM stem cells therapeutically. Evidence of the existence of a myeloma stem cell has been provided by Matsui et al. showing that the CD138- and CD20+ fraction, which is a minor population of the MM cells, has a greater clonogenic potential and has the phenotype of a memory B-cell (CD19+, CD27+). In this review, we report recent progress of cell surface markers in cancer stem cells, especially in myeloma and the molecular mechanisms related to drug resistance and myeloma disease progression.

Cashew nut extract (De BCC) in the treatment of basal cell carcinoma

PURPOSE OF THE STUDY: Basal cell carcinoma (BCC) remains as the most common cutaneous neoplasm in the Philippines consisting of more than 60% of all skin cancers. Anacardium occidentale (Linn.) cashew extract, which had been used successfully in the removal of warts and moles in previous studies, is presented as a therapeutic option in BCC. METHODS: An open-label prospective study was conducted on 36 patients (mean age of 65 years) with documented BCC lesions on middle third of the face. Cashew nut extract (DeBCC) application was offered to these patients as an alternative option to very unacceptable extirpative surgery offered by general and plastic surgeons as treatment for their lesions. Lesion size ranged from 7.5- 64 mm. (26.26 mm). Topical treatment was applied every 1-2 weeks, as needed. Follow-up examinations with photographic documentation were made every week to evaluate success of the treatment. RESULTS: After a mean of 7 treatment applications (range of 1-20) all the lesions were undetectable on clinical examinations. Mild tingling sensation, which was reported by all patients during the treatment applications, was tolerable on all occasions. With follow-up ranging from 5-60 months (38.72 months), 16 patients completed the planned 5 - year post-treatment follow-up period. There were no recurrences detected. CONCLUSIONS: Anacardium occidentale (Linn.) cashew extract (DeBCC) presents a viable and acceptable treatment option in primary BCC. The importance of this treatment option could be stressed in patients with lesions not amenable to the prescribed wide margin of resection needed in surgery.

Disruption of a tight cluster surrounding tyrosine 131 in the native conformation of antithrombin III activates it for factor Xa inhibition.

The native conformation of antithrombin III (ATIII) is a poor inhibitor of its coagulation pathway target enzymes because of the partial insertion of its reactive center loop (RCL) in its central A beta-sheet. This study focused on tyrosine 131, which is located at the helix D-sheet A interface, adjacent to the ATIII pentasaccharide and heparin cofactor-binding sites and some 17A away from the RCL insertion. Crystallographic structures show that the Tyr(131) ring is buried in native ATIII and then becomes exposed when pentasaccharide binds to the inhibitor and activates it. This change suggested that Tyr(131) might serve as a switch for ATIII conformational activation. The hypothesis is supported by results from this study, which progressively removed atoms from the Tyr(131) side chain. Rates of heparin-independent Y131L and Y131A factor Xa inhibition were 25 and 29 times faster than for the control and Y131F, suggesting that Tyr(131) ring interactions with neighboring helix D and strand 2A residues shift the uncatalyzed native-to-activated conformational equilibrium toward the RCL-inserted state. Thermal denaturation experiments showed Y131A and Y131L were less stable than the control and Y131F, implying an increased tendency toward A-sheet mobility in these genetically activated molecules. Thus, the tight Tyr(131)-Asn(127)-Leu(130)-Leu(140)-Ser(142) cluster at the helix D-strand 2A interface of native antithrombin contributes significantly to the stability of the ground state conformation, and tyrosine 131 serves as a heparin-responsive molecular switch during the allosteric activation of ATIII anticoagulant activity.

Aortic counterpulsation: a review of the hemodynamic effects and indications for use.

In the ever evolving field of cardiovascular medicine and coronary intervention, the intra-aortic balloon pump (IABP) is a mature technology, which still plays an important role. The balloon pump invasively supports patient hemodynamics by augmenting diastolic perfusion and increasing diastolic blood pressure, thereby increasing coronary perfusion and reducing afterload. Its efficacy has been demonstrated in a multitude of clinical situations, including acute coronary syndromes, high-risk coronary interventions, cardiogenic shock, and cardiovascular surgery. The potential complications of aortic counterpulsation are serious, although much lower than once feared. With proper patient selection, insertion technique, and management, the IABP is a powerful tool to assist in the treatment of patients with cardiovascular disease. This article will review the hemodynamics, indications, and complications associated with its use.

Clinical predictors and characteristics of patients with chronic liver disease and intrapulmonary shunts.

BACKGROUND: Intrapulmonary shunting (IPS) is a well-described phenomenon in chronic liver disease but its significance is not known. HYPOTHESIS: The study was undertaken to enhance our understanding of the characteristics and prevalence of IPS. METHODS: We retrospectively studied 204 consecutive patients with end-stage chronic liver disease who underwent a dobutamine stress echocardiogram, along with a saline contrast bubble study, as part of their pretransplant evaluation. RESULTS: Intrapulmonary shunting of any degree was present in 56.4% of patients. Patients with IPS were more likely to report alcohol use and less likely to have diabetes mellitus. Patients in Child-Pugh classification C were more likely to have IPS than those with classification A or B. The resting room air PaO2 levels were significantly lower in patients with grade 3-4 IPS than in those with grade 1-2. Elevated estimated pulmonary systolic pressure on echocardiography was more prevalent in patients with than in those without IPS. CONCLUSIONS: A majority of patients with end-stage chronic liver disease undergoing transplant evaluation have IPS. There are important baseline differences between patients with and without IPS. The presence of IPS is associated with increased severity of chronic liver disease. Further study is required to define the prognostic significance of IPS and its impact on future liver transplantation.

Clopidogrel: how good is it and how does it work?

Until recently, long-term antiplatelet therapy for the treatment and prevention of the complications of atherothrombotic disease was limited to aspirin. Although an incredibly cost-effective therapy, in placebo-controlled clinical trials approximately 75% of patients at risk continue to experience thrombotic events despite chronic aspirin therapy. The availability of the thienopyridines, in particular clopidogrel, represents an important addition to the physician's armamentarium. A number of clinical trials have confirmed the efficacy of the combination of clopidogrel and aspirin therapy compared with aspirin alone, with multiple other important large-scale clinical trials currently ongoing. The exact mechanism of this benefit is still being elucidated but is clearly related to the inhibition of the many consequences of platelet activation--vascular inflammation, endothelial dysfunction, and localized angiogenesis/mitogenesis--and not just aggregation.