Risk factors for ischemic cerebral stroke in patients with acute amaurosis fugax.

OBJECTIVE: The National Stroke Association and the American Heart Association consider retinal ischemia, as in the case of amaurosis fugax (AF), to be a stroke event. The purpose of this study was to evaluate the risk factors for ischemic cerebral stroke in patients hospitalized for acute AF. METHODS: The National Inpatient Sample Database from 2002 to 2014 was used to identify patients 21 years of age and older with a primary admission diagnosis of AF with the ICD-9 code 362.34. Comorbidity measures and in-hospital events were extracted using relevant ICD-9 codes. Statistical analyses were performed using IBM SPSS 25 and R package. RESULTS: A weighted total of 12,142 patients was identified. The most common comorbidities in this cohort with AF included hypertension, dyslipidemia, tobacco use, coronary artery disease (CAD), and diabetes mellitus. Multivariable regression analysis showed comorbidities of hypercoagulable state, systemic vasculitis, CAD, and atherosclerosis to be independent risk factors for ischemic stroke in patients with AF. In contrast, dyslipidemia was associated with a decreased risk. Asian/Pacific Islander race conferred a 5-fold increased risk compared with Whites. CONCLUSION: Ischemic stroke and myocardial infarction were diagnosed in 0.3%-0.9% of hospitalized acute AF cases. Presence of hypercoagulable state, systemic vasculitis, CAD, and atherosclerosis each individually increased the risk of ischemic stroke by more than 3-fold; patients with these risk factors and acute AF should be closely monitored for developing acute systemic thrombotic events.

Risk factors for central retinal vein occlusion in young adults.

PURPOSE: Several risk factors have been identified for central retinal vein occlusion (CRVO) in older population. CRVO in young is uncommon, and the risk factors for this group are unclear. This large retrospective, cross-sectional study used the National Inpatient Sample (NIS) database to evaluate the risk factors for CRVO in patients 18 to 40 years of age. METHODS: The 2002 to 2014 NIS database was used. All patients 18 to 40 years of age with a primary diagnosis of CRVO were identified. Age- and gender-matched non-CRVO controls were randomly selected. The primary outcome was identification of risk factors for CRVO. Chi-square analysis and Firth logistic regression were performed with IBM SPSS 23 and R packages versions 3.4.3, respectively. p < 0.05 was considered significant. RESULTS: A total of 95 weighted young CRVO patients were identified. The average age was 31.44 ± 6.41 years with no gender predilection. Systemic and ocular conditions found to have statistically significant associations with CRVO included primary open-angle glaucoma (POAG) (OR 836.72, p < 0.001), retinal vasculitis (OR 705.82, p < 0.001), pseudotumor cerebri (OR 35.94, p < 0.001), hypercoagulable state (OR 25.25, p < 0.001), history of deep vein thrombosis/pulmonary embolism (DVT/PE) (OR 21.88, p < 0.001), and hyperlipidemia (OR 3.60, p = 0.003). CONCLUSION: The most significant risk factors for CRVO in young adults were POAG, retinal vasculitis, and pseudotumor cerebri. Hypercoagulable states and DVT/PE were also associated with CRVO in this population. Systemic inflammatory conditions were not associated with CRVO. Traditional risk factors such as hypertension and diabetes did not pose significant risks, whereas hyperlipidemia was deemed a significant risk factor.

Refractive surgery for the patient with autoimmune diseases.

PURPOSE OF REVIEW: Autoimmune and immune-mediated diseases are considered contraindications for laser refractive surgeries according to the US Food and Drug Administration's guideline. This guideline, however, is based on limited case reports or complications reported during other intraocular procedures. There have been only a handful of new clinical studies that evaluate the efficacy and safety of refractive surgery in this specific patient population. The aim of this article is to review currently available research and offer updated recommendations for the evaluation and management of laser refractive surgery (LRS) in patients with autoimmune diseases. RECENT FINDINGS: More recent retrospective studies have reported good refractive outcomes in patients with well controlled autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, seronegative spondyloarthropathy, among others. No severe sight-threatening complications have been reported in these reports. Although postoperative complications occur, the risk of refractive surgery is comparable with those without autoimmune diseases. SUMMARY: With the exception of primary Sjogren's syndrome, patients with autoimmune diseases may be good candidates for LRS if diseases are well controlled and have minimal ophthalmic manifestation. Patients should be made aware of the potential surgical complications and be informed of the currently available data. More multicenter and larger prospective studies are needed to compare the refractive outcomes and surgical complications in patients with and without autoimmune diseases. This will help patients make better informed medical decisions.

Structural and Genetic Analyses of the Mycobacterium tuberculosis Protein Kinase B Sensor Domain Identify a Potential Ligand-binding Site.

Monitoring the environment with serine/threonine protein kinases is critical for growth and survival of Mycobacterium tuberculosis, a devastating human pathogen. Protein kinase B (PknB) is a transmembrane serine/threonine protein kinase that acts as an essential regulator of mycobacterial growth and division. The PknB extracellular domain (ECD) consists of four repeats homologous to penicillin-binding protein and serine/threonine kinase associated (PASTA) domains, and binds fragments of peptidoglycan. These properties suggest that PknB activity is modulated by ECD binding to peptidoglycan substructures, however, the molecular mechanisms underpinning PknB regulation remain unclear. In this study, we report structural and genetic characterization of the PknB ECD. We determined the crystal structures of overlapping ECD fragments at near atomic resolution, built a model of the full ECD, and discovered a region on the C-terminal PASTA domain that has the properties of a ligand-binding site. Hydrophobic interaction between this surface and a bound molecule of citrate was observed in a crystal structure. Our genetic analyses in M. tuberculosis showed that nonfunctional alleles were produced either by deletion of any of single PASTA domain or by mutation of individual conserved residues lining the putative ligand-binding surface of the C-terminal PASTA repeat. These results define two distinct structural features necessary for PknB signal transduction, a fully extended ECD and a conserved, membrane-distal putative ligand-binding site.

DNA-damage-inducible 1 protein (Ddi1) contains an uncharacteristic ubiquitin-like domain that binds ubiquitin.

Ddi1 belongs to a family of shuttle proteins targeting polyubiquitinated substrates for proteasomal degradation. Unlike the other proteasomal shuttles, Rad23 and Dsk2, Ddi1 remains an enigma: its function is not fully understood and structural properties are poorly characterized. We determined the structure and binding properties of the ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains of Ddi1 from Saccharomyces cerevisiae. We found that while Ddi1UBA forms a characteristic UBA:ubiquitin complex, Ddi1UBL has entirely uncharacteristic binding preferences. Despite having a ubiquitin-like fold, Ddi1UBL does not interact with typical UBL receptors but unexpectedly binds ubiquitin, forming a unique interface mediated by hydrophobic contacts and by salt bridges between oppositely charged residues of Ddi1UBL and ubiquitin. In stark contrast to ubiquitin and other UBLs, the ß-sheet surface of Ddi1UBL is negatively charged and therefore is recognized in a completely different way. The dual functionality of Ddi1UBL, capable of binding both ubiquitin and proteasome, suggests an intriguing mechanism for Ddi1 as a proteasomal shuttle.

Delayed hematuria secondary to bleeding papilla--potential complication of laparoscopic partial nephrectomy.

The complications of partial nephrectomy include hemorrhage, urinary leak, infection, formation of urinary fistula, and the development of renal insufficiency. We report a unique case of a patient who was found to have necrotic-appearing, bleeding, renal papillae after undergoing laparoscopic partial nephrectomy. A 66-year-old man was diagnosed with a left-sided, solid, enhancing, 2.5-cm, exophytic renal mass. Laparoscopic partial nephrectomy was performed, and the warm ischemia time was 31 minutes. He recovered uneventfully from surgery, but he started having episodes of gross hematuria approximately 5 months later. Computed tomography scan showed changes consistent with previous partial nephrectomy but no other abnormality. Ureterorenoscopy allowed us to identify several necrotic-appearing papillae in the same kidney that had undergone laparoscopic partial nephrectomy. A papilla in the lower pole was actively bleeding, and it was successfully obliterated using neodymium:yttrium-aluminum-garnet laser technology. Papillary necrosis can be a rare complication of laparoscopic or open partial nephrectomy. Additional study and close follow-up of patients who undergo partial nephrectomy is warranted.

Feasibility of extended use of an electromagnetic lithotripter beyond the manufacturer's recommended maintenance schedule.

OBJECTIVES: The study evaluates the effect of chronic usage, beyond the recommended maintenance schedule, on the efficacy of electromagnetic lithotripter. To our knowledge, there is no publication investigating the effect of chronic usage on the electromagnetic lithotripter, despite the maintenance schedule established by the manufacturers. Our goal is to verify if the acoustic parameters of the shock wave changed with usage, and if this change could be associated with change in clinical efficacy. METHODS: This study lasted 18 months. Every 6 months the lithotripter's efficacy was evaluated in two ways: objectively and clinically. Objective efficacy was measured using a piezoelectric hydrophone and artificial stones to capture the acoustic parameters and the crater of fragmentation, respectively. Clinical efficacy data was collected by studying the rate of successful extracorporeal shock wave lithotripsy treatment in patients with urolithiasis. The changes in clinical efficacy, acoustic parameters, and craters of fragmentation were compared and analyzed with appropriate statistical methods. RESULTS: Five hundred twenty five patients participated in the study. The clinical efficacy remained stable throughout the three observation periods (55.7%, 66.2% and 55.5%; p = 0.11). The focal head of the lithotripter was used three times the recommended schedule. There was no obvious change in the acoustic parameters of the shock waves, and the focal zone remained stable. CONCLUSIONS: The clinical efficacy of the electromagnetic lithotripter appears to be stable despite usage beyond the recommended maintenance schedule. More studies are needed to validate the safety of this practice.

A single mutation in the active site swaps the substrate specificity of N-acetyl-L-ornithine transcarbamylase and N-succinyl-L-ornithine transcarbamylase.

Transcarbamylases catalyze the transfer of the carbamyl group from carbamyl phosphate (CP) to an amino group of a second substrate such as aspartate, ornithine, or putrescine. Previously, structural determination of a transcarbamylase from Xanthomonas campestris led to the discovery of a novel N-acetylornithine transcarbamylase (AOTCase) that catalyzes the carbamylation of N-acetylornithine. Recently, a novel N-succinylornithine transcarbamylase (SOTCase) from Bacteroides fragilis was identified. Structural comparisons of AOTCase from X. campestris and SOTCase from B. fragilis revealed that residue Glu92 (X. campestris numbering) plays a critical role in distinguishing AOTCase from SOTCase. Enzymatic assays of E92P, E92S, E92V, and E92A mutants of AOTCase demonstrate that each of these mutations converts the AOTCase to an SOTCase. Similarly, the P90E mutation in B. fragilis SOTCase (equivalent to E92 in X. campestris AOTCase) converts the SOTCase to AOTCase. Hence, a single amino acid substitution is sufficient to swap the substrate specificities of AOTCase and SOTCase. X-ray crystal structures of these mutants in complexes with CP and N-acetyl-L-norvaline (an analog of N-acetyl-L-ornithine) or N-succinyl-L-norvaline (an analog of N-succinyl-L-ornithine) substantiate this conversion. In addition to Glu92 (X. campestris numbering), other residues such as Asn185 and Lys30 in AOTCase, which are involved in binding substrates through bridging water molecules, help to define the substrate specificity of AOTCase. These results provide the correct annotation (AOTCase or SOTCase) for a set of the transcarbamylase-like proteins that have been erroneously annotated as ornithine transcarbamylase (OTCase, EC 2.1.3.3).

Prospective, randomized, double-blind study of safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC).

OBJECTIVE: To determine the safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC) patients. MATERIALS AND METHODS: IC patients were instilled with 50 cc of test solution containing either placebo, 0.05 microM or 0.10 microM RTX in the bladder. Plasma concentration of RTX and its degradant resiniferonol 9-, 13-, 14-orthophenylacetate was measured. Immediate post-treatment blood sampling and cystoscopy were performed. Symptoms were evaluated before treatment, at 4- and at 12-week follow-ups, using VAS indicator for pain, voiding diary, and O'Leary's IC symptom/problem indices. RESULTS: Among 22 patients observed (ten in 0.10 microM RTX, eight in 0.05 microM RTX, and four in placebo groups), the most commonly reported adverse event was pain during instillation (80.0%, 87.5%, and 25.0%). No serious adverse events were reported. CONCLUSIONS: Use of intravesical RTX in IC patients is associated with important tolerability issues but safe at 0.10 microM and 0.05 microM.