Balloon cell melanoma: a systematic review.

Balloon cell melanoma (BCM) is a rare presentation of malignant melanoma characterized by large, foamy melanocytes lacking pigmentation. This is a comprehensive review of the clinical, dermoscopic, and histological features among BCM cases reported in the literature. A systematic review of all case reports and series published since 1970 was conducted via MEDLINE, Embase, and Web of Science, using "balloon cell melanoma" and synonymous search terms. Our systematic search identified 76 cases (49% male, 51% female) of BCM in the literature. The mean age at presentation was 57.81 years. Prior skin cancer, particularly melanoma (47%), accounted for 58% of pertinent medical history. Prominent clinical exam findings included raised (46%), ulcerated (73%) lesions larger than 1 cm (68%) in the lower extremities (35%). Median Breslow thickness of primary BCM cases was 2.5 mm. Hairpin vessels (75%) and structureless architecture (75%) were predominant on dermoscopy. Notable histopathology included large (47%), vacuolated (58%) cells with foamy cytoplasm (62%) and conspicuous nucleoli (27%). Positive S-100 immunohistochemistry (73%) was most frequently employed to diagnose BCM. We observed 47% primary and 53% metastatic BCM cases. Of metastatic BCMs, balloon cells in the primary lesion were unknown in 48%, devoid in 33%, and present in 20% of cases. All metastases displayed predominant balloon cell morphology. BCM may represent an advanced phase in the progression of malignant melanoma. Improved awareness of BCM characteristics among clinicians may reduce the risk of misdiagnoses.

More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations.

BACKGROUND: Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. OBJECTIVE: We sought to discover characteristics that account for poor outcomes in lethal KID syndrome. METHODS: We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. RESULTS: Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 "lethal" mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V. LIMITATIONS: This clinical review was retrospective. CONCLUSION: GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion.

IgG4-related skin disease may have distinct systemic manifestations: a systematic review.

IgG4-related disease (IgG4-RD) is an increasingly prevalent protean multisystem disorder characterized by single or multi-organ infiltration of IgG4-bearing plasma cells. Skin involvement has been recognized and is relevant to proper diagnosis. A systematic literature review of 50 cases involving the skin reveals that patients with IgG4-related skin disease show predominant involvement of the head and neck and have a distinct pattern of systemic involvement, also favoring the head and neck - lymphatics, orbit, salivary, and lacrimal glands - but generally lacking pancreaticobiliary involvement (16% of cases), which by contrast is a predominant manifestation in systemic IgG4-RD (60% with pancreaticobiliary involvement). We summarize clinical and pathologic descriptive data from this systematic review. We review differential diagnosis and propose a diagnostic scheme for stratifying probability of disease based upon comprehensive integration of clinical, histopathologic, and laboratory data. Plasmacyte infiltration and storiform fibrosis are prominent in IgG4-related skin disease, but obliterative venulitis is less common than in the prototypical IgG4-related disease manifestation of autoimmune pancreatitis. IgG4 tissue and serum values, with a mean (±95% CI) in the reviewed cases of 132.8 ± 32.6 IgG4-positive plasma cells per high-power field and 580 ± 183.8 mg/dl, respectively, are incorporated into the suggested criteria. The distinct set of manifestations identified by this systematic review and the proposed diagnostic considerations, while requiring further validation in prospective studies, highlight the need to consider that IgG4-related skin disease defines a unique systemic disease complex along the spectrum of IgG4-RD.

Ion-abrasion scanning electron microscopy reveals surface-connected tubular conduits in HIV-infected macrophages.

HIV-1-containing internal compartments are readily detected in images of thin sections from infected cells using conventional transmission electron microscopy, but the origin, connectivity, and 3D distribution of these compartments has remained controversial. Here, we report the 3D distribution of viruses in HIV-1-infected primary human macrophages using cryo-electron tomography and ion-abrasion scanning electron microscopy (IA-SEM), a recently developed approach for nanoscale 3D imaging of whole cells. Using IA-SEM, we show the presence of an extensive network of HIV-1-containing tubular compartments in infected macrophages, with diameters of approximately 150-200 nm, and lengths of up to approximately 5 microm that extend to the cell surface from vesicular compartments that contain assembling HIV-1 virions. These types of surface-connected tubular compartments are not observed in T cells infected with the 29/31 KE Gag-matrix mutant where the virus is targeted to multi-vesicular bodies and released into the extracellular medium. IA-SEM imaging also allows visualization of large sheet-like structures that extend outward from the surfaces of macrophages, which may bend and fold back to allow continual creation of viral compartments and virion-lined channels. This potential mechanism for efficient virus trafficking between the cell surface and interior may represent a subversion of pre-existing vesicular machinery for antigen capture, processing, sequestration, and presentation.

Evaluation of denoising algorithms for biological electron tomography.

Tomograms of biological specimens derived using transmission electron microscopy can be intrinsically noisy due to the use of low electron doses, the presence of a "missing wedge" in most data collection schemes, and inaccuracies arising during 3D volume reconstruction. Before tomograms can be interpreted reliably, for example, by 3D segmentation, it is essential that the data be suitably denoised using procedures that can be individually optimized for specific data sets. Here, we implement a systematic procedure to compare various nonlinear denoising techniques on tomograms recorded at room temperature and at cryogenic temperatures, and establish quantitative criteria to select a denoising approach that is most relevant for a given tomogram. We demonstrate that using an appropriate denoising algorithm facilitates robust segmentation of tomograms of HIV-infected macrophages and Bdellovibrio bacteria obtained from specimens at room and cryogenic temperatures, respectively. We validate this strategy of automated segmentation of optimally denoised tomograms by comparing its performance with manual extraction of key features from the same tomograms.

Electron tomography of viruses.

Understanding the molecular architectures of enveloped and complex viruses is a challenging frontier in structural biology. In these viruses, the structural and compositional variation from one viral particle to another generally precludes the use of either crystallization or image averaging procedures that have been successfully implemented in the past for highly symmetric viruses. While advances in cryo electron tomography of unstained specimens provide new opportunities for identification and molecular averaging of individual subcomponents such as the surface glycoprotein spikes on purified viruses, electron tomography of stained and plunge-frozen cells is being used to visualize the cellular context of viral entry and replication. Here, we review recent developments in both areas as they relate to our understanding of the biology of heterogeneous and pleiomorphic viruses.

Electron tomography of the contact between T cells and SIV/HIV-1: implications for viral entry.

The envelope glycoproteins of primate lentiviruses, including human and simian immunodeficiency viruses (HIV and SIV), are heterodimers of a transmembrane glycoprotein (usually gp41), and a surface glycoprotein (gp120), which binds CD4 on target cells to initiate viral entry. We have used electron tomography to determine the three-dimensional architectures of purified SIV virions in isolation and in contact with CD4+ target cells. The trimeric viral envelope glycoprotein surface spikes are heterogeneous in appearance and typically approximately 120 A long and approximately 120 A wide at the distal end. Docking of SIV or HIV-1 on the T cell surface occurs via a neck-shaped contact region that is approximately 400 A wide and consistently consists of a closely spaced cluster of five to seven rod-shaped features, each approximately 100 A long and approximately 100 A wide. This distinctive structure is not observed when viruses are incubated with T lymphocytes in the presence of anti-CD4 antibodies, the CCR5 antagonist TAK779, or the peptide entry inhibitor SIVmac251 C34. For virions bound to cells, few trimers were observed away from this cluster at the virion-cell interface, even in cases where virus preparations showing as many as 70 envelope glycoprotein trimers per virus particle were used. This contact zone, which we term the "entry claw", provides a spatial context to understand the molecular mechanisms of viral entry. Determination of the molecular composition and structure of the entry claw may facilitate the identification of improved drugs for the inhibition of HIV-1 entry.