Miracle-dz/UniFAR-FTUs huggingface dataset:
Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling

ABSTRACT Expanding echinocandin use to prevent or treat invasive fungal infections has led to an increase in the number of breakthrough infections due to resistant Candida species. Although it is uncommon, echinocandin resistance is well documented for Candida albicans, which is among the most prevalent bloodstream organisms. A better understanding is needed to assess the cellular factors that promote tolerance and predispose infecting cells to clinical breakthrough. We previously showed that some mutants that were adapted to growth in the presence of toxic sorbose due to loss of one chromosome 5 (Ch5) also became more tolerant to caspofungin. We found here, following direct selection of mutants on caspofungin, that tolerance can be conferred by at least three mechanisms: (i) monosomy of Ch5, (ii) combined monosomy of the left arm and trisomy of the right arm of Ch5, and (iii) an aneuploidy-independent mechanism. Tolerant mutants possessed cell walls with elevated chitin and showed downregulation of genes involved in cell wall biosynthesis, namely, FKS, located outside Ch5, and CHT2, located on Ch5, irrespective of Ch5 ploidy. Also irrespective of Ch5 ploidy, the CNB1 and MID1 genes on Ch5, which are involved in the calcineurin signaling pathway, were expressed at the diploid level. Thus, multiple mechanisms can affect the relative expression of the aforementioned genes, controlling them in similar ways. Although breakthrough mutations in two specific regions of FKS1 have previously been associated with caspofungin resistance, we found mechanisms of caspofungin tolerance that are independent of FKS1 and thus represent an earlier event in resistance development.
The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated

Background Mental comorbidity is common in multiple sclerosis (MS), but some studies suggest that mental comorbidity may be underrecognized and undertreated. Objective Using the North American Research Committee on MS Registry, we assessed the frequency of mental comorbidities in MS and sociodemographic characteristics associated with diagnosis and treatment of depression. Methods We queried participants regarding depression, anxiety, bipolar disorder, and schizophrenia. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CESD); a score ≥21 indicated probable major depression. Results Mental comorbidity affected 4264 (48%) responders; depression most frequently (4012, 46%). Among participants not reporting mental comorbidity, 751 (16.2%) had CESD scores ≥21 suggesting undiagnosed depression. Lower socioeconomic status was associated with increased odds of depression (Income $15,000–30,000 vs >$100,000 OR 1.34; 1.11–1.62), undiagnosed depression (Income $15,000–30,000 vs >$100,000 OR 1.52; 1.08–2.13), and untreated depression (<high school vs postgraduate degree OR 3.13; 1.65–5.99). Conclusions Mental comorbidity remains underdiagnosed and undertreated in MS. Patients of lower socioeconomic status bear a disproportionate share of the burden of depression.
In Vitro Activity of Nemonoxacin, a Novel Nonfluorinated Quinolone, against 2,440 Clinical Isolates

ABSTRACT The in vitro activity of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, was tested against 2,440 clinical isolates. Nemonoxacin was at least fourfold more active than levofloxacin and moxifloxacin against most gram-positive cocci tested (shown by the following MIC90/range [μg/ml] values; community-associated methicillin [meticillin]-resistant Staphylococcus aureus, 0.5/0.015 to 2; Staphylococcus epidermidis, 0.5/0.015 to 4 for methicillin-susceptible staphylococci and 2/0.12 to 2 for methicillin-resistant staphylococci; Streptococcus pneumoniae, 0.015/≤0.008 to 0.25; Enterococcus faecalis, 1/0.03 to 128). Nemonoxacin activity against gram-negative bacilli was similar to levofloxacin and moxifloxacin (MIC90/range [μg/ml]; Escherichia coli, 32/≤0.015 to ≥512; Klebsiella pneumoniae, 2/≤0.015 to 128; K. oxytoca, 0.5/0.06 to 1; Proteus mirabilis, 16/0.25 to ≥512; Pseudomonas aeruginosa, 32/≤0.015 to ≥512; Acinetobacter baumannii, 1/0.12 to 16).
Experiences of partners of people in the early stages of multiple sclerosis

Background Partners of people with multiple sclerosis are known to experience a heavy physical and psychological burden. However, little research has explored, in detail, the partners’ experience in the first years after diagnosis. The aim of this study was to explore and describe the experiences of partners of people who are in the relatively early stages of multiple sclerosis. Methods Fifteen semi-structured telephone interviews were conducted to assess partners’ concerns and difficulties. Data were audio-taped, transcribed, and analysed using an inductive thematic analysis. Results Key themes were being unsure of what the future might hold and feeling helpless and out of control. Furthermore, partners reported that other people could not understand and support them, which led to a feeling of social isolation. Conclusion The research illustrates the disruptive impact that MS has on partners’ lives and highlights the need for support to focus on partners’ needs even in early stages of the disease.
Outpatient Treatment Programs: A Review Article on Substances of Abuse Outpatients Treatment Outcomes in the United States

A number of treatment approaches and techniques have been developed and used for management of drug abuse and alcoholism during the last 50 years in the United States. These treatment methods have been categorized based on the treatment settings (outpatient, short-term residential, long-term residential) or based on treatment techniques [pharmacological or nonpharmacological (behavioral, psychosocial)]. The relative effectiveness and appropriateness of these treatments has always been an issue of concern to health policy, and decision makers, treatment providers and the users. For example, naltrexone, a long acting orally effective opioid antagonist, has been tried in patients of opioid or alcohol dependence. In controlled clinical studies, the drug has shown positive effects when added to counseling. It is reported to significantly reduce heavy drinking in patients who are willing to take the drug as prescribed. However, the beneficial effects of naltrexone are limited due to the serious problem of noncompliance or lack of willingness of patients to continue it for sufficient duration. Buprenorphine is an opioid agonist-antagonist effective for the treatment of opiate abuse besides its analgesic indication in patients with advanced painful cancer. Three national studies evaluating drug abuse treatment programs have been carried out to evaluate the suitability of the different outpatient treatment programs. However, methodological differences used in these programs have been a limitation to arrive at solid conclusions. Furthermore, the treatment modalities also varied as they evolved across time and change in their components. The client characteristics changed across last 3 decades particularly regarding the drug of abuse. The admission to specific treatment modalities depended on client criteria based on admission guidelines in force from time to time. These variations may limit the comparability of treatment outcome across these studies and across different treatment modalities, though adequate measures have been taken during analysis to minimize these limitations. Despite these limitations, some generalizations about the effectiveness of outpatient treatment can be made from the findings that have been consistent across studies. Outpatient drug-free treatment program is effective in reducing drug abuse and in improving other parameters like criminality and employment. Furthermore, it is effective as methadone maintenance; however, it is less effective than long-term residential treatment program. The program is effective primarily if patients receive treatment for 3 months or longer.
Is neuromyelitis optica associated with human leukocyte antigen?

Background To establish whether or not multiple sclerosis (MS) and neuromyelitis optica (NMO) are different pathological entities, we wondered whether MS patients and NMO patients share the same pattern of human leukocyte antigen (HLA) predisposition. Objective To study a putative association between susceptibility to NMO and HLA class I or class II loci in Caucasians. Methods A total of 39 unrelated Caucasian patients with NMO and six patients at a high risk of converting to NMO were studied. DNA genotyping of HLA class I and class II loci was assessed and allelic frequencies were reported at a high-resolution level. A case-control study by comparing the allelic distribution in the NMO patients with that of a French Caucasian MS group and a French Caucasian healthy group was carried out. Results The frequencies of HLA-DQA1, DQB1, and HLA-DRB1 DR2 alleles in the NMO group were intermediate between the healthy control group and the MS group. The DPB1*0501 allele was not increased in the NMO group compared with the healthy control group. The distribution of HLA-DRB1 allele enabled to distinguish between NMO-IgG-positive patients and healthy controls (P = 0.01). NMO-IgG-negative patients presented an HLA II pattern closer to that of the MS group (P = 0.01). Conclusion In contrast to the reported results in Asian opticospinal MS, we found no association between the DPB1*0501 allele and NMO in our Caucasian patients. Moreover, we suggest that NMO-IgG-positive patients could represent a distinct NMO group in terms of their genetic susceptibility.
Identification of Amino Acids Conferring High-Level Resistance to Expanded-Spectrum Cephalosporins in the penA Gene from Neisseria gonorrhoeae Strain H041

ABSTRACT The recent identification of a high-level-ceftriaxone-resistant (MIC = 2 to 4 μg/ml) isolate of Neisseria gonorrhoeae from Japan (H041) portends the loss of ceftriaxone as an effective treatment for gonococcal infections. This is of grave concern because ceftriaxone is the last remaining option for first-line empirical antimicrobial monotherapy. The penA gene from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance (Cephi) worldwide but has 13 additional mutations compared to the mosaic penA gene from the previously studied Cephi strain 35/02 (penA35). When transformed into the wild-type strain FA19, the penA41 allele confers 300- and 570-fold increases in the MICs for ceftriaxone and cefixime, respectively. In order to understand the mechanisms involved in high-level ceftriaxone resistance and to improve surveillance and epidemiology during the potential emergence of ceftriaxone resistance, we sought to identify the minimum number of amino acid alterations above those in penA35 that confer high-level resistance to ceftriaxone. Using restriction fragment exchange and site-directed mutagenesis, we identified three mutations, A311V, T316P, and T483S, that, when incorporated into the mosaic penA35 allele, confer essentially all of the increased resistance of penA41. A311V and T316P are close to the active-site nucleophile Ser310 that forms the acyl-enzyme complex, while Thr483 is predicted to interact with the carboxylate of the β-lactam antibiotic. These three mutations have thus far been described only for penA41, but dissemination of these mutations in other mosaic alleles would spell the end of ceftriaxone as an effective treatment for gonococcal infections.
Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis

Background Studies evaluating interferon beta (IFNβ) for multiple sclerosis (MS) showed only partial efficacy. In many patients, IFNβ does not halt relapses or disability progression. One strategy to potentially enhance efficacy is to combine IFNβ with classical immunosuppressive agents, such as azathioprine (AZA) or corticosteroids, commonly used for other autoimmune disorders. Objective The Avonex–Steroids–Azathioprine study was placebo-controlled trial and evaluated efficacy of IFNβ-1a alone and combined with low-dose AZA alone or low-dose AZA and low-dose corticosteroids as initial therapy. Methods A total of 181 patients with relapsing–remitting MS (RRMS) were randomized to receive IFNβ-1a 30 μg intramuscularly (IM) once weekly, IFNβ-1a 30 μg IM once weekly plus AZA 50 mg orally once daily, or IFNβ-1a 30 μg IM once weekly plus AZA 50 mg orally once daily plus prednisone 10 mg orally every other day. The primary end point was annualized relapse rate (ARR) at 2 years. Patients were eligible for enrollment in a 3-year extension. Results At 2 years, adjusted ARR was 1.05 for IFNβ-1a, 0.91 for IFNβ-1a plus AZA, and 0.73 for combination. The cumulative probability of sustained disability progression was 16.8% for IFNβ-1a, 20.7% for IFNβ-1a plus AZA, and 17.5% for combination. There were no statistically significant differences among groups for either measure at 2 and 5 years. Percent T2 lesion volume change at 2 years was significantly lower for combination (+14.5%) versus IFNβ-1a alone (+30.3%, P < 0.05). Groups had similar safety profiles. Conclusion In IFNβ-naïve patients with early active RRMS, combination treatment did not show superiority over IFNβ-1a monotherapy.
A Case of New Delhi Metallo-β-Lactamase 1 (NDM-1)-Producing Klebsiella pneumoniae with Putative Secondary Transmission from the Balkan Region in the Netherlands

New Delhi metallo-beta-lactamase 1 (NDM-1) was first identified in 2008 in a Klebsiella pneumoniae strain from a Swedish patient of Indian origin with a history of medical treatment in a New Delhi hospital for a urinary tract infection ([12][1]). Since then, more such cases in different parts of the
Probing the Differential Interactions of Quinazolinedione PD 0305970 and Quinolones with Gyrase and Topoisomerase IV

ABSTRACT Quinazoline-2,4-diones, such as PD 0305970, are new DNA gyrase and topoisomerase IV (topo IV) inhibitors with potent activity against gram-positive pathogens, including quinolone-resistant isolates. The mechanistic basis of dione activity vis-à-vis quinolones is not understood. We present evidence for Streptococcus pneumoniae gyrase and topo IV that PD 0305970 and quinolones interact differently with the enzyme breakage-reunion and Toprim domains, DNA, and Mg2+-four components that are juxtaposed in the topoisomerase cleavage complex to effect DNA scission. First, PD 0305970 targets primarily gyrase in Streptococcus pneumoniae. However, unlike quinolones, which select predominantly for gyrA (or topo IV parC) mutations in the breakage-reunion domain, unusually the dione selected for novel mutants with alterations that map to a region of the Toprim domain of GyrB (R456H and E474A or E474D) or ParE (D435H and E475A). This “dione resistance-determining region” overlaps the GyrB quinolone resistance-determining region and the region that binds essential Mg2+ ions, each function involving conserved EGDSA and PLRGK motifs. Second, dione-resistant gyrase and topo IV were inhibited by ciprofloxacin, whereas quinolone-resistant enzymes (GyrA S81F and ParC S79F) remained susceptible to PD 0305970. Third, dione-promoted DNA cleavage by gyrase occurred at a distinct repertoire of sites, implying that structural differences with quinolones are sensed at the DNA level. Fourth, unlike the situation with quinolones, the Mg2+ chelator EDTA did not reverse dione-induced gyrase cleavage nor did the dione promote Mg2+-dependent DNA unwinding. It appears that PD 0305970 interacts uniquely to stabilize the cleavage complex of gyrase/topo IV perhaps via an altered orientation directed by the bidentate 3-amino-2,4-dione moiety.
Coccidioidomycosis in Renal Transplant Recipients

Abstract: Coccidioidomycosis is endemic in the southwest United States, and impaired cellular immunity profoundly increases the susceptibility to life-threatening Coccidioides immitis infections. This study combines the clinical presentation of coccidioidomycosis in 5 renal transplant recipients in El Paso from 1987 to 2002 with details from 28 other cases published in the literature from 1966 to 2002. The 5 cases in El Paso occurred in a population of 297 transplant recipients. Overall, the 33 renal transplant recipients with coccidioidomycosis included 24 men and 9 women with a median age of 38 years. Fifty-eight percent of the patients were white, 33% Hispanic, 3% African American, 3% Native American, and 3% Asian. Twenty-three (70%) of the patients had cadaveric donors, and the remainder had living donors. Underlying renal diseases included chronic glomerulonephritis (48%), diabetes mellitus (30%), autoimmune diseases (3%), Alport syndrome (3%), and others not documented (16%). C. immitis was isolated from the lung in 75% of the patients; in the remaining 25%, it involved the spleen, urine, skin, pancreas, bone marrow, thyroid, choroid, and lymph nodes. In the majority of the patients, the initial clinical presentation included fever with clinical and radiographic evidence of pneumonia. The median time between transplantation and the diagnosis of infection was 6 months (15 days to 50 months). Disseminated coccidioidomycosis occurred in 18 patients. Treatment modalities included amphotericin B in 29 patients (88%) and fluconazole in 6 patients (18%). Death occurred in 55% (18) of the patients with 9 of them dying from coccidioidomycosis and the other 9 dying of other causes. There did not appear to be a significant increase in the mortality in patients who had underlying diabetes mellitus.
A Tick Antivirulence Protein Potentiates Antibiotics against Staphylococcus aureus

ABSTRACT New strategies are needed to combat antibiotic resistance, especially against pathogens such as methicillin-resistant Staphylococcus aureus. A tick antifreeze glycoprotein, IAFGP, possesses potent antibiofilm properties against a variety of clinical pathogens, including S. aureus. Synergy between IAFGP, or a peptide (P1) representative of a repeat region of the protein, with different antibiotics was assessed in vitro. Antibiotics that synergized with either IAFPG or P1 were further evaluated in vivo using vertebrate and invertebrate infection models. IAFGP readily enhanced the efficacy of antibiotics against S. aureus. Synergy with daptomycin, an antibiotic used to treat methicillin-resistant S. aureus, was observed in vitro and in vivo using iafgp-transgenic mice and flies. Furthermore, synergy with ciprofloxacin or gentamicin, antibiotics not generally used to treat S. aureus, was also perceived. The combined effect of the antibiotic and IAFGP was associated with improved permeation of the antibiotic into the cell. Our results highlight that synergy of IAFGP with antibiotics traditionally used to treat this pathogen, and enhancement of the potency of antibiotics not commonly used against this microbe, can provide novel alternative therapeutic strategies to combat bacterial infections.
The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue

Fatigue symptoms are reported by a majority of patients with multiple sclerosis (MS). Reliable assessment, however, is a demanding issue as the symptoms are experienced subjectively and as objective assessment strategies are missing. The objective of this study was to develop and validate a new tool, the Fatigue Scale for Motor and Cognitive Functions (FSMC), for the assessment of MS-related cognitive and motor fatigue. A total of 309 MS patients and 147 healthy controls were included into the validation study. The FSMC was tested against several external criteria (e.g. cognition, motivation, personality and other fatigue scales). The item-analysis and validation procedure showed that the FSMC is highly sensitive and specific in detecting fatigued MS patients, that both subscales significantly differentiated between patients and controls (p < 0.01), and that internal consistency (Cronbach’s alpha α > 0.91) as well as test—retest reliability (r > 0.80) were high. Cut-off values were determined to classify patients as mildly, moderately or severely fatigued. In conclusion, the FSMC is a new scale that has undergone validation based on a large sample of patients and that provides differential quantification and graduation of cognitive and motor fatigue.
Predictive direct torque control for the PM synchronous machine

This paper shows that a predictive digital control combined with the principle of direct torque control (DTC) leads to an excellent dynamic behavior of the synchronous machine with surface-mounted permanent magnets and is a real alternative to the classical field-orientated control. The advantages are a DTC control scheme with constant switching frequency and a predictable torque ripple. The settling times of the torque are reduced compared to the classical field-orientated control. The application in servo drives in which the rotor position is always measured can easily be achieved by using a commercial digital signal processor. Numerous simulations and measurements confirm the theoretical work.
Damage of the Bacterial Cell Envelope by Antimicrobial Peptides Gramicidin S and PGLa as Revealed by Transmission and Scanning Electron Microscopy

ABSTRACT Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to examine the ultrastructural changes in bacteria induced by antimicrobial peptides (AMPs). Both the β-stranded gramicidin S and the α-helical peptidyl-glycylleucine-carboxyamide (PGLa) are cationic amphiphilic AMPs known to interact with bacterial membranes. One representative Gram-negative strain, Escherichia coli ATCC 25922, and one representative Gram-positive strain, Staphylococcus aureus ATCC 25923, were exposed to the AMPs at sub-MICs and supra-MICs in salt-free medium. SEM revealed a shortening and swelling of the E. coli cells, and multiple blisters and bubbles formed on their surface. The S. aureus cells seemed to burst upon AMP exposure, showing open holes and deep craters in their envelope. TEM revealed the formation of intracellular membranous structures in both strains, which is attributed to a lateral expansion of the lipid membrane upon peptide insertion. Also, some morphological alterations in the DNA region were detected for S. aureus. After E. coli was incubated with AMPs in medium with low ionic strength, the cells appeared highly turgid compared to untreated controls. This observation suggests that the AMPs enhance osmosis through the inner membrane, before they eventually cause excessive leakage of the cellular contents. The adverse effect on the osmoregulatory capacity of the bacteria is attributed to the membrane-permeabilizing action of the amphiphilic peptides, even at low (sub-MIC) AMP concentrations. Altogether, the results demonstrate that both TEM and SEM, as well as appropriate sample preparation protocols, are needed to obtain detailed mechanistic insights into peptide function.