Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is the most common finding on renal biopsy in HIV-infected black patients and is also the commonest cause of end-stage renal disease in these patients. Early detection of HIVAN may be beneficial in evaluating early treatment. This study examined the pattern of renal diseases in HIV-infected South Africans and also attempted to diagnose HIVAN at an early stage. In this single-center cross-sectional study, 615 HIV-infected patients were screened for proteinuria. Thirty patients with varying degrees of proteinuria underwent renal biopsy. Patients with diabetes mellitus, uncontrolled hypertension, known causes of chronic kidney disease, and serum creatinine above 250 mumol/l were excluded. Patients in this study were not on antiretroviral therapy. HIVAN was found in 25 (83%) patients. Six of them (24%) had microalbuminuria. Altogether, seven patients with persistent microalbuminuria were biopsied and six (86%) showed HIVAN. Other biopsy findings included membranoproliferative nephropathy in two (7%) and interstitial nephritis in three (10%). Four patients with HIVAN had associated membranous nephropathy. HIVAN is the commonest biopsy finding among our study patients with HIV infection who present with varying degrees of proteinuria. Microalbuminuria is a manifestation of HIVAN in our study patients. Therefore, microalbuminuria may be an early marker of HIVAN, and screening for its presence may be beneficial. Renal biopsy may be considered in seropositive patients who present with persistent microalbuminuria, especially with low CD4 counts irrespective of good renal function. This will allow diagnosis and treatment of HIVAN at an early stage and may prevent further disease progression.

Tuberculosis (TB) in humans is characterized by formation of immune-rich granulomas in infected tissues, the architecture and composition of which are thought to affect disease outcome. However, our understanding of the spatial relationships that control human granulomas is limited. Here, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) to image 37 proteins in tissues from patients with active TB. We constructed a comprehensive atlas that maps 19 cell subsets across 8 spatial microenvironments. This atlas shows an IFN-γ-depleted microenvironment enriched for TGF-β, regulatory T cells and IDO1+ PD-L1+ myeloid cells. In a further transcriptomic meta-analysis of peripheral blood from patients with TB, immunoregulatory trends mirror those identified by granuloma imaging. Notably, PD-L1 expression is associated with progression to active TB and treatment response. These data indicate that in TB granulomas, there are local spatially coordinated immunoregulatory programs with systemic manifestations that define active TB.

The ubiquitous gasotransmitter hydrogen sulfide (H2S) has been recognized to play a crucial role in human health. Using cystathionine γ-lyase (CSE)-deficient mice, we demonstrate an unexpected role of H2S inMycobacterium tuberculosis(Mtb) pathogenesis. We showed thatMtb-infected CSE−/−mice survive longer than WT mice, and support reduced pathology and lower bacterial burdens in the lung, spleen, and liver. Similarly, in vitroMtbinfection of macrophages resulted in reduced colony forming units in CSE−/−cells. Chemical complementation of infected WT and CSE−/−macrophages using the slow H2S releaser GYY3147 and the CSE inhibitor DL-propargylglycine demonstrated that H2S is the effector molecule regulatingMtbsurvival in macrophages. Furthermore, we demonstrate that CSE promotes an excessive innate immune response, suppresses the adaptive immune response, and reduces circulating IL-1β, IL-6, TNF-α, and IFN-γ levels in response toMtbinfection. Notably,Mtbinfected CSE−/−macrophages show increased flux through glycolysis and the pentose phosphate pathway, thereby establishing a critical link between H2S and central metabolism. Our data suggest that excessive H2S produced by the infected WT mice reduce HIF-1α levels, thereby suppressing glycolysis and production of IL-1β, IL-6, and IL-12, and increasing bacterial burden. Clinical relevance was demonstrated by the spatial distribution of H2S-producing enzymes in human necrotic, nonnecrotic, and cavitary pulmonary tuberculosis (TB) lesions. In summary, CSE exacerbates TB pathogenesis by altering immunometabolism in mice and inhibiting CSE or modulating glycolysis are potential targets for host-directed TB control.

Iron is an essential factor for the growth and virulence of Mycobacterium tuberculosis (Mtb). However, little is known about the mechanisms by which the host controls iron availability during infection. Since ferritin heavy chain (FtH) is a major intracellular source of reserve iron in the host, we hypothesized that the lack of FtH would cause dysregulated iron homeostasis to exacerbate TB disease. Therefore, we used knockout mice lacking FtH in myeloid-derived cell populations to study Mtb disease progression. We found that FtH plays a critical role in protecting mice against Mtb, as evidenced by increased organ burden, extrapulmonary dissemination, and decreased survival in Fth−/− mice. Flow cytometry analysis showed that reduced levels of FtH contribute to an excessive inflammatory response to exacerbate disease. Extracellular flux analysis showed that FtH is essential for maintaining bioenergetic homeostasis through oxidative phosphorylation. In support of these findings, RNAseq and mass spectrometry analyses demonstrated an essential role for FtH in mitochondrial function and maintenance of central intermediary metabolism in vivo. Further, we show that FtH deficiency leads to iron dysregulation through the hepcidin–ferroportin axis during infection. To assess the clinical significance of our animal studies, we performed a clinicopathological analysis of iron distribution within human TB lung tissue and showed that Mtb severely disrupts iron homeostasis in distinct microanatomic locations of the human lung. We identified hemorrhage as a major source of metabolically inert iron deposition. Importantly, we observed increased iron levels in human TB lung tissue compared to healthy tissue. Overall, these findings advance our understanding of the link between iron-dependent energy metabolism and immunity and provide new insight into iron distribution within the spectrum of human pulmonary TB. These metabolic mechanisms could serve as the foundation for novel host-directed strategies.

PF occurs more commonly in black people, while most cases in Indians present with the PV subtype. Pemphigus patients present with severe and extensive disease, and PV patients share features in common with patients from their land of origin (India), suggesting a genetic link.

Although these lesions share histopathologic features of the so-called acral pseudolymphomatous angiokeratoma of children (APACHE), they occur in a completely different clinical setting, present in solitary and polypoid fashion and are T-cell rich. We propose the diagnostic label T-cell-rich angiomatoid polypoid pseudolymphoma for this distinctive but presumably reactive lesion.

bcl-2, the well known anti-apoptotic gene, cloned more than a decade ago, promotes cell viability without promoting cell proliferation. With few exceptions, high bcl-2 protein expression is associated with a favourable outcome in epithelial tumours. bcl-2 immunoreactivity in basal cell carcinomas (BCCs) is contradictory, with 67-100% immunopositivity being reported. Although BCCs are traditionally regarded as low-grade, indolent tumours, aggressive BCCs (A-BCCs) are mutilative, locally destructive tumours that often recur. bcl-2 protein expression as a predictor of BCC aggressiveness is poorly documented in the English-language literature. The bcl-2 protein immunoprofile of 50 clinically non-aggressive (NA-BCCs) and 25 clinically A-BCCs was investigated. Of the latter, 17 manifested with one, two or three recurrences. bcl-2 protein expression in each of the recurrences was also evaluated. bcl-2 expression was scored as follows: 0-5% positive cells=negative, 6-25%=1+, 26-50%=2+, 51-75%=3+, >75%=4+. "High" labeling encompassed 3+ or 4+ labeling while "low" labeling referred to 1 + or 2 + labeling. Although bcl-2 positivity was noted in all BCCs, low bcl-2 labeling was a statistically significant feature of A-BCCs (p < 0.01). High bcl-2 labeling of NA-BCCs was a reflection of the bcl-2 labeling of the dominant constituent nodular or superficial subtypes. Micronodular BCCs revealed 2+ or 3+ labeling. Initial and recurrent A-BCCs with a pure or predominantly infiltrative component, demonstrated 1+ or 2+ bcl-2 labeling. The differential bcl-2 expression in the various clinicopathological subtypes of BCCs suggests that, despite the common derivation of these tumours from a primitive basaloid stem cell and a limited potential for metastasis, they form a heterogeneous group of tumours that differ markedly in histologic and biological behaviour. While the superficial and nodular BCCs are indolent slow-growing tumours with high bcl-2 labeling, the aggressive BCCs are infiltrative, desmoplastic tumours with low bcl-2 labeling. In mixed tumours, heterogeneity of labeling is a distinctive feature and is contributed to in part by the labeling trends of the different histological subtypes. The micronodular BCC shows varied bcl-2 labeling but in combined tumours occupies a niche intermediate between the non-aggressive nodular and superficial and the aggressive infiltrative subtypes. The initial and subsequent biopsies of recurrent, adequately excised BCCs share a pure or mixed, predominantly infiltrative, stroma-rich histomorphology with low bcl-2 labeling, reflecting the immunoprofile of a more aggressive growth pattern.

An established relationship exists between human immunodeficiency virus (HIV) and the vascular system, which is characterised by clinical expressions of aneurysmal and occlusive disease that emanate from a common pathological process. The exact pathogenesis is currently unknown; attempts to implicate opportunistic pathogens have been futile. Theories converge on leucocytoclastic vasculitis with the vaso vasora as the vasculopathic epicentre. It is thought that the virus itself or viral proteins trigger the release of inflammatory mediators that cause endothelial dysfunction and smooth muscle proliferation leading to vascular injury and thrombosis. The beneficial effects of highly active anti-retroviral therapy alter the natural history of the disease profile and promote longevity but are negated by cardiovascular complications. Atherosclerosis is an emerging challenge. Presently patients are managed by standard surgical protocols because of non-existent universal surgical interventional guidelines. Clinical response to treatment is variable and often compounded by complications of graft occlusion, sepsis and poor wound healing. The clinical, imaging and pathological observations position HIV-associated large-vessel vasculopathy as a unique entity. This review highlights the spectrum of HIV-associated large-vessel aneurysmal, occlusive and atherosclerotic disease in vascular surgical practice.