Blastomycosis Complicated by Adult Respiratory Distress Syndrome in an Immunocompetent Adult: A Case Report and Literature Review.

Blastomycosis is an endemic mycotic infection caused by inhalation of thermally dimorphic fungi from the genus Blastomyces. Blastomyces dermatitidis is the species most related to human infection in the USA and North America. Adult respiratory distress syndrome (ARDS) is a rare complication of blastomycosis and is associated with high mortality. Due to its rarity, evidence-based guidelines for diagnosing and treating ARDS associated with blastomycosis are scarce. In this case presentation, a 22-year-old male with a history of chronic cannabis use presented with severe respiratory symptoms, initially treated as community-acquired pneumonia. Despite antibiotic treatment, his condition deteriorated, necessitating intubation and resulting in the development of ARDS. A delayed diagnosis of pulmonary blastomycosis was confirmed through polymerase chain reaction testing. Treatment with amphotericin B and corticosteroids proved successful in addressing the fungal infection, leading to the recovery of the patient from his severe clinical condition. This case highlights the challenges associated with diagnosing and treating blastomycosis, particularly when complicated by ARDS, emphasizing the importance of considering fungal infections in the differential diagnosis of non-responsive pulmonary infections. Additionally, it suggests the potential utility of corticosteroids in severe cases and emphasizes the crucial role of early diagnosis and a combination of diagnostic modalities for the timely management of this rare and potentially life-threatening condition.

Spontaneous Proteus mirabilis Meningitis in Adults Requiring an Extended Antibiotic Course: Case Report and Literature Review.

Most cases of gram-negative bacillary meningitis occur in neonates and infants. Meningitis in adults caused by Proteus mirabilis has been reported rarely. Evidence-based guidelines for the treatment of adult patients with gram-negative bacillus meningitis are scarce. The optimal duration of antibiotic therapy for these patients is an unanswered question in the medical literature. This article outlines a case of community-acquired meningitis caused by P. mirabilis in an adult patient who required an extended antimicrobial treatment, after failing to a three-week antibiotic regime. Our patient, a 66-year-old man with a history of neurogenic bladder, remote spinal cord trauma, and recurrent urinary tract infections presented to the emergency department reporting a two-day history of severe headache, fever, and confusion. Cerebrospinal fluid (CSF) revealed significant neutrophil-predominant pleocytosis, low glucose level, and elevated protein level. CSF culture grew few pan-susceptible P. mirabilis. The patient initially completed 21 days of ceftriaxone guided by susceptibility testing. Nine days after finishing antibiotic therapy, the patient was readmitted with recurrent headache, fever, and neck rigidity. A new CSF study again revealed pleocytosis, elevated polymorphonuclear cells, low glucose level, and elevated protein level, but with a negative CSF culture. The patient became afebrile, and his symptoms improved after two days of ceftriaxone. He completed an additional six-week regime of ceftriaxone. On the one-month follow-up visit, the patient remained afebrile, with no recurrent symptoms. Spontaneous community-acquired P. mirabilis meningitis is rare among adult patients. Experiences in the treatment of gram-negative bacillus meningitis in adults must be shared with the scientific community to build up a better understanding of this condition. In the context of this case, sterilization of the CSF, extended antibiotic therapy, and a close post-treatment follow-up are crucial for treating this life-threatening condition.

Descriptive Data on Trends Among Patients Hospitalized With Lyme Disease in Southwest Michigan, 2017-2021.

This retrospective chart review identifies hospitalizations for Lyme disease at two southwest Michigan hospital systems, 2017-2021. Lyme admissions increased sharply, while admissions for Lyme carditis and neuroborreliosis increased in parallel. Southwest Michigan is becoming an endemic area for Lyme disease.

Analysis of antibiotic use and clinical outcomes in adults with known and suspected pleural empyema.

BACKGROUND: There is not a prevailing consensus on appropriate antibiotic choice, route, and duration in the treatment of bacterial pleural empyema after appropriate source control. Professional society guidelines note the lack of comparative trials with which to guide recommendations. We assessed clinical outcomes in the treatment of known and suspected empyema based upon three aspects of antibiotic use: (1) total duration, (2) duration of intravenous (IV) antibiotics, and (3) duration of anti-anaerobic antibiotics. METHODS: We performed a hypothesis-generating retrospective chart review analysis of 355 adult inpatients who had pleural drainage, via either chest tube or surgical intervention, for known or suspected empyema. The primary outcome variable was clinician assessment of resolution or lack thereof. The secondary outcomes were death within 90 days, hospital readmission within 30 days for empyema, and all-cause hospital readmission within 30 days. Mann-Whitney U test was used to compare outcomes with regard to these variables. RESULTS: None of the independent variables was significantly associated with a difference in clinical resolution rate despite trends for total antibiotic duration and anti-anaerobic antibiotic duration. None of the independent variables was associated with mortality. Longer total antibiotic duration was associated with lower readmission rate for empyema (median 17 [interquartile range 11-28] antibiotic days in non-readmission group vs. 13 [6-15] days in readmission group), with a non-significant trend for all-cause readmission rate (17 [11-28] days vs. 14 [9-21] days). IV antibiotic duration was not associated with a difference in any of the defined outcomes. Longer duration of anti-anaerobic antibiotics was associated with both lower all-cause readmission (8.5 [0-17] vs. 2 [0-11]) and lower readmission rate for empyema (8 [0-17] vs. 2 [0-3]). CONCLUSION: Our data support the premise that routine use of anti-anaerobic antibiotics is indicated in the treatment of pleural empyema. However, our study casts doubt on the benefits of extended IV rather than oral antibiotics in the treatment of empyema. This represents a target for future investigation that could potentially limit complications associated with the excessive use of IV antibiotics.

Neutrophil-derived extracellular vesicles modulate the phenotype of naïve human neutrophils.

Neutrophils (PMN) regulate inflammation in many ways, including communication with other immune cells via extracellular vesicles (EVs). EVs released by human neutrophils activated with N-formylmethionyl-leucyl-phenylalanine (fMLF) (PMN-fMLF EVs) had an outside-out orientation and contained functionally important neutrophil plasma membrane proteins, including flavocytochrome b558, and enzymatically active granule proteins, elastase, and myeloperoxidase. Treatment of naïve PMN with PMN-fMLF EVs primed fMLF-stimulated NADPH oxidase activity, increased surface expression of the complement receptors CD11b/CD18 and CD35, the specific granule membrane protein CD66, and flavocytochrome b558 , and promoted phagocytosis of serum-opsonized Staphylococcus aureus. The primed oxidase activity reflected increased surface expression of flavocytochrome b558 and phosphorylation of SER345 in p47phox , two recognized mechanisms for oxidase priming. Taken together, these data demonstrate that stimulated PMN released EVs that altered the phenotype of naïve phagocytes by priming of the NADPH oxidase activity and augmenting phagocytosis, two responses that are integral to optimal PMN host defense.

Overcoming drug resistance in multi-drug resistant cancers and microorganisms: a conceptual framework.

Resistance development against multiple drugs is a common feature among many pathogens--including bacteria such as Pseudomonas aeruginosa, viruses, and parasites--and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their large size and are often released only on contact with the perceived competitor. Thus, multi-domain proteins are missed during traditional methods of looking for growth zone inhibition of susceptible bacteria as demonstrated by antibiotics, but may represent the weapons of the future in the fights against both drug-resistant cancers and pathogens such as P. aeruginosa.

Myocardial infarction in mice alters sarcomeric function via post-translational protein modification.

Myocardial physiology in the aftermath of myocardial infarction (MI) before remodeling is an under-explored area of investigation. Here, we describe the effects of MI on the cardiac sarcomere with focus on the possible contributions of reactive oxygen species. We surgically induced MI in 6-7-month-old female CD1 mice by ligation of the left anterior descending coronary artery. Data were collected 3-4 days after MI or sham (SH) surgery. MI hearts demonstrated ventricular dilatation and systolic dysfunction upon echo cardiographic analysis. Sub-maximum Ca-activated tension in detergent-extracted fiber bundles from papillary muscles increased significantly in the preparations from MI hearts. Ca(2+) sensitivity increased after MI, whereas cooperativity of activation decreased. To assess myosin enzymatic integrity we measured splitting of Ca-ATP in myofibrillar preparations, which demonstrated a decline in Ca-ATPase activity of myofilament myosin. Biochemical analysis demonstrated post-translational modification of sarcomeric proteins. Phosphorylation of cardiac troponin I and myosin light chain 2 was reduced after MI in papillary samples, as measured using a phospho-specific stain. Tropomyosin was oxidized after MI, forming disulfide products detectable by diagonal non-reducing-reducing SDS-PAGE. Our analysis of myocardial protein oxidation post-MI also demonstrated increased S-glutathionylation. We functionally linked protein oxidation with sarcomere function by treating skinned fibers with the sulfhydryl reducing agent dithiothreitol, which reduced Ca(2+) sensitivity in MI, but not SH, samples. Our data indicate important structural and functional alterations to the cardiac sarcomere after MI, and the contribution of protein oxidation to this process.

H2O2 alters rat cardiac sarcomere function and protein phosphorylation through redox signaling.

ROS, such as H(2)O(2), are a component of pathological conditions in many organ systems and have been reported to be elevated in cardiac pathophysiology. The experiments presented here test the hypothesis that H(2)O(2) induces alterations in cardiac myofilament function by the posttranslational modification of sarcomeric proteins indirectly through PKC signaling. In vitro assessment of actomyosin Mg(2+)-ATPase activity of myofibrillar fractions showed blunted relative ATP consumption in the relaxed state (pCa 8.0) in response to treatment with 0.5 mM H(2)O(2) before myofilament isolation. The effect was attributable to downstream "redox signaling," inasmuch as the direct application of H(2)O(2) to isolated myofibrils did not alter Mg(2+)-ATPase activity. Ca(2+)-ATPase activity, which was used as a measure of myofibrillar myosin function, was unaffected by H(2)O(2). Functional experiments using rat cardiac trabeculae treated with 0.5 or 5 mM H(2)O(2) followed by detergent extraction of membranes demonstrated increased Ca(2+) sensitivity of force production, a faster rate of force redevelopment, and (for 5 mM) decreased maximum tension. Biochemical analysis of myocardial samples treated with 0.5 mM H(2)O(2) demonstrated increased phosphorylation of two sarcomeric proteins: cardiac troponin I and myosin-binding protein-C. These changes were eliminated by a general PKC inhibitor. However, H(2)O(2) and the general PKC activator PMA induced different phosphorylation patterns in cardiomyocytes in which PKC-delta was elevated by viral infection. These data provide evidence that PKC-dependent redox signaling affects the function of cardiac myofilaments and indicate modification of specific proteins through this signaling mechanism.

Specific recognition of apoptotic cells reveals a ubiquitous and unconventional innate immunity.

The purpose of physiological cell death is the noninflammatory clearance of cells that have become inappropriate or nonfunctional. Consistent with this function, the recognition of apoptotic cells by professional phagocytes, including macrophages and dendritic cells, triggers a set of potent anti-inflammatory responses manifest on multiple levels. The immediate-early inhibition of proinflammatory cytokine gene transcription in the phagocyte is a proximate consequence of recognition of the apoptotic corpse, independent of subsequent engulfment and soluble factor involvement. Here, we show that recognition is linked to a characteristic signature of responses, including MAPK signaling events and the ablation of proinflammatory transcription and cytokine secretion. Specific recognition and response occurs without regard to the origin (species, tissue type, or suicidal stimulus) of the apoptotic cell and does not involve Toll-like receptor signaling. These features mark this as an innate immunity fundamentally distinct from the discrimination of "self" versus "other" considered to be the hallmark of conventional immunity. This profound unconventional innate immune discrimination of effete from live cells is as ubiquitous as apoptotic cell death itself, manifest by professional and nonprofessional phagocytes and nonphagocytic cell types alike. Innate apoptotic immunity provides an intrinsic anti-inflammatory circuit that attenuates proinflammatory responses dynamically and may act systemically as a powerful physiological regulator of immunity.

Apoptosis or growth arrest: Modulation of tumor suppressor p53's specificity by bacterial redox protein azurin.

The tumor suppressor protein p53 is known to induce either apoptosis or growth arrest depending on cellular background. We have previously reported that a bacterial redox protein azurin induces apoptosis in J774 cell line-derived macrophages whereas a site-directed mutant M44KM64E azurin shows very little cytotoxicity and fails to induce apoptosis in J774 cells. We now report that purified M44KM64E mutant azurin protein can enter both J774 cells as well as the human breast cancer MCF-7 cells. Entry of M44KM64E mutant azurin in J774 cells causes strong inhibition of cell-cycle progression at the G1 to S phase and a higher level of transcription of the p21 gene. Corresponding to high p21 levels, the levels of cyclins and cyclin-dependent kinases were greatly lowered in M44KM64E mutant azurin-treated J774 cells. Interestingly, M44KM64E mutant azurin protein failed to elicit inhibition of cell-cycle progression in MCF-7 cells, presumably because of mutation at the retinoblastoma tumor suppressor protein that allows functional E2F formation in MCF-7 cells even in the presence of high intracellular p21 level. Thus, the WT azurin induces apoptosis but little inhibition of cell-cycle progression whereas the M44KM64E mutant azurin is deficient in the induction of apoptosis but mediates strong inhibition of cell-cycle progression, demonstrating the role of a single bacterial protein and its hydrophobic patch in modulating two important functions of p53.