Whipple's disease unmasked by TNF inhibitor therapy for treatment of seronegative rheumatoid arthritis.

We report a patient with seronegative rheumatoid arthritis diagnosed with Whipple's disease following treatment of tumour necrosis factor inhibitor (TNFI) therapy. Whipple's disease should be considered in patients with seronegative rheumatoid arthritis and other unexplained multisystem illness. The TNFI therapy and immunosuppressive therapies can unmask latent Whipple's disease.

Tuberculosis and Leprosy Coinfection: A Perspective on Diagnosis and Treatment.

Both leprosy and tuberculosis (TB) are known to have similar geographic endemicity. In the setting of coinfection, interferon-gamma release assays (IGRAs) to detect latent TB can be falsely positive. We report a case of leprosy with a positive IGRA and asymptomatic active pulmonary TB. Minocycline and dapsone therapy was initiated during the workup for TB and changed to rifampin (Rif), isoniazid, pyrazinamide, and ethambutol, with the addition of dapsone once coinfection was confirmed. Our review of the literature revealed a preponderance of coinfection reported with borderline and lepromatous disease. Ten patients were diagnosed with leprosy as the first infection; 7 of these patients (70%) were treated with Rif before TB diagnosis, and 70% (7/10) of coinfected patients were on steroids. If treatment for leprosy is a consideration before ruling out active TB, then minocycline may temporarily replace the Rif. The dire implications of Rif monotherapy in undiagnosed coinfection may warrant chest radiography with or without sputum microbiology as routine initial workup for all leprosy cases.

HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome.

HIV protease is known to cause cell death, which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41, which directly binds Bak with nanomolar affinity, causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity, in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2, possibly explaining why those cells do not die when they reactivate HIV. Here, we determine that the Casp8p41-Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway, increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41-dependent manner.IMPORTANCE The Casp8p41 pathway of cell death is unique to HIV-infected cells yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV-infected cells to die.

Increasing procaspase 8 expression using repurposed drugs to induce HIV infected cell death in ex vivo patient cells.

HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell-associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8. However, cell death is prevented, possibly due to low procaspase 8 expression. Here, we tested whether increasing procaspase 8 levels in CD4 T cells will produce more Casp8p41 following HIV reactivation, causing more reactivated cells to die. Screening 1277 FDA approved drugs identified 168 that increased procaspase 8 expression by at least 1.7-fold. Of these 30 were tested for anti-HIV effects in an acute HIVIIIb infection model, and 9 drugs at physiologic relevant levels significantly reduced cell-associated HIV DNA. Primary CD4 T cells from ART suppressed HIV patients were treated with one of these 9 drugs and reactivated with αCD3/αCD28. Four drugs significantly increased Casp8p41 levels following HIV reactivation, and decreased total cell associated HIV DNA levels (flurbiprofen: p = 0.014; doxycycline: p = 0.044; indomethacin: p = 0.025; bezafibrate: P = 0.018) without effecting the viability of uninfected cells. Thus procaspase 8 levels can be increased pharmacologically and, in the context of HIV reactivation, increase Casp8p41 causing death of reactivating cells and decreased HIV DNA levels. Future studies will be required to define the clinical utility of this or similar approaches.

Cardiothoracic Transplant Recipient Mycoplasma hominis: An Uncommon Infection with Probable Donor Transmission.

The role of infection with Mycoplasma hominis following cardiothoracic organ transplantation and its source of transmission have not been well-defined. Here, we identify and describe infection with M. hominis in patients following cardiothoracic organ transplantation after reviewing all cardiothoracic transplantations performed at our center between 1998 and July 2015. We found seven previously unreported cases of M. hominis culture positive infection all of whom presented with pleuritis, surgical site infection, and/or mediastinitis. PCR was used to establish the diagnosis in four cases. In two instances, paired single lung transplant recipients manifested infection, and in one of these pairs, isolates were indistinguishable by multilocus sequence typing (MLST). To investigate the prevalence of M. hominis in the lower respiratory tract, we tested 178 bronchoalveolar lavage (BAL) fluids collected from immunocompromised subjects for M. hominis by PCR; all were negative. Review of the literature revealed an additional 15 cases of M. hominis in lung transplant recipients, most with similar clinical presentations to our cases. We recommend that M. hominis should be considered in post-cardiothoracic transplant infections presenting with pleuritis, surgical site infection, or mediastinitis. M. hominis PCR may facilitate early diagnosis and prompt therapy. Evaluation for possible donor transmission should be considered.

Disseminated Mycobacterium chimaera Infection After Cardiothoracic Surgery.

Ten case reports of disseminated Mycobacterium chimaera infections associated with cardiovascular surgery were published from Europe. We report 3 cases of disseminated M chimaera infections with histories of aortic graft and/or valvular surgery within the United States. Two of 3 patients demonstrated ocular involvement, a potentially important clinical finding.

Casp8p41: The Protean Mediator of Death in CD4 T-cells that Replicate HIV.

HIV cure is now the focus of intense research after Timothy Ray Brown (the Berlin patient) set the precedent of being the first and only person cured. A major barrier to achieving this goal on a meaningful scale is an elimination of the latent reservoir, which is thought to comprise CD4-positive cells that harbor integrated, replication-competent HIV provirus. These cells do not express viral proteins, are indistinguishable from uninfected CD4 cells, and are thought to be responsible for HIV viral rebound-that occurs within weeks of combination anti retroviral therapy (cART) interruption. Modalities to engineer transcriptional stimulation (reactivation) of this dormant integrated HIV provirus, leading to expression of cytotoxic viral proteins, are thought to be a specific way to eradicate the latently infected CD4 pool and are becoming increasingly relevant in the era of HIV cure. HIV protease is one such protein produced after HIV reactivation that cleaves procaspase-8 to generate a novel protein Casp8p41. Casp8p41 then binds to the BH3 domain of BAK, leading to BAK oligomerization, mitochondrial depolarization, and apoptosis. In central memory T cells (TCMs) from HIV-infected patients, an elevated Bcl-2/procaspase-8 ratio was observed, and Casp8p41 binding to Bcl-2 was associated with a lack of reactivation-induced cell death. This was reversed by priming cells with a specific Bcl-2 antagonist prior to reactivation, resulting in increased cell death and decreased HIV DNA in a Casp8p41-dependent pathway. This review describes the biology, clinical relevance, and implications of Casp8p41 for a potential cure.

Twenty years of human immunodeficiency virus care at the Mayo Clinic: Past, present and future.

The Mayo human immunodeficiency virus (HIV) Clinic has been providing patient centered care for persons living with HIV in Minnesota and beyond for the past 20 years. Through multidisciplinary engagement, vital clinical outcomes such as retention in care, initiation of antiretroviral therapy and virologic suppression are maximized. In this commentary, we describe the history of the Mayo HIV Clinic and its best practices, providing a "Mayo Model" of HIV care that exceeds national outcomes and may be applicable in other settings.

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size.

UNLABELLED: Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Further, we show that central memory CD4 T cells (TCM) from HIV-infected individuals have heightened expression of BCL-2 relative to procaspase 8, possibly explaining the persistence of HIV-infected TCMdespite generation of Casp8p41. Consistent with this hypothesis, the selective BCL-2 antagonist venetoclax induced minimal killing of uninfected CD4 T cells but markedly increased the death of CD4 T cells and diminished cell-associated HIV DNA when CD4 T cells from antiretroviral therapy (ART)-suppressed HIV patients were induced with αCD3/αCD28 to reactivate HIVex vivo Thus, priming CD4 T cells from ART suppressed HIV patients with a BCL-2 antagonist, followed by HIV reactivation, achieves reductions in cell-associated HIV DNA, whereas HIV reactivation alone does not. IMPORTANCE: HIV infection is incurable due to a long-lived reservoir of HIV(+)memory CD4 T cells, and no clinically relevant interventions have been identified that reduce the number of these HIV DNA-containing cells. Since postintegration HIV replication can result in HIV protease generation of Casp8p41, which activates BAK, causing infected CD4 T cell death, we sought to determine whether this occurs in memory CD4 T cells. Here, we demonstrate that memory CD4 T cells can generate Casp8p41 and yet are intrinsically resistant to death induced by diverse stimuli, including Casp8p41. Furthermore, BCL-2 expression is relatively increased in these cells and directly binds and inhibits Casp8p41's proapoptotic effects. Antagonizing BCL-2 with venetoclax derepresses this antagonism, resulting in death, preferentially in HIV DNA containing cells, since only these cells generate Casp8p41. Thus, BCL-2 antagonism is a clinically relevant intervention with the potential to reduce HIV reservoir size in patients.

Postobstructive Pneumonia: An Underdescribed Syndrome.

BACKGROUND: Postobstructive community-acquired pneumonia (PO-CAP) is relatively common in clinical practice. The clinical syndrome is poorly defined, and the role of infection as a cause of the infiltrate is uncertain. We prospectively studied patients with PO-CAP and compared them to a cohort of patients with bacterial community-acquired pneumonia (B-CAP). METHODS: We prospectively studied patients hospitalized for CAP; 5.4% had PO-CAP, defined as a pulmonary infiltrate occurring distal to an obstructed bronchus. Sputum and blood cultures, viral polymerase chain reaction, urinary antigen tests, and serum procalcitonin (PCT) were done in nearly all cases. Clinical and laboratory characteristics of patients with PO-CAP were compared to those of patients with B-CAP. RESULTS: In a 2-year period, we identified 30 patients with PO-CAP. Compared to patients with B-CAP, patients with PO-CAP had longer duration of symptoms (median, 14 vs 5 days;P< .001). Weight loss and cavitary lesions were more common (P< .01 for both comparisons) and leukocytosis was less common (P< .01) in patients with PO-CAP. A bacterial pathogen was implicated in only 3 (10%) PO-CAP cases. PCT was <0.25 ng/mL in 19 (63.3%) patients. Although no differences were observed in disease severity or rates of intensive care unit admissions, 30-day mortality was significantly higher in PO-CAP vs B-CAP (40.0% vs 11.7%;P< .01). CONCLUSIONS: Although there is substantial overlap, PO-CAP is a clinical entity distinct from B-CAP; a bacterial cause was identified in only 10% of patients. Our study has important implications for the clinical recognition of patients with PO-CAP, the role of microorganisms as etiologic agents, and the use of antibiotic therapy.

Case series of Bartonella quintana blood culture-negative endocarditis in Washington, DC.

INTRODUCTION: Prior studies (predominantly from Europe) have demonstrated blood culture-negative endocarditis due to Bartonella. Our objective was to describe three cases of Bartonella quintana endocarditis identified within one year at a large hospital in Washington, DC, USA. CASE PRESENTATION: We constructed a descriptive case series from a retrospective review of medical records from April to December 2013 at an 800-bed urban hospital. All three patients (ages: 52, 55 and 57 years) were undomiciled/homeless men with a history of alcoholism. Although they had negative blood cultures, echocardiography demonstrated aortic/mitral valve perforation and regurgitation in one patient, aortic/mitral valve vegetation with mitral regurgitation in the second patient, and aortic valve vegetation with regurgitation in the third patient. The patients had positive Bartonella quintana serum immunoglobulin G (IgG) with negative immunoglobulin M (IgM). PCR on DNA extracted from cardiac valves was positive for Bartonella, and DNA sequencing of PCR amplicons identified Bartonella quintana. Patients received treatment with doxycycline/rifampin or doxycycline/gentamicin. CONCLUSION: Clinicians should consider Bartonella endocarditis as a differential diagnosis in patients who fit elements of the Duke Criteria, as well as having a history of homelessness and alcoholism.

The potential role for protein-conjugate pneumococcal vaccine in adults: what is the supporting evidence?

Vaccination with protein-conjugate pneumococcal vaccine (PCV) provides children with extraordinary protection against pneumococcal disease, although the protective effect may be blunted by the emergence of replacement strains. Studies in adults have compared PCV with pneumococcal polysaccharide vaccine (PPV) using surrogate markers of protection, namely, serum anticapsular IgG antibody and opsonic activity. Results suggest that PCV is at least as effective as PPV for the strains covered, but a definitive and consistent advantage has not been demonstrated. Unfortunately, persons who are most in need of vaccine do not respond as well as otherwise healthy adults to either vaccine. Newer formulations of PCV will protect against the most prevalent of the current replacement strains, but replacement strains will create a moving target for PCVs. Unless an ongoing trial comparing 13-valent PCV with placebo (not to PPV) demonstrates a clearly better effect than that seen in the past with PPV, cost-effectiveness considerations are likely to prevent widespread use of PCV in adults.

Scaling of surface roughness in perfectly plastic disordered media.

This paper investigates surface roughness characteristics of localized plastic yield surface in a perfectly plastic disordered material. We model the plastic disordered material using perfectly plastic random spring model. Our results indicate that plasticity in a disordered material evolves in a diffusive manner until macroscopic yielding, which is in contrast to the localized failure observed in brittle fracture of disordered materials. On the other hand, the height-height fluctuations of the plastic yield surfaces generated by the spring model exhibit roughness exponents similar to those obtained in the brittle fracture of disordered materials, albeit anomalous scaling of plastic surface roughness is not observed. The local and global roughness exponents (ζ(loc) and ζ, respectively) are equal to each other, and the two-dimensional crack roughness exponent is estimated to be ζ(loc)=ζ=0.67±0.03. The probability density distribution p[Δh(ℓ)] of the height differences Δh(ℓ)=[h(x+ℓ)-h(x)] of the crack profile follows a Gaussian distribution.