Use of Isoquercetin in the Treatment of Prurigo Nodularis.

Atopic dermatitis and prurigo nodularis result from complex interactions between the skin, the immune system, and the external environment. The pruritus associated with these conditions greatly impacts patients' quality of life and lacks uniformly effective treatment. A 57-year-old patient presented with severe atopic dermatitis and subsequent prurigo nodularis refractory to numerous standard therapies. The supplement isoquercetin was initiated and he noted significant, sustained reduction in his pruritus after only four weeks. Isoquercetin is a glycoside derivative with antihistamine properties of quercetin, a natural polyphenol flavonoid found in many plants. It may offer itch relief in patients who have failed more conventional therapies.

J Drugs Dermatol. 2017;16(11):1156-1158.

Importance of the brow in facial expressiveness during human communication.

OBJECTIVE: The objective of this study was to evaluate laterality and upper/lower face dominance of expressiveness during prescribed speech using a unique validated image subtraction system capable of sensitive and reliable measurement of facial surface deformation. RATIONALE: Observations and experiments of central control of facial expressions during speech and social utterances in humans and animals suggest that the right mouth moves more than the left during nonemotional speech. However, proficient lip readers seem to attend to the whole face to interpret meaning from expressed facial cues, also implicating a horizontal (upper face-lower face) axis. STUDY DESIGN: Prospective experimental design. Experimental maneuver: recited speech. OUTCOME MEASURE: image-subtraction strength-duration curve amplitude. METHODS: Thirty normal human adults were evaluated during memorized nonemotional recitation of 2 short sentences. Facial movements were assessed using a video-image subtractions system capable of simultaneously measuring upper and lower specific areas of each hemiface. RESULTS: The results demonstrate both axes influence facial expressiveness in human communication; however, the horizontal axis (upper versus lower face) would appear dominant, especially during what would appear to be spontaneous breakthrough unplanned expressiveness. CONCLUSION: These data are congruent with the concept that the left cerebral hemisphere has control over nonemotionally stimulated speech; however, the multisynaptic brainstem extrapyramidal pathways may override hemiface laterality and preferentially take control of the upper face. Additionally, these data demonstrate the importance of the often-ignored brow in facial expressiveness. LEVEL OF EVIDENCE: Experimental study. EBM levels not applicable.

Computerized objective measurement of facial motion: normal variation and test-retest reliability.

OBJECTIVE: Objective quantitative measurements of facial motion for the assessment of outcomes in patients with facial paralysis have been elusive. This paper will reintroduce an objective computerized program for measurement of facial motion and present data on symmetry in healthy subjects and test-retest reliability in patients with facial paralysis. STUDY DESIGN: Cross-sectional analysis of archived images. SETTING: Tertiary referral center. PATIENTS: Good quality video-recordings of 38 healthy subjects and 30 facial paralysis subjects with a wide range of paralysis that had been tested twice were selected. INTERVENTION: Using image subtraction techniques of digital video recordings, computer-generated strength-duration curves of prescribed facial movements were automatically constructed. MAIN OUTCOME MEASURES: The areas under the curve for specific regions of each side of the face were compared as a proportion described as a percentage (left/right in healthy subjects, abnormal/normal side in paralysis) in which 100% would be perfect symmetry. RESULTS: Thirty-eight healthy subjects had the following left/right symmetry means (95% confidence interval): brow, 98.95 (93.94-103.95); eye, 99.18 (96.31-102.06); and mouth, 96.87 (93.10-100.63).Thirty patients with varying degrees of facial paralysis, tested twice, were evaluated to determine the degree of agreement between trials as measured by the intraclass correlation coefficient. The results showed the intraclass correlation coefficient (95% confidence interval) for brow was 0.972 (0.943-0.987), eye 0.950 (0.898-0.976), and mouth 0.951 (0.901-0.976). CONCLUSION: These results demonstrate no substantial side bias in healthy subjects and excellent test-retest reliability in patients with facial paralysis. This program may be made available for interested investigators upon request.

Spontaneous extracranial decompression of epidural hematoma.

Epidural hematoma (EDH) is a common sequela of head trauma in children. An increasing number are managed nonsurgically, with close clinical and imaging observation. We report the case of a traumatic EDH that spontaneously decompressed into the subgaleal space, demonstrated on serial CT scans that showed resolution of the EDH and concurrent enlargement of the subgaleal hematoma.

Embolization of an arterioportal fistula by injection of D-stat into the portal venous outflow.

Arterioportal fistulas may occur in liver transplant recipients after percutaneous biopsy. This report describes a case in which a 13-year-old liver transplant patient developed an arterioportal fistula after multiple liver biopsies and underwent coil embolization; however, at that time, there were at least two small arterial feeders that were not amenable to subselection. He later developed recurrent variceal bleeding, and repeat angiogram revealed multiple tiny serpentine feeding arteries. Because these arteries could not be subselectively catheterized, the collagen-thrombin mixture, D-Stat, was used to occlude the portal venous outflow of the arterioportal fistula. Subsequent angiography demonstrated successful complete occlusion of the arterioportal fistula.

Cerebral infarction in Hunter syndrome.

Hunter syndrome, or mucopolysaccharidosis type II, is an X-linked recessive disorder resulting from iduronate sulfatase deficiency. Typical manifestations include short stature, mental retardation, hydrocephalus, macroglossia and cardiac valvulopathy. We describe a 21-year-old patient who presented with acute ischemic stroke and evidence of cerebral embolization. The echocardiogram demonstrated thickened mitral and aortic valves as potential sources of emboli. We conclude that ischemic stroke secondary to cardioembolization is a potential complication of Hunter syndrome.

Plasmodium-infected Anopheles mosquitoes collected in Virginia and Maryland following local transmission of Plasmodium vivax malaria in Loudoun County, Virginia.

Two recent outbreaks of locally acquired, mosquito-transmitted malaria in Virginia in 1998 and 2002 demonstrate the continued risk of endemic mosquito-transmitted malaria in heavily populated areas of the eastern United States. Increasing immigration, growth in global travel, and the presence of competent anopheline vectors throughout the eastern United States contribute to the increasing risk of malaria importation and transmission. On August 23 and 25, 2002, Plasmodium vivax malaria was diagnosed in 2 teenagers in Loudoun County, Virginia. The Centers for Disease Control and Prevention (CDC) deemed these cases to be locally acquired because of the lack of risk factors for malaria, such as international travel, blood transfusion, organ transplantation, or needle sharing. The patients lived approximately 0.5 mi apart; however, 1 patient reported numerous visits to friends who lived directly across the street from the other patient. Two Anopheles quadrimaculatus s.l. female pools collected in Loudoun County, Virginia, and 1 An. punctipennis female pool collected in Fairfax County, Virginia, tested positive for P. vivax 210 with the VecTest panel assay and enzyme-linked immunosorbent assay (ELISA). In addition, 2 An. quadrimaculatus s.l. female pools collected in Montgomery, Maryland, tested positive for P. vivax 210. The CDC confirmed these initial results with the circumsporozoite ELISA. The authors believe that this is the 1st demonstration of Plasmodium-infected mosquitoes collected in association with locally acquired human malaria in the United States since the current national malaria surveillance system began in 1957.

Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood-brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia.

The formation of brain edema, commonly occurring as a potentially lethal complication of acute hyponatremia, is delayed following knockout of the water channel aquaporin-4 (AQP4). Here we show by high-resolution immunogold analysis of the blood-brain-barrier that AQP4 is expressed in brain endothelial cells as well as in the perivascular membranes of astrocyte endfeet. A selective removal of perivascular AQP4 by alpha-syntrophin deletion delays the buildup of brain edema (assessed by Diffusion-weighted MRI) following water intoxication, despite the presence of a normal complement of endothelial AQP4. This indicates that the perivascular membrane domain, which is peripheral to the endothelial blood-brain barrier, may control the rate of osmotically driven water entry. This study is also the first to demonstrate that the time course of edema development differs among brain regions, probably reflecting differences in aquaporin-4 distribution. The resolution of the molecular basis and subcellular site of osmotically driven brain water uptake should help design new therapies for acute brain edema.

Aquaporin-4 square array assembly: opposing actions of M1 and M23 isoforms.

Osmotic homeostasis in the brain involves movement of water through aquaporin-4 (AQP4) membrane channels. Perivascular astrocyte end-feet contain distinctive orthogonal lattices (square arrays) assembled from 4- to 6-nm intramembrane particles (IMPs) corresponding to individual AQP4 tetramers. Two isoforms of AQP4 result from translation initiation at methionine residues M1 and M23, but no functional differences are known. In this study, Chinese hamster ovary cells were transfected with M1, M23, or M1+M23 isoforms, and AQP4 expression was confirmed by immunoblotting, immunocytochemistry, and immunogold labeling. Square array organization was examined by freeze-fracture electron microscopy. In astrocyte end-feet, >90% of 4- to 6-nm IMPs were found in square arrays, with 65% in arrays of 13-30 IMPs. In cells transfected with M23, 95% of 4- to 6-nm IMPs were in large assemblies (rafts), 85% of which contained >100 IMPs. However, in M1 cells, >95% of 4- to 6-nm IMPs were present as singlets, with <5% in incipient arrays of 2-12 IMPs. In M1+M23 cells, 4- to 6-nm IMPs were in arrays of intermediate sizes, resembling square arrays in astrocytes. Structural cross-bridges of 1 x 2 nm linked >90% of IMPs in M23 arrays ( approximately 1,000 cross-bridges per microm2) but were rarely seen in M1 cells. These studies show that M23 and M1 isoforms have opposing effects on intramembrane organization of AQP4: M23 forms large square arrays with abundant cross-bridges; M1 restricts square array assembly.

Altered erythrocyte endothelial adherence and membrane phospholipid asymmetry in hereditary hydrocytosis.

The risk for thrombosis is increased in patients with hereditary hydrocytosis, an uncommon variant of hereditary stomatocytosis. Erythrocytes from 2 patients with hydrocytosis were studied to gain insight into the mechanism of thrombosis in this disorder. Erythrocytes demonstrated abnormal osmotic scan ektacytometry and decreased erythrocyte filtration rates. There was also a mild increase in adherence of erythrocytes to endothelial monolayers in a micropipette assay. Adhesion of erythrocytes to the subendothelial matrix proteins thrombospondin and laminin, however, was not significantly increased. Percentages of hydrocytosis erythrocytes and reticulocytes with phosphatidylserine exposed on the outer surfaces were increased in both patients compared with healthy controls, indicating altered membrane phospholipid asymmetry. Increased phosphatidylserine exposure accelerating thrombin-forming processes has been proposed as a mechanism for thrombosis in sickle cell disease and beta-thalassemia and may play a similar role in hereditary hydrocytosis.

An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain.

The water channel AQP4 is concentrated in perivascular and subpial membrane domains of brain astrocytes. These membranes form the interface between the neuropil and extracerebral liquid spaces. AQP4 is anchored at these membranes by its carboxyl terminus to alpha-syntrophin, an adapter protein associated with dystrophin. To test functions of the perivascular AQP4 pool, we studied mice homozygous for targeted disruption of the gene encoding alpha-syntrophin (alpha-Syn(-/-)). These animals show a marked loss of AQP4 from perivascular and subpial membranes but no decrease in other membrane domains, as judged by quantitative immunogold electron microscopy. In the basal state, perivascular and subpial astroglial end-feet were swollen in brains of alpha-Syn(-/-) mice compared to WT mice, suggesting reduced clearance of water generated by brain metabolism. When stressed by transient cerebral ischemia, brain edema was attenuated in alpha-Syn(-/-) mice, indicative of reduced water influx. Surprisingly, AQP4 was strongly reduced but alpha-syntrophin was retained in perivascular astroglial end-feet in WT mice examined 23 h after transient cerebral ischemia. Thus alpha-syntrophin-dependent anchoring of AQP4 is sensitive to ischemia, and loss of AQP4 from this site may retard the dissipation of postischemic brain edema. These studies identify a specific, syntrophin-dependent AQP4 pool that is expressed at distinct membrane domains and which mediates bidirectional transport of water across the brain-blood interface. The anchoring of AQP4 to alpha-syntrophin may be a target for treatment of brain edema, but therapeutic manipulations of AQP4 must consider the bidirectional water flux through this molecule.

Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice.

Cerebral water accumulation was studied during induction of brain edema in dystrophin-null transgenic mice (mdx-betageo) and control mice. Immunofluorescence and immunoelectron microscopic analyses of dystrophin-null brains revealed a dramatic reduction of AQP4 (aquaporin-4) in astroglial end-feet surrounding capillaries (blood-brain barrier) and at the glia limitans (cerebrospinal fluid-brain interface). The AQP4 protein is mislocalized, because immunoblotting showed that the total AQP4 protein abundance was unaltered. Brain edema was induced by i.p. injection of distilled water and 8-deamino-arginine vasopressin. Changes in cerebral water compartments were assessed by diffusion-weighted MRI with determination of the apparent diffusion coefficient (ADC). In dystrophin-null mice and control mice, ADC gradually decreased by 5-6% from baseline levels during the first 35 min, indicating the initial phase of intracellular water accumulation is similar in the two groups. At this point, the control mice sustained an abrupt, rapid decline in ADC to 58% +/- 2.2% of the baseline at 52.5 min, and all of the animals were dead by 56 min. After a consistent delay, the dystrophin-null mice sustained a similar decline in ADC to 55% +/- 3.4% at 66.5 min, when all of the mice were dead. These results demonstrate that dystrophin is necessary for polarized distribution of AQP4 protein in brain where facilitated movements of water occur across the blood-brain barrier and cerebrospinal fluid-brain interface. Moreover, these results predict that interference with the subcellular localization of AQP4 may have therapeutic potential for delaying the onset of impending brain edema.

S9, a 19 S proteasome subunit interacting with ubiquitinated NF-kappaB2/p100.

Proteasome-mediated processing of the nfkappab2 gene product p100 is a regulated event that generates the NF-kappaB subunit p52. This event can be induced through p100 phosphorylation by a signaling pathway involving the nuclear factor-kappaB-inducing kinase (NIK). The C-terminal region of p100, which contains its phosphorylation site and a death domain, plays a pivotal role in regulating the processing of p100. To understand the biochemical mechanism of p100 processing, we searched for cellular factors interacting with the C-terminal regulatory region of p100 using the yeast two-hybrid system. This led to the identification of S9, a non-ATPase subunit of the 19 S proteasome with no known functions. Interestingly, the S9/p100 interaction could be induced by NIK but not by a catalytically inactive NIK mutant. This inducible molecular interaction required p100 ubiquitination and was dependent on the intact death domain. We further demonstrated that the death domain is essential for NIK-induced post-translational processing of p100, thus providing a functional link between the S9 binding and the processing of p100. Finally, we provide genetic evidence for the essential role of S9 in the inducible processing of p100.