Cryptococcosis Associated With Biologic Therapy: A Narrative Review.

Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification

AIDS-Kaposi Sarcoma and Classic Kaposi Sarcoma: are different ultrasound patterns related to different variants?

<p>Abstract</p> <p>Background</p> <p>Kaposi Sarcoma (KS) is a malignancy of endothelial skin cells with multifocal localization on the skin, lymph nodes and visceral organs. Although all clinical variants are associated with HHV-8 infection, specific differences in the clinical onset and in the natural history of AIDS-KS and Classic-KS have been described. The present randomised prospective-observational study aimed to investigate whether the ultrasound pattern and color Doppler flow imaging of vascularisation of skin lesions of patients with Classic KS (CKS) or AIDS-KS could provide useful information to the evaluation of clinical activity of the disease.</p> <p>Methods</p> <p>Cutaneous lesions of 24 patients with histologically confirmed KS were investigated using very high frequency ultrasound probes; 16 patients had CKS and 8 had AIDS-KS. HHV-8 infection was confirmed in all patients by investigating the specific humoral response to viral antigens. Immunological and virological parameters were also assessed to monitor HIV or HHV-8 viral infection. For each patient, a target skin lesion was selected on the basis of size (diameter from 0.4 to 2 cm). Each lesion was analyzed in terms of size, depth and color Doppler pattern.</p> <p>Results</p> <p>The B-mode ultrasound patterns of skin lesions did not differ when comparing CKS patients to AIDS-KS patients, whereas the color Doppler signal, which is associated with vascular activity, was detected in the KS lesions of 6/8 AIDS-KS patients (75.0%) and in 2/16 CKS (16,7%); the latter two patients showed a clinically progressive and extensive disease stage (IV B).</p> <p>Conclusions</p> <p>Our preliminary results suggest that small cutaneous KS lesions - in both CKS and AIDS-KS patients- display similar B-mode ultrasound patterns ( hypoechoic, well defined, superficial lesions). However, the color Doppler signal, which is associated with endothelial activity and angiogenesis, which play a substantial role in KS progression, could constitute a useful tool for evaluating disease activity.</p

On the isoperimetric problem for the Laplacian with Robin and Wentzell boundary conditions

Doctor of PhilosophyWe consider the problem of minimising the eigenvalues of the Laplacian with Robin boundary conditions $\frac{\partial u}{\partial \nu} + \alpha u = 0$ and generalised Wentzell boundary conditions $\Delta u + \beta \frac{\partial u}{\partial \nu} + \gamma u = 0$ with respect to the domain $\Omega \subset \mathbb R^N$ on which the problem is defined. For the Robin problem, when $\alpha > 0$ we extend the Faber-Krahn inequality of Daners [Math. Ann. 335 (2006), 767--785], which states that the ball minimises the first eigenvalue, to prove that the minimiser is unique amongst domains of class $C^2$. The method of proof uses a functional of the level sets to estimate the first eigenvalue from below, together with a rearrangement of the ball's eigenfunction onto the domain $\Omega$ and the usual isoperimetric inequality. We then prove that the second eigenvalue attains its minimum only on the disjoint union of two equal balls, and set the proof up so it works for the Robin $p$-Laplacian. For the higher eigenvalues, we show that it is in general impossible for a minimiser to exist independently of $\alpha > 0$. When $\alpha < 0$, we prove that every eigenvalue behaves like $-\alpha^2$ as $\alpha \to -\infty$, provided only that $\Omega$ is bounded with $C^1$ boundary. This generalises a result of Lou and Zhu [Pacific J. Math. 214 (2004), 323--334] for the first eigenvalue. For the Wentzell problem, we (re-)prove general operator properties, including for the less-studied case $\beta 0$ establish a type of equivalence property between the Wentzell and Robin minimisers for all eigenvalues. This yields a minimiser of the second Wentzell eigenvalue. We also prove a Cheeger-type inequality for the first eigenvalue in this case

Therapeutic and immunomodulatory activities of short-course treatment of murine visceral leishmaniasis with KALSOME™10, a new liposomal amphotericin B

Visceral leishmaniasis (VL), a potentially fatal disease, is most prevalent in the Indian subcontinent, East Africa and South America. Since the conventional antileishmanial drugs have many limitations we evaluated a new ergosterol rich liposomal amphotericin B formulation, KALSOME™10 for its leishmanicidal efficacy, tolerability and immunomodulatory activity. Normal healthy mice were treated with 3.5 mg/kg single and 7.5 mg/kg single and double doses ofKALSOME™10. Liver and kidney function tests were performed fourteen days after treatment. Next, normal mice were infected with Leishmania donovani amastigotes. Two months post infection they were treated with the above mentioned doses of KALSOME™10 and sacrificed one month after treatment for estimation of parasite burden in the liver and spleen by Limiting Dilution Assay. Leishmanial antigen stimulated splenocyte culture supernatants were collected for cytokine detection through ELISA. Flow cytometric studies were performed on normal animals treated with KALSOME™10, Amphotericin B (AmB) and AmBiosome to compare their immunomodulatory activities. The drug was found to induce no hepato- or nephrotoxicities at the studied doses. Moreover, at all doses, it led to significant reduction in parasite burden in two month infected BALB/c mice, with 7.5 mg/kg double dose resulting in almost complete clearance of parasites from both liver and spleen. Interestingly, the drug at 7.5 mg/kg double dose could almost completely inhibit the secretion of disease promoting cytokines, IL-10 and TGFβ, and significantly elevate the levels of IFNγ and IL-12, cytokines required for control of the disease. Mice treated with KALSOME™10 showed elevated levels of IFNγ and suppressed IL-10 secretion from both CD4+ and CD8+ subsets of T cells, as well as from culture supernatants of splenocytes, compared to that of normal, AmB and AmBisome treated animal Treatment of infected mice with 7.5 mg/kg double dose of KALSOME™10 was safe and effective in clearing the parasites from the sites of infection. The drug maintains the inherent immunomodulatory activities of AmB by effectively suppressing disease promoting cytokines IL-10 and TGFβ, thereby boosting IL-12 and IFNγ levels. This emphasizes KALSOME™10 as a promising drug alternative for lifelong protection from VL

Evidence for Cognitive Impairment in Mastocytosis: Prevalence, Features and Correlations to Depression

Mastocytosis is a heterogeneous disease characterized by mast cells accumulation in one or more organs. We have reported that depression is frequent in mastocytosis, but although it was already described, little is known about the prevalence and features of cognitive impairment. Our objective was to describe the prevalence and features of cognitive impairment in a large cohort of patients with this rare disease (n = 57; mean age = 45) and to explore the relations between memory impairment and depression. Objective memory impairment was evaluated using the 3rd edition of the Clinical Memory scale of Wechsler. Depression symptoms were evaluated using the Hamilton Depression Rating Scale. Age and education levels were controlled for all patients. Patients with mastocytosis presented high levels of cognitive impairment (memory and/or attention) (n = 22; 38.6%). Cognitive impairment was moderate in 59% of the cases, concerned immediate auditory (41%) and working memory (73%) and was not associated to depression (p≥0.717). In conclusion, immediate auditory memory and attention impairment in mastocytosis are frequent, even in young individuals, and are not consecutive to depression. In mastocytosis, cognitive complaints call for complex neuropsychological assessment. Mild-moderate cognitive impairment and depression constitute two specific but somewhat independent syndromes in mastocytosis. These results suggest differential effects of mast-cell activity in the brain, on systems involved in emotionality and in cognition

Incidence and Risk Factors of Serious Adverse Events during Antituberculous Treatment in Rwanda: A Prospective Cohort Study

BACKGROUND: Tuberculosis (TB) and TB-human immunodeficiency virus infection (HIV) coinfection is a major public health concern in resource-limited settings. Although TB treatment is challenging in HIV-infected patients because of treatment interactions, immunopathological reactions, and concurrent infections, few prospective studies have addressed this in sub-Saharan Africa. In this study we aimed to determine incidence, causes of, and risk factors for serious adverse events among patients on first-line antituberculous treatment, as well as its impact on antituberculous treatment outcome. METHODS AND FINDINGS: Prospective observational cohort study of adults treated for TB at the Internal Medicine department of the Kigali University Hospital from May 2008 through August 2009. Of 263 patients enrolled, 253 were retained for analysis: median age 35 (Interquartile range, IQR 28-40), 55% male, 66% HIV-positive with a median CD4 count 104 cells/mm(3) (IQR 44-248 cells/mm(3)). Forty percent had pulmonary TB, 43% extrapulmonary TB and 17% a mixed form. Sixty-four (26%) developed a serious adverse event; 58/167 (35%) HIV-infected vs. 6/86 (7%) HIV-uninfected individuals. Commonest events were concurrent infection (n = 32), drug-induced hepatitis (n = 24) and paradoxical reactions/TB-IRIS (n = 23). HIV-infection (adjusted Hazard Ratio, aHR 3.4, 95% Confidence Interval, CI 1.4-8.7) and extrapulmonary TB (aHR 2, 95%CI 1.1-3.7) were associated with an increased risk of serious adverse events. For TB/HIV co-infected patients, extrapulmonary TB (aHR 2.0, 95%CI 1.1-3.9) and CD4 count <100 cells/mm3 at TB diagnosis (aHR 1.7, 95%CI 1.0-2.9) were independent predictors. Adverse events were associated with an almost two-fold higher risk of unsuccessful treatment outcome at 6 months (HR 1.89, 95%CI 1.3-3.0). CONCLUSION: Adverse events frequently complicate the course of antituberculous treatment and worsen treatment outcome, particularly in patients with extrapulmonary TB and advanced immunodeficiency. Concurrent infection accounts for most events. Our data suggest that deterioration in a patient already receiving antituberculous treatment should prompt an aggressive search for additional infections

Depression in Patients with Mastocytosis: Prevalence, Features and Effects of Masitinib Therapy

Depression in patients with mastocytosis is often reported but its prevalence and characteristics are not precisely described. In addition, the impact of therapies targeting mast cells proliferation, differentiation and degranulation on psychic symptoms of depression have never been investigated. Our objective was to determine the prevalence and to describe features of depression in a large cohort of mastocytosis patients (n = 288) and to investigate the therapeutic impact of the protein kinase inhibitor masitinib in depression symptoms. The description of depression was based on the analysis of a database with Hamilton scores using Principal Component Analysis (PCA). Efficacy of masitinib therapy was evaluated using non parametric Wilcoxon test for paired data within a three months period (n = 35). Our results show that patients with indolent mastocytosis present an elevated prevalence of depression (64%). Depression was moderate in 56% but severe in 8% of cases. Core symptoms (such as psychic anxiety, depressed mood, work and interests) characterized depression in mastocytosis patients. Masitinib therapy was associated with significant improvement (67% of the cases) of overall depression, with 75% of recovery cases. Global Quality of Life slightly improved after masitinib therapy and did not predicted depression improvement. In conclusion, depression is very frequent in mastocytosis patients and masitinib therapy is associated with the reduction its psychic experiences. We conclude that depression in mastocytosis may originate from processes related to mast cells activation. Masitinib could therefore be a useful treatment for mastocytosis patients with depression and anxiety symptoms

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode