Development and validation of a simple and practical method for differentiating MS from other neuroinflammatory disorders based on lesion distribution on brain MRI.

There is an unmet need to develop practical methods for differentiating multiple sclerosis (MS) from other neuroinflammatory disorders using standard brain MRI. To develop a practical approach for differentiating MS from neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disorder (MOGAD) with brain MRI, we first identified lesion locations in the brain that are suggestive of MS-associated demyelination ("MS Lesion Checklist") and compared frequencies of brain lesions in the "MS Lesion Checklist" locations in a development sample of patients (n = 82) with clinically definite MS, NMOSD, and MOGAD. Patients with MS were more likely than patients with non-MS to have lesions in 3 locations only: anterior temporal horn (p < 0.0001), periventricular ("Dawson's finger") (p < 0.0001), and cerebellar hemisphere (p = 0.02). These three lesion locations were used as predictor variables in a multivariable regression model for discriminating MS from non-MS. The model had area under the curve (AUC) of 0.853 (95% confidence interval: 0.76-0.945), sensitivity of 87.1%, and specificity of 72.5%. We then used an independent validation sample with equal representation of MS and NMOSD/MOGAD cases (n = 97) to validate our prediction model. In the validation sample, the model was 76.3% accurate in discriminating MS from non-MS. Our simple method for predicting MS versus NMOSD/MOGAD only requires a neuroradiologist or clinician to ascertain the presence of lesions in three locations on conventional MRI sequences. It can therefore be readily applied in the real-world setting for training and clinical practice.

Brain Imaging Use and Findings in COVID-19: A Single Academic Center Experience in the Epicenter of Disease in the United States.

Coronavirus disease 2019 (COVID-19) is a serious public health crisis and can have neurologic manifestations. This is a retrospective observational case series performed March 1-31, 2020, at New York University Langone Medical Center campuses. Clinical and imaging data were extracted, reviewed, and analyzed. Two hundred forty-two patients with COVID-19 underwent CT or MRI of the brain within 2 weeks after the positive result of viral testing (mean age, 68.7 ± 16.5 years; 150 men/92 women [62.0%/38.0%]). The 3 most common indications for imaging were altered mental status (42.1%), syncope/fall (32.6%), and focal neurologic deficit (12.4%). The most common imaging findings were nonspecific white matter microangiopathy (134/55.4%), chronic infarct (47/19.4%), acute or subacute ischemic infarct (13/5.4%), and acute hemorrhage (11/4.5%). No patients imaged for altered mental status demonstrated acute ischemic infarct or acute hemorrhage. White matter microangiopathy was associated with higher 2-week mortality (P < .001). Our data suggest that in the absence of a focal neurologic deficit, brain imaging in patients with early COVID-19 with altered mental status may not be revealing.

Two energetically disparate folding pathways of alpha-lytic protease share a single transition state.

The Lysobacter enzymogenes alpha-lytic protease (alphaLP) is synthesized with a 166 amino acid pro region (Pro) that catalyzes the folding of the 198 amino acid protease into its native conformation. An extraordinary feature of this system is the very high energy barrier (DeltaG = 30 kcal mol-1) that effectively prevents alphaLP from folding in the absence of Pro (t1/2 = 1800 years). A pair of mutations has been isolated in the protease that completely suppresses the catalytic defect incurred in Pro by truncation of its last three amino acids. These mutations also accelerate the folding of alphaLP in the absence of Pro by 400-fold. An energetic analysis of the two folding reactions indicates that the mutations stabilize the transition states of both the catalyzed and uncatalyzed folding reactions by 3 kcal mol-1. This finding points to a single transition state for these two distinct and energetically disparate folding pathways, and raises the possibility that all alphaLP folding pathways share the same transition state.

Escherichia coli alkaline phosphatase localized to the cytoplasm slowly acquires enzymatic activity in cells whose growth has been suspended: a caution for gene fusion studies.

Alkaline phosphatase is normally localized to the periplasm of Escherichia coli and is unable to fold into its native conformation if retained in the cytoplasm of growing cells. The alkaline phosphatase activity of E. coli expressing a version of the protein without a signal sequence was nonetheless found to increase gradually when the growth of cells was suspended. At least 30% of the protein was activated over the course of several hours when freshly grown exponential-phase cells were held on ice. Similar behavior was observed with cells expressing certain other mutant versions of alkaline phosphatase that are retained in the cytoplasm. The activation resulted not from the passage of the alkaline phosphatase into the periplasm but from the slow folding of alkaline phosphatase into its native conformation in the cytoplasm. These findings indicate that the mechanism by which proteins are normally kept reduced in the cytoplasm fails to function if cells are not growing. It was found that the addition of the sulfhydryl-alkylating agent iodoacetamide to cells after growth blocks this activation completely. This treatment can therefore diminish the likelihood of spurious enzyme activity measurements in studies that make use of alkaline phosphatase fusion proteins.

Mutations that allow disulfide bond formation in the cytoplasm of Escherichia coli.

Disulfide bonds are rarely found in cytoplasmic proteins. Mutations were selected for in Escherichia coli that allow disulfide bond formation in the cytoplasm. In the presence of these mutations, export-defective versions of alkaline phosphatase and mouse urokinase were able to fold into their enzymatically active conformations in the cytoplasm because their disulfide bonds were formed. The mutations were mapped to the gene for thioredoxin reductase and diminish or eliminate the activity of this enzyme. Thioredoxin itself was found to be unnecessary for this disulfide bond formation. Thioredoxin reductase, but not thioredoxin, is thus implicated in keeping cysteines reduced in cytoplasmic proteins.

A signal sequence is not required for protein export in prlA mutants of Escherichia coli.

The prlA/secY gene, which codes for an integral membrane protein component of the Escherichia coli protein export machinery, is the locus of the strongest suppressors of signal sequence mutations. We demonstrate that two exported proteins of E.coli, maltose-binding protein and alkaline phosphatase, each lacking its entire signal sequence, are exported to the periplasm in several prlA mutants. The export efficiency can be substantial; in a strain carrying the prlA4 allele, 30% of signal-sequenceless alkaline phosphatase is exported to the periplasm. Other components of the E.coli export machinery, including SecA, are required for this export. SecB is required for the export of signal-sequenceless alkaline phosphatase even though the normal export of alkaline phosphatase does not require this chaperonin. Our findings indicate that signal sequences confer speed and efficiency upon the export process, but that they are not always essential for export. Entry into the export pathway may involve components that so overlap in function that the absence of a signal sequence can be compensated for, or there may exist one or more means of entry that do not require signal sequences at all.

[Gastrectomy at the peak of gastric bleeding]. / Gastrektomiia na vysote zheludochnogo krovotecheniia.

The technique for performance of gastrectomy under conditions of emergency surgery permitting to shorten the duration of intervention and increase its effectiveness is presented. Gastrectomy was performed in 7 patients with gastric cancer complicated by profuse bleeding. All the patients are alive, no anastomotic suture failure occurred.

Escherichia coli alkaline phosphatase fails to acquire disulfide bonds when retained in the cytoplasm.

The cysteines of the Escherichia coli periplasmic enzyme alkaline phosphatase, which are involved in disulfide bonds in the native enzyme, were found to be fully reduced when the protein was retained in the cytoplasm. Under these circumstances the cysteines remained reduced for at least several minutes after the synthesis of the protein was completed. This contrasted with the normally exported protein, wherein disulfide bonds formed rapidly. Disulfide bond formation accompanied export and processing. The implications of these findings for the inactivity of the enzyme in the cytoplasm are discussed.

[Total gastrectomy in the surgery of malignant stomach neoplasms]. / Total'naia gastréktomiia v khirurgii zlokachestvennykh novoobrazovanii zheludka.

An analysis of surgical treatment of 100 patients with malignant tumors of the stomach with using total gastrectomy has shown that postoperative lethality made up 90%, unfavorable results of using total gastrectomy being associated with insufficient sutures of the esophageal-intestinal anastomosis. The modified method used allows to elevate reliability of the esophageal intestinal anastomosis, to shorten the time of operative procedure. Total gastrectomy followed by chemotherapy in the postoperative period prolongs the patient's life, but does not secure against recurrences of the disease in later terms.

[Results of surgical treatment of bleeding gastric tumors]. / Rezul'taty khirurgicheskogo lecheniia krovotochashchikh opukholei zheludka.

The results of surgical treatment of 132 patients with gastric tumors complicated by bleeding are presented. In 58.4% of the patients, the radical intervention was performed, in uncomplicated course of a disease--in 73.2%. Lethality after the emergency operations was 38.1% and considerably exceeded that after the elective interventions (7.8%). This dictates the necessity to improve the conservative hemostatic measures.

[Serum gastrin level after surgical treatment of duodenal ulcer hemorrhage]. / Soderzhanie gastrina v syvorotke krovi bol'nykh pri khirurgicheskom lechenii iazvennogo duodenal'nogo krovotecheniia.

The serum gastrin content in patients with ulcerous duodenal bleeding was studied in the process of surgical treatment. A significant decrease in the hormone concentration with increase in the volume of acute blood loss was noted.

[Organization of medical services for patients with nonspecific diseases of the respiratory organs in the regions with predominantly rural population]. / Organizatsiia meditsinskoi pomoshchi bol'nym s nespetsificheskimi bolezniami organov dykhaniia v regionakh s preobladaniem sel'skogo naseleniia.

Pneumologic bed demand for adult population was established (0.6 per 1000 residents) and data are given concerning the organization of specialized pneumologic departments at the republican, urban and rural level. The expediency of establishing payment rate for pneumotologists at CRH polyclinics in regions with numerous adult population (40,000 residents and more) was shown. Data are presented on the coverage of outpatient follow-up of patients with nonspecific respiratory diseases, on mortality from all nonspecific pulmonary diseases and pneumonia for 1986-1989. The mortality rates were found to be reduced during this period by 34.9% and 47.4%, respectively.

[Individual active surgical tactics in acute gastroduodenal hemorrhage caused by peptic ulcer]. / Individua'lno-aktivnaia khirurgicheskaia taktika pri ostrykh gastroduodena'lnykh krovotecheniiakh iazvennogo geneza.

The current possibilities for identifying the sources and volumes of bleeding as well as the methods of local and general hemostatic therapy allow individual-active surgical tactics to be employed in acute hemorrhage from an ulcer. It is based on consideration for the severity, volume, rate, and duration of bleeding, the localization and visual appraisal of the ulcerous substrate and the vessel undergoing erosion, the patient's age, the concomitant pathological conditions, and the degree of the operative risk. Operations in such cases should be distributed into 3 groups: emergency, postponed, and early planned. Individual choice with due account for the indications for each group of operations, which was determined in 1,789 operative interventions, made it possible to reduce the total postoperative mortality to 2.9%.