Perforating Gout: Expanding the Differential for Transepidermal Elimination.

Perforating dermatoses are dermatologic disorders with transepidermal elimination (TE) of dermal substances. While TE is typically associated with collagen and elastin, it can also occur as a secondary event in other processes, and it is important to keep a broad differential. We present a case of perforating tophaceous gout, which underscores the need for a thoughtful approach to perforating disorders. An updated review of recent literature is also presented.

Midline shift in patients with closed traumatic brain injury may be driven by cerebral perfusion pressure not intracranial pressure.

BACKGROUND: In traumatic brain injury (TBI), swelling may disturb the potentially uniform pressure distribution in the brain, producing sustained intercompartmental pressure gradients which may associate with midline shift. The presence of pressure gradients is often neglected since bilateral invasive intracranial pressure (ICP) monitoring is not usually considered because of risks and high costs. We evaluated the presence of interhemispheric pressure gradients using bilateral transcranial Doppler (TCD) as means for noninvasive ICP (nICP) monitoring in TBI patients presenting midline shift. METHODS: From a retrospective cohort of 97 TBI patients with arterial blood pressure (ABP), ICP and bilateral TCD monitoring, 24 presented unilateral lesion and midline shift confirmed by computer tomography. nICP and noninvasive cerebral perfusion pressure (nCPP) on the left and right brain hemispheres were retrospectively calculated using a mathematical model associating TCD-derived cerebral blood flow velocity and ABP. RESULTS: The nCPP difference was correlated with midline shift (R=-0.34, P<0.01) showing a tendency to record higher CPP at the side of expansion. Accordingly, nICP at the side of expansion was significantly lower in comparison to the compressed side (18.86 [±5.71] mmHg [mean±standard deviation] versus 20.30 [±6.78] mmHg for expansion and compressed sides, respectively). Subsequently, nCPP was greater on the side of brain expansion (79.48±7.84, 78.03±8.93 mmHg [P<0.01], for expansion and compressed sides, respectively). CONCLUSIONS: TCD-based interhemispheric nCPP difference showed significant correlation with midline shift. Cerebral perfusion pressure was greater on the side of brain expansion, acting as the driving force to shift brain structures.

Systemic Immunomodulatory Treatments for Patients With Atopic Dermatitis: A Systematic Review and Network Meta-analysis.

Importance: Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled. Objective: To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019. Study Selection: English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included. Data Extraction and Synthesis: Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. Main Outcomes and Measures: Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events. Results: A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, -1.1; 95% CrI, -1.7 to -0.5 [low certainty]) and dupilumab (standardized mean difference, -0.9; 95% CrI, -1.0 to -0.8 [high certainty]) were similarly effective vs placebo in clearing clinical signs of atopic dermatitis and may be superior to methotrexate (standardized mean difference, -0.6; 95% CrI, -1.1 to 0.0 [low certainty]) and azathioprine (standardized mean difference, -0.4; 95% CrI, -0.8 to -0.1 [low certainty]). Several investigational medications for atopic dermatitis are promising, but data to date are limited to small early-phase trials. Safety analyses were limited by low event rates. Conclusions and Relevance: Dupilumab and cyclosporine may be more effective for up to 16 weeks of treatment than methotrexate and azathioprine for treating adult patients with atopic dermatitis. More studies directly comparing established and novel treatments beyond 16 weeks are needed and will be incorporated into future updates of this review.

Targetoid form of polymorphic eruption of pregnancy: A case report.

Polymorphic eruption of pregnancy, formerly known as pruritic and urticarial papules and plaques of pregnancy, is an uncommon cutaneous eruption that can affect women during their third trimester of pregnancy. As its name implies, it has a variety of morphologies and it is important to consider other diagnoses, such as pemphigoid gestationis, which polymorphic eruption of pregnancy can mimic. Sometimes, as in this case, polymorphic eruption of pregnancy can have a targetoid morphology reminiscent of erythema multiforme. A thorough workup and conservative management plan helps reassure the patient that the correct approach is being taken during the challenging period of a pregnancy nearing completion.

Cutaneous Crohn's disease of the vulva after a total colectomy and without gastrointestinal manifestations: A case report.

Crohn's disease has many cutaneous manifestations. We report a case of a 54-year-old woman, who had non-contiguous vulvar Crohn's disease despite a total colectomy and the absence of gastrointestinal Crohn's disease on ileoscopy.

Refractory Palmoplantar Pustular Psoriasis Treated With High-Dose Ustekinumab After Initial Failure.

Palmoplantar pustular psoriasis (PPPP) is a form of psoriasis that can be difficult to treat. We describe a case of PPPP in a patient who failed multiple therapies, including ustekinumab. The patient subsequently developed inflammatory bowel disease (IBD), and restarting ustekinumab, with inflammatory bowel disease loading doses and optimization, resulted in complete resolution of her PPPP. This success occurred after she developed tachyphylaxis against the usual dosing of ustekinumab, demonstrating a recapture of the treatment response.

Prospective Study on Noninvasive Assessment of Intracranial Pressure in Traumatic Brain-Injured Patients: Comparison of Four Methods.

Elevation of intracranial pressure (ICP) may occur in many diseases, and therefore the ability to measure it noninvasively would be useful. Flow velocity signals from transcranial Doppler (TCD) have been used to estimate ICP; however, the relative accuracy of these methods is unclear. This study aimed to compare four previously described TCD-based methods with directly measured ICP in a prospective cohort of traumatic brain-injured patients. Noninvasive ICP (nICP) was obtained using the following methods: 1) a mathematical "black-box" model based on interaction between TCD and arterial blood pressure (nICP_BB); 2) based on diastolic flow velocity (nICP_FVd); 3) based on critical closing pressure (nICP_CrCP); and 4) based on TCD-derived pulsatility index (nICP_PI). In time domain, for recordings including spontaneous changes in ICP greater than 7 mm Hg, nICP_PI showed the best correlation with measured ICP (R = 0.61). Considering every TCD recording as an independent event, nICP_BB generally showed to be the best estimator of measured ICP (R = 0.39; p < 0.05; 95% confidence interval [CI] = 9.94 mm Hg; area under the curve [AUC] = 0.66; p < 0.05). For nICP_FVd, although it presented similar correlation coefficient to nICP_BB and marginally better AUC (0.70; p < 0.05), it demonstrated a greater 95% CI for prediction of ICP (14.62 mm Hg). nICP_CrCP presented a moderate correlation coefficient (R = 0.35; p < 0.05) and similar 95% CI to nICP_BB (9.19 mm Hg), but failed to distinguish between normal and raised ICP (AUC = 0.64; p > 0.05). nICP_PI was not related to measured ICP using any of the above statistical indicators. We also introduced a new estimator (nICP_Av) based on the average of three methods (nICP_BB, nICP_FVd, and nICP_CrCP), which overall presented improved statistical indicators (R = 0.47; p < 0.05; 95% CI = 9.17 mm Hg; AUC = 0.73; p < 0.05). nICP_PI appeared to reflect changes in ICP in time most accurately. nICP_BB was the best estimator for ICP "as a number." nICP_Av demonstrated to improve the accuracy of measured ICP estimation.

Diacylglycerol kinases terminate diacylglycerol signaling during the respiratory burst leading to heterogeneous phagosomal NADPH oxidase activation.

It is commonly assumed that all phagosomes have identical molecular composition. This assumption has remained largely unchallenged due to a paucity of methods to distinguish individual phagosomes. We devised an assay that extends the utility of nitro blue tetrazolium for detection and quantification of NAPDH oxidase (NOX) activity in individual phagosomes. Implementation of this assay revealed that in murine macrophages there is heterogeneity in the ability of individual phagosomes to generate superoxide, both between and within cells. To elucidate the molecular basis of the variability in NOX activation, we employed genetically encoded fluorescent biosensors to evaluate the uniformity in the distribution of phospholipid mediators of the oxidative response. Despite variability in superoxide generation, the distribution of phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3-phosphate, and phosphatidic acid was nearly identical in all phagosomes. In contrast, diacylglycerol (DAG) was not generated uniformly across the phagosomal population, varying in a manner that directly mirrored superoxide production. Modulation of DAG levels suggested that NOX activation is precluded when phagosomes fail to reach a critical DAG concentration. In particular, forced expression of diacylglycerol kinase ß abrogated DAG accumulation at the phagosome, leading to impaired respiratory burst. Conversely, pharmacological inhibition of DAG kinases or expression of an inactive diacylglycerol kinase ß mutant increased the proportion of DAG-positive phagosomes, concomitantly potentiating phagosomal NOX activity. Our data suggest that diacylglycerol kinases limit the extent of NADPH oxidase activation, curtailing the production of potentially harmful reactive oxygen species. The resulting heterogeneity in phagosome responsiveness could enable the survival of a fraction of invading microorganisms.

Phosphatidic acid is required for the constitutive ruffling and macropinocytosis of phagocytes.

Macrophages and dendritic cells continuously survey their environment in search of foreign particles and soluble antigens. Such surveillance involves the ongoing extension of actin-rich protrusions and the consequent formation of phagosomes and macropinosomes. The signals inducing this constitutive cytoskeletal remodeling have not been defined. We report that, unlike nonphagocytic cells, macrophages and immature dendritic cells have elevated levels of phosphatidic acid (PA) in their plasma membrane. The plasmalemmal PA is synthesized by phosphorylation of diacylglycerol, which is in turn generated by a G protein-stimulated phospholipase C. Inhibition of diacylglycerol kinase activity results in the detachment of T-cell lymphoma invasion and metastasis-inducing protein 1 (TIAM1)-a Rac guanine exchange factor-from the plasma membrane, thereby depressing Rac activity and abolishing the constitutive ruffling and macropinocytosis that characterize macrophages and immature dendritic cells. Accumulation of PA and binding of TIAM1 to the membrane require the activity of phosphatidylinositol-4,5-bisphosphate 3-kinase. Thus a distinctive, constitutive pathway of PA biosynthesis promotes the actin remodeling required for immune surveillance.

Role of phospholipids in endocytosis, phagocytosis, and macropinocytosis.

Endocytosis, phagocytosis, and macropinocytosis are fundamental processes that enable cells to sample their environment, eliminate pathogens and apoptotic bodies, and regulate the expression of surface components. While a great deal of effort has been devoted over many years to understanding the proteins involved in these processes, the important contribution of phospholipids has only recently been appreciated. This review is an attempt to collate and analyze the rapidly emerging evidence documenting the role of phospholipids in clathrin-mediated endocytosis, phagocytosis, and macropinocytosis. A primer on phospholipid biosynthesis, catabolism, subcellular distribution, and transport is presented initially, for reference, together with general considerations of the effects of phospholipids on membrane curvature and charge. This is followed by a detailed analysis of the critical functions of phospholipids in the internalization processes and in the maturation of the resulting vesicles and vacuoles as they progress along the endo-lysosomal pathway.

Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling.

Sealing of phagosomes is accompanied by the disappearance of phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P(2)) from their cytoplasmic leaflet. Elimination of PtdIns(4,5)P(2), which is required for actin remodeling during phagosome formation, has been attributed to hydrolysis by phospholipase C and phosphorylation by phosphatidylinositol 3-kinase. We found that two inositol 5-phosphatases, OCRL and Inpp5B, become associated with nascent phagosomes. Both phosphatases, which are Rab5 effectors, associate with the adaptor protein APPL1, which is recruited to the phagosomes by active Rab5. Knockdown of APPL1 or inhibition of Rab5 impairs association of OCRL and Inpp5B with phagosomes and prolongs the presence of PtdIns(4,5)P(2) and actin on their membranes. Even though APPL1 can serve as an anchor for Akt, its depletion accentuated the activation of the kinase, likely by increasing the amount of PtdIns(4,5)P(2) available to generate phosphatidylinositol (3,4,5)-trisphosphate. Thus, inositol 5-phosphatases are important contributors to the phosphoinositide remodeling and signaling that are pivotal for phagocytosis.

Rapamycin-based inducible translocation systems for studying phagocytosis.

Phagocytosis is an immune receptor-mediated process whereby cells engulf large particles. The process is dynamic and requires several localized factors acting in concert with and sequentially after the engagement of immune receptors to envelope the particle. Once the particle is internalized, the nascent -phagosome undergoes a series of events leading to its maturation to the microbicidal phagolysosome. Investigating these dynamic and temporally controlled series of events in live cells requires noninvasive methods. The ability to rapidly recruit the proteins of interest to the sites of phagocytosis or to nascent phagosomes would help dissect the regulatory mechanisms involved during phagocytosis. Here, we describe a general approach to express in RAW264.7 murine macrophages, a genetically encoded rapamycin--induced heterodimerization system. In the presence of rapamycin, tight association between FK506-binding protein (FKBP) and FKBP rapamycin-binding protein (FRB) is observed. Based on this principle, a synthetic system consisting of a targeting domain attached to FKBP can recruit a protein of interest fused to FRB upon the addition of rapamycin. Previously, this technique has been used to target lipid-modifying enzymes and small GTPases to the phagosome or plasma membrane. The recruitment of the FRB module can be monitored by fluorescent microscopy if a fluorescent protein is fused to the FRB sequence. While the focus of this chapter is on phagocytic events, this method can be employed to study any organelle of interest when the appropriate targeting sequence is used.

Class I and class III phosphoinositide 3-kinases are required for actin polymerization that propels phagosomes.

Actin polymerization drives the extension of pseudopods that trap and engulf phagocytic targets. The polymerized actin subsequently dissociates as the phagocytic vacuole seals and detaches from the plasma membrane. We found that phagosomes formed by engagement of integrins that serve as complement receptors (CR3) undergo secondary waves of actin polymerization, leading to the formation of "comet tails" that propel the vacuoles inside the cells. Actin tail formation was accompanied by and required de novo formation of PI(3,4)P(2) and PI(3,4,5)P(3) on the phagosomal membrane by class I phosphoinositide 3-kinases (PI3Ks). Although the phosphatidylinositide phosphatase Inpp5B was recruited to nascent phagosomes, it rapidly detached from the membrane after phagosomes sealed. Detachment of Inpp5B required the formation of PI(3)P. Thus, class III PI3K activity was also required for the accumulation of PI(4,5)P(2) and PI(3,4,5)P(3) and for actin tail formation. These experiments reveal a new PI(3)P-sensitive pathway leading to PI(3,4)P(2) and PI(3,4,5)P(3) formation and signaling in endomembranes.

Vesicular traffic: a Rab SANDwich.

The small GTPases Rab5 and Rab7 mark temporally distinct but sequentially connected stages in phagosome maturation, but the mechanism underlying the transition between these stages has been unclear. Recent studies in Caenorhabditis elegans have now uncovered a new protein complex that connects Rab5 to Rab7.