Molecular mechanism of kNBC1–carbonic anhydrase II interaction in proximal tubule cells

We have recently shown that carbonic anhydrase II (CAII) binds in vitro to the C-terminus of the electrogenic sodium bicarbonate cotransporter kNBC1 (kNBC1-ct). In the present study we determined the molecular mechanisms for the interaction between the two proteins and whether kNBC1 and CAII form a transport metabolon in vivo wherein bicarbonate is transferred from CAII directly to the cotransporter. Various residues in the C-terminus of kNBC1 were mutated and the effect of these mutations on both the magnitude of CAII binding and the function of kNBC1 expressed in mPCT cells was determined. Two clusters of acidic amino acids, L⁹⁵⁸DDV and D⁹⁸⁶NDD in the wild-type kNBC1-ct involved in CAII binding were identified. In both acidic clusters, the first aspartate residue played a more important role in CAII binding than others. A significant correlation between the magnitude of CAII binding and kNBC1-mediated flux was shown. The results indicated that CAII activity enhances flux through the cotransporter when the enzyme is bound to kNBC1. These data are the first direct evidence that a complex of an electrogenic sodium bicarbonate cotransporter with CAII functions as a transport metabolon.     

Irritable bowel syndrome: in search of an etiology: role of Blastocystis hominis

This study was designed to examine stool specimens of irritable bowel syndrome (IBS) patients for Blastocystis hominis, a common intestinal parasite. One hundred fifty patients were enrolled, 95 IBS cases and 55 controls. These patients provided a medical history, and underwent physical and laboratory evaluations that included stool microscopy and culture for B. hominis and colonoscopy. The 95 cases (51 males and 44 females) had a mean +/- SD age of 37.8 +/- 13.2 years. Stool microscopy was positive for B. hominis in 32% (30 of 95) of the cases and 7% (4 of 55) of the controls (P = 0.001). Stool culture was positive in 46% (44 of 95) of the cases and 7% (4 of 55) of the controls (P < 0.001). Stool culture for B. hominis in IBS was more sensitive than microscopy (P < 0.001). Blastocystis hominis was frequently demonstrated in the stool samples of IBS patients; however, its significance in IBS still needs to be investigated. Stool culture has a higher positive yield for B. hominis than stool microscopy.     

Analysis of the direct cost of surgery for four diagnostic categories of adult spinal deformity

Background contextExisting literature on adult spinal deformity (ASD) offers little guidance regarding an evidence-based approach to care. To optimize the value of medical treatment, a thorough understanding of the cost of surgical treatment for ASD is required.PurposeTo evaluate four clinically and radiographically distinct groups of ASD and identify and compare the cost of surgical treatment among the groups.Study design/settingMulticenter retrospective study of consecutive surgeries for ASD.Patient sampleThree hundred twenty-five consecutive ASD patients treated between 2008 and 2010.Outcome measuresCost data were collected from hospital administrative records on the direct costs (DCs) incurred for the episode of surgical care, excluding overhead.MethodsBased on preoperative radiographs and history, patients were categorized into one of four diagnostic categories of deformity: primary idiopathic scoliosis (PIS), primary degenerative scoliosis (PDS), primary sagittal plane deformity (PSPD), and revision (R). Analysis of variance and generalized linear model regressions were used to analyze the DCs of surgery and to assess differences in costs across the four diagnostic categories considered.ResultsSignificant differences were observed in DC of surgery for different categories of ASD, with surgical treatment for PDS the most expensive followed in decreasing order by PSPD, PIS, and R (p<.01). Results further revealed a significant positive relationship between age and DC (p<.01) and a significant positive relationship between length of stay and DC (p<.01). Among PIS patients, for every incremental increase in levels fused, the expected DC increased by $3,997 (p=.00). Fusion to pelvis also significantly increased the DC of surgery for patients aged 18 to 29 years (p<.01) and 30 to 59 years (p<.01) but not for 60 years or more (p=.86).ConclusionsThere is an increasing DC of surgery with increasing age, length of hospital stay, length of fusion, and fusions to the pelvis. Revision surgery is the least expensive surgery on average and should therefore not preclude its consideration from a pure cost perspective.     

cheML.io: an online database of ML-generated molecules

Several recent ML algorithms for de novo molecule generation have been utilized to create an open-access database of virtual molecules. The algorithms were trained on samples from ZINC, a free database of commercially available compounds. Generated molecules, stemming from 10 different ML frameworks, along with their calculated properties were merged into a database and coupled to a web interface, which allows users to browse the data in a user friendly and convenient manner. ML-generated molecules with desired structures and properties can be retrieved with the help of a drawing widget. For the case of a specific search leading to insufficient results, users are able to create new molecules on demand. These newly created molecules will be added to the existing database and as a result, the content as well as the diversity of the database keeps growing in line with the user''s requirements.

Several recent ML algorithms for de novo molecule generation have been utilized to create an open-access database of virtual molecules.     

Characterization of Adverse Events Detected in a Large Health Care Delivery System Using an Enhanced Global Trigger Tool over a Five‐Year Interval

Objective

To report 5 years of adverse events (AEs) identified using an enhanced Global Trigger Tool (GTT) in a large health care system.

Study Setting

Records from monthly random samples of adults admitted to eight acute care hospitals from 2007 to 2011 with lengths of stay ≥3 days were reviewed.

Study Design

We examined AE incidence overall and by presence on admission, severity, stemming from care provided versus omitted, preventability, and category; and the overlap with commonly used AE-detection systems.

Data Collection

Professional nurse reviewers abstracted 9,017 records using the enhanced GTT, recording triggers and AEs. Medical record/account numbers were matched to identify overlapping voluntary reports or AHRQ Patient Safety Indicators (PSIs).

Principal Findings

Estimated AE rates were as follows: 61.4 AEs/1,000 patient-days, 38.1 AEs/100 discharges, and 32.1 percent of patients with ≥1 AE. Of 1,300 present-on-admission AEs (37.9 percent of total), 78.5 percent showed NCC-MERP level F harm and 87.6 percent were “preventable/possibly preventable.” Of 2,129 hospital-acquired AEs, 63.3 percent had level E harm, 70.8 percent were “preventable/possibly preventable”; the most common category was “surgical/procedural” (40.5 percent). Voluntary reports and PSIs captured <5 percent of encounters with hospital-acquired AEs.

Conclusions

AEs are common and potentially amenable to prevention. GTT-identified AEs are seldom caught by commonly used AE-detection systems.     

Alterations of Ca-responsive proteins within cholinergic neurons in aging and Alzheimer's disease

The molecular basis of selective neuronal vulnerability in Alzheimer's disease (AD) remains poorly understood. Using basal forebrain cholinergic neurons (BFCNs) as a model and immunohistochemistry, we have demonstrated significant age-related loss of the calcium-binding protein calbindin-D_28K (CB) from BFCN, which was associated with tangle formation and degeneration in AD. Here, we determined alterations in RNA and protein for CB and the Ca²⁺-responsive proteins Ca²⁺/calmodulin-dependent protein kinase I (CaMKI), growth-associated protein-43 (GAP43), and calpain in the BF. We observed progressive downregulation of CB and CaMKI RNA in laser-captured BFCN in the normal-aged-AD continuum. We also detected progressive loss of CB, CaMKIδ, and GAP43 proteins in BF homogenates in aging and AD. Activated μ-calpain, a calcium-sensitive protease that degrades CaMKI and GAP43, was significantly increased in the normal aged BF and was 10 times higher in AD BF. Overactivation of μ-calpain was confirmed using proteolytic fragments of its substrate spectrin. Substantial age- and AD-related alterations in Ca²⁺-sensing proteins most likely contribute to selective vulnerability of BFCN to degeneration in AD.