Reactive Oxygen Species Modulation of Na/K-ATPase Regulates Fibrosis and Renal Proximal Tubular Sodium Handling

The Na/K-ATPase is the primary force regulating renal sodium handling and plays a key role in both ion homeostasis and blood pressure regulation. Recently, cardiotonic steroids (CTS)-mediated Na/K-ATPase signaling has been shown to regulate fibrosis, renal proximal tubule (RPT) sodium reabsorption, and experimental Dahl salt-sensitive hypertension in response to a high-salt diet. Reactive oxygen species (ROS) are an important modulator of nephron ion transport. As there is limited knowledge regarding the role of ROS-mediated fibrosis and RPT sodium reabsorption through the Na/K-ATPase, the focus of this review is to examine the possible role of ROS in the regulation of Na/K-ATPase activity, its signaling, fibrosis, and RPT sodium reabsorption

Multivalent Recognition of Peptides by Modular Self-Assembled Receptors

Developing nontraditional approaches to the synthesis and characterization of multivalent compounds is critical to our efforts to study and interface with biological systems and to build new noncovalent materials. This paper demonstrates a biomimetic approach to the construction of discrete, modular, multivalent receptors via molecular self-assembly in aqueous solution. Scaffolds presenting 1−3 viologen groups recruit a respective 1−3 copies of the synthetic host, cucurbit[8]uril, in a noncooperative manner and with a consistent equilibrium association constant (Ka) value of 2 × 106 M−1 per binding site. The assembled mono-, di-, and trivalent receptors bind to their cognate target peptides containing 1−3 Trp residues with Ka values in the range 1.7 × 104−4.7 × 106 M−1 and in predetermined mono- or multivalent binding modes with 31−280-fold enhancements in affinity and additive enthalpies due to multivalency. The extent of valency was determined directly by measuring the visible charge-transfer absorptivity due to the viologen−indole pair. The predictable behavior of this system and its ease of synthesis and analysis make it well suited to serve as a model for multivalent binding and for the multivalent recognition of peptides by design

Note and Comment

Attendance at the Law School; An Extreme Case in the Application of the Safety Appliance Act; Advisory Opinions; Refusal of Specific Performance Where Subsequent Unexpected Events Render it Inequitable; Is Vasectomy a Cruel Punishmen

Note and Comment

The Renvoi Theory Repudiated as a Test for Determining the Negotiability of a Note - A recent case decided by the Supreme Court of Oklahoma (Bell v. Riggs, 127 Pac. 427) involving, among others, a question as to what law governs the negotiability of a note made in one State and payable in another, though of little intrinsic value so far as that point is concerned, is of some interest because the attorney for the holder of the note made a curious attempt to adapt the renvoi theory to his case. The term renvoi is used as a convenient descriptive term denoting that when the transaction involves a conflict of laws, the judge of the forum shall take into account not the particular law of the situs to which the le.x fori refers the transaction, but the rules of private international law prevailing in that country, without regard to the particular law which may be deemed to control in the end. For example, suppose a citizen of New York, formerly a resident of that State, dies domiciled in Italy having personal property in New York, and suppose that a question arises in the New York courts with respect to. the distribution of the property. By the law of the forum, the rule has been adopted that the law of the domicile of the deceased at the time of his death shall govern the distribution of his personal estate. Hence distribution must be determined by the Italian law. But what is meant by Italian law

Rapid Stereomicroscopic Imaging of HER2 Overexpression in Ex Vivo Breast Tissue Using Topically Applied Silica-Based Gold Nanoshells

Tumor margin detection for patients undergoing breast conservation surgery primarily occurs postoperatively. Previously, we demonstrated that gold nanoshells rapidly enhance contrast of HER2 overexpression in ex vivo tissue sections. Our ultimate objective, however, is to discern HER2 overexpressing tissue from normal tissue in whole, nonsectioned, specimens to facilitate rapid diagnoses. Here, we use targeted nanoshells to quickly and effectively visualize HER2 receptor expression in intact ex vivo human breast tissue specimens. Punch biopsies of human breast tissue were analyzed after a brief 5-minute incubation with and without HER2-targeted silica-gold nanoshells using two-photon microscopy and stereomicroscopy. Labeling was subsequently verified using reflectance confocal microscopy, darkfield hyperspectral imaging, and immunohistochemistry to confirm levels of HER2 expression. Our results suggest that anti-HER2 nanoshells used in tandem with a near-infrared reflectance confocal microscope and a standard stereomicroscope may potentially be used to discern HER2-overexpressing cancerous tissue from normal tissue in near real time and offer a rapid supplement to current diagnostic techniques

Dosimetry, clinical factors and medication intake influencing urinary symptoms after prostate radiotherapy: An analysis of data from the RADAR prostate radiotherapy trial

Purpose/Objective: To identify dosimetry, clinical factors and medication intake impacting urinary symptoms after prostate radiotherapy. Material and Methods: Data describing clinical factors and bladder dosimetry (reduced with principal component (PC) analysis) for 754 patients treated with external beam radiotherapy accrued by TROG 03.04 RADAR prostate radiotherapy trial were available for analysis. Urinary symptoms (frequency, incontinence, dysuria and haematuria) were prospectively assessed using LENT-SOMA to a median of 72 months. The endpoints assessed were prevalence (grade≥1) at the end of radiotherapy (representing acute symptoms), at 18-, 36- and 54-month follow-ups (representing late symptoms) and peak late incidence including only grade≥2. Impact of factors were assessed using multivariate logistic regression models with correction for over-optimism. Results: Baseline symptoms, non-insulin dependent diabetes mellitus, age and PC1 (correlated to the mean dose) impact symptoms at \u3e1 timepoints. Associations at a single timepoint were found for cerebrovascular condition, ECOG status and non-steroidal anti-inflammatory drug intake. Peak incidence analysis shows the impact of baseline, bowel and cerebrovascular condition and smoking status. Conclusions: The prevalence and incidence analysis provide a complementary view for urinary symptom prediction. Sustained impacts across time points were found for several factors while some associations were not repeated at different time points suggesting poorer or transient impact

Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response

Background: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value

Clinical selection strategies to identify ischemic stroke patients with large anterior vessel occlusion: results from SITS-ISTR (Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry)

Background and Purpose—The National Institutes of Health Stroke Scale (NIHSS) correlates with presence of large anterior vessel occlusion (LAVO). However, the application of the full NIHSS in the prehospital setting to select patients eligible for treatment with thrombectomy is limited. Therefore, we aimed to evaluate the prognostic value of simple clinical selection strategies. Methods—Data from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry (January 2012–May 2014) were analyzed retrospectively. Patients with complete breakdown of NIHSS scores and documented vessel status were included. We assessed the association of prehospital stroke scales and NIHSS symptom profiles with LAVO (internal carotid artery, carotid-terminus or M1-segment of the middle cerebral artery). Results—Among 3505 patients, 23.6% (n=827) had LAVO. Pathological finding on the NIHSS item best gaze was strongly associated with LAVO (adjusted odds ratio 4.5, 95% confidence interval 3.8–5.3). All 3 face–arm–speech–time test (FAST) items identified LAVO with high sensitivity. Addition of the item gaze to the original FAST score (G-FAST) or high scores on other simplified stroke scales increased specificity. The NIHSS symptom profiles representing total anterior syndromes showed a 10-fold increased likelihood for LAVO compared with a nonspecific clinical profile. If compared with an NIHSS threshold of ≥6, the prehospital stroke scales performed similarly or even better without losing sensitivity. Conclusions—Simple modification of the face–arm–speech–time score or evaluating the NIHSS symptom profile may help to stratify patients’ risk of LAVO and to identify individuals who deserve rapid transfer to comprehensive stroke centers. Prospective validation in the prehospital setting is required

Comprehensive Record of Volcanic Eruptions in the Holocene (11,000 years) From the WAIS Divide, Antarctica Ice Core

A comprehensive record (WHV2020) of explosive volcanic eruptions in the last 11,000 years is reconstructed from the West Antarctica Ice Sheet Divide deep ice core (WDC). The chronological list of 426 large volcanic eruptions in the Southern Hemisphere and the low latitudes during the Holocene are of the highest quality of all volcanic records from ice cores, owing to the high-resolution chemical measurement of the ice core and the exceptionally accurate WDC timescale. No apparent trend is found in the frequency (number of eruptions per millennium) of volcanic eruptions, and the number of eruptions in the most recent millennium (1,000–2,000 CE) is only slightly higher than the average in the last 11 millennia. The atmospheric aerosol mass loading of climate-impacting sulfur, estimated from measured volcanic sulfate deposition, is dominated by explosive eruptions with extraordinarily high sulfur mass loading. Signals of three major volcanic eruptions are detected in the second half of the 17th century (1700–1600) BCE when the Thera volcano in the eastern Mediterranean was suspected to have erupted; the fact that these signals are synchronous with three volcanic eruptions detected in Greenland ice cores suggests that these are likely eruptions in the low latitudes and none should be attributed exclusively to Thera. A number of eruptions with very high sulfur mass loading took place shortly before and during an early Holocene climatic episode, the so-called 8.2 ka event, and are speculated to have contributed to the initiation and magnitude of the cold event