De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.

Quantification of regional aerosol deposition patterns as a function of aerodynamic particle size in rhesus macaques using PET/CT imaging.

Aerosol aerodynamic particle size is known to affect deposition patterns of inhaled aerosol particles, as well as the virulence of inhaled bioaerosol particles. While a significant amount of work has been performed to describe the deposition of aerosol particles in the human respiratory tract, only a limited amount of work has been performed to describe the deposition of aerosol particles in the respiratory tract of nonhuman primates, an animal model commonly utilized in pharmacological and toxicological studies, especially in the biodefense field. In this study, anesthetized rhesus macaques inhaled radiolabeled aerosols with MMADs of 1.7, 3.6, 7.4 and 11.8 µm to characterize regional deposition patterns. The results demonstrate that the regional deposition pattern shifts as particle size increases, with greater deposition in more proximal regions of the respiratory tract and decreased deposition in the pulmonary region. The results of this study extend the findings of previous studies which demonstrated a similar shift in the deposition pattern as a function of particle size by providing greater resolution of deposition patterns. These data on regional deposition patterns provide a starting point to begin to explore potential mechanisms responsible for the differences in virulence of infectious bioaerosols as a function of particle size and deposition pattern reported in previous studies. Additionally, the data are useful to assess the performance of various deposition models that have been published in the literature.

Impact system for ultrafast synchrotron experiments.

The impact system for ultrafast synchrotron experiments, or IMPULSE, is a 12.6-mm bore light-gas gun (<1 km/s projectile velocity) designed specifically for performing dynamic compression experiments using the advanced imaging and X-ray diffraction methods available at synchrotron sources. The gun system, capable of reaching projectile velocities up to 1 km/s, was designed to be portable for quick insertion/removal in the experimental hutch at Sector 32 ID-B of the Advanced Photon Source (Argonne, IL) while allowing the target chamber to rotate for sample alignment with the beam. A key challenge in using the gun system to acquire dynamic data on the nanosecond time scale was synchronization (or bracketing) of the impact event with the incident X-ray pulses (80 ps width). A description of the basic gun system used in previous work is provided along with details of an improved launch initiation system designed to significantly reduce the total system time from launch initiation to impact. Experiments were performed to directly measure the gun system time and to determine the gun performance curve for projectile velocities ranging from 0.3 to 0.9 km/s. All results show an average system time of 21.6 ± 4.5 ms, making it possible to better synchronize the gun system and detectors to the X-ray beam.

Gas gun shock experiments with single-pulse x-ray phase contrast imaging and diffraction at the Advanced Photon Source.

The highly transient nature of shock loading and pronounced microstructure effects on dynamic materials response call for in situ, temporally and spatially resolved, x-ray-based diagnostics. Third-generation synchrotron x-ray sources are advantageous for x-ray phase contrast imaging (PCI) and diffraction under dynamic loading, due to their high photon fluxes, high coherency, and high pulse repetition rates. The feasibility of bulk-scale gas gun shock experiments with dynamic x-ray PCI and diffraction measurements was investigated at the beamline 32ID-B of the Advanced Photon Source. The x-ray beam characteristics, experimental setup, x-ray diagnostics, and static and dynamic test results are described. We demonstrate ultrafast, multiframe, single-pulse PCI measurements with unprecedented temporal (<100 ps) and spatial (∼2 µm) resolutions for bulk-scale shock experiments, as well as single-pulse dynamic Laue diffraction. The results not only substantiate the potential of synchrotron-based experiments for addressing a variety of shock physics problems, but also allow us to identify the technical challenges related to image detection, x-ray source, and dynamic loading.

Adhesive properties of some fluoropolymer binders with the insensitive explosive 1,3,5-triamino-2,4,6-trinitrobenzene (TATB).

Adhesion between binders and explosive crystals is of critical importance for the mechanical performance of plastic-bonded explosives (PBXs). The surface properties of several prospective binders have been determined from static advancing contact angle measurements. The surface energies have been used to calculate theoretical work of adhesion to 1,3,5-triamino-2,4,6-trinitrobenzene (TATB), a common insensitive high explosive. The fluorinated terpolymer Oxy-461™, and Kel-F™ chlorotrifluoroethylene-vinylidene fluoride copolymers show the greatest potential for wetting TATB surfaces, and should promote the best adhesion to TATB in PBX formulations. In general, none of the fluoropolymer binders investigated here exhibit markedly superior adhesion to TATB. Thus, bulk physical properties are likely to be more important when choosing a binder.

Characterization of a head-only aerosol exposure system for nonhuman primates.

A well-characterized exposure chamber is necessary to generate reproducible atmospheres for inhalation toxicology studies. The aim of the present study was to characterize a head-only exposure chamber for non-human primates. Aerosols containing bovine serum albumin (BSA) were used to characterize a 16-L dynamic airflow head-only exposure chamber. A 250-ml plastic bottle with a respirator attached located inside the chamber was used to simulate a breathing head. Chamber leak rate, mixing, and aerosol spatial distributions were quantified. The chamber concentration profile was measured at the chamber exhaust using an aerodynamic particle sizer. Aerosol spatial distribution was determined by collecting filter samples at several chamber locations. The particle size distribution was determined by collecting cascade impactor samples at several chamber locations. The estimated chamber leak rate was within standards suggested in the literature. The measured average aerosol residence time was similar to theoretical aerosol residence time, suggesting that the chamber was mixing well. Additionally, the average concentration measured at each of the sampling locations within the chamber was similar, and the within-run coefficients of variation (CV) across all sampling locations was similar to those reported in previously published studies, again suggesting that the aerosol concentration throughout the chamber was uniform. The particle size distribution was similar throughout the exposure chamber. Additionally, the BSA concentration and particle size distributions measured in the breathing zone of the simulated head were not significantly different from measurements made elsewhere in the chamber, suggesting that respiration does not affect the average aerosol concentration or particle size distribution at the mouth.

Retention and migration of alprostadil cream applied topically to the glans meatus for erectile dysfunction.

Retention and migration of a specially designed alprostadil transdermal cream was assessed after single-dose administration to the glans meatus of the penis. Seven men were enrolled in this two-way crossover study. Three subjects self-administered the radio-labeled alprostadil transdermal cream (approximately 100 mg of cream containing 300 microg alprostadil) by inserting the tip of the dispenser into the meatus. In three others, the dose was administered by dispensing the cream dropwise into the metal opening without touching the penis (the preferred and directed method). Retention and migration of the cream mass was measured in the penis with a gamma scintillation camera. The alprostadil transdermal cream was retained in the fossa navicularis at or near 99% in five of six subjects regardless of the method of dosing, thus indicating that the cream formulation performed as designed. A mild, transient burning sensation in the penis was the most common adverse event.

The efficacy and safety of a topical alprostadil cream, Alprox-TD, for the treatment of erectile dysfunction: two phase 2 studies in mild-to-moderate and severe ED.

In two multicenter, placebo controlled, phase 2 studies, patients with mild-to-moderate (n=161, Study 1) or severe (n=142, Study 2) erectile dysfunction (ED) were randomized to receive placebo, 0.05, 0.1, or 0.2 mg (Study 1) or placebo, 0.1, 0.2, or 0.3 mg (Study 2) of topically applied alprostadil (containing a proprietary skin permeation enhancer). The primary efficacy end point in both studies was the change in erectile function (EF) score from baseline to final visit. The changes from baseline for EF scores were -0.8+/-1.1, 1.8+/-1.1, 0.7+/-1.2, and 3.7+/-1.2 (P<0.01; Study 1) and 2.7+/-1.3, 6.29+/-1.4, 6.49+/-1.5, and 9.44+/-1.5 (P<0.001; Study 2) for ascending dose groups in each study. Topical alprostadil was well tolerated with the most common adverse event being urogenital pain. These results suggest this topical alprostadil formulation may be a potentially useful agent for the treatment of ED.

Cholesterol embolization syndrome: cutaneous histopathological features and the variable onset of symptoms in patients with different risk factors.

Cholesterol embolization syndrome (CES) may not only be due to direct dislodgement of cholesterol crystals from atherosclerotic plaques on the walls of arteries by surgery, angiogram or trauma, but may occur after anticoagulant and thrombolytic therapy. The latter two therapies both weaken the fibrin clot that stabilizes the atheromas in place; however, these two therapies commonly have different onsets of CES after their institution. We present three patients with different risk factors for CES who all presented with the pathognomonic triad of leg and/or foot pain, livedo reticularis and good peripheral pulses. In all three patients cholesterol emboli were demonstrated in cutaneous biopsy sections. In two patients there was associated renal involvement, which was fatal in one case. These cases illustrate that cutaneous biopsy may be diagnostic in patients with livedo reticularis, which progresses to necrosis and gangrene. In addition, they illustrate the problems and contradictions involved in treating patients with CES.

Effects of Rootstock and Budding Height on Bacterial Canker in French Prune.

Bacterial canker is one of the most economically important diseases of stone fruit trees, including 'French' prune (Prunus domestica). Field trials were conducted to evaluate the effect of rootstock selection and budding height on the incidence and severity of bacterial canker in four orchards with low to high disease pressure. Treatments included French prune scions low-grafted on 'Lovell' peach (Prunus persica) rootstocks as well as Myrobalan 29C (Prunus cerasifera) plum rootstocks grafted at 15, 50, and 90 cm above the rootstock crown. Another treatment consisted of growing Myrobalan 29C plum rootstocks in the field for one growing season, then field-grafting French prune buds onto rootstock scaffolds. Lovell peach rootstock provided the greatest protection from bacterial canker as measured by disease incidence and tree mortality in all orchards. Field-budded rootstocks and rootstocks grafted at the highest budding height provided moderate levels of resistance to bacterial canker. These treatments reduced the incidence but not the severity of disease.

Pseudocyst of the auricle: diagnosis and management with a punch biopsy.

A case of pseudocyst of the ear diagnosed and treated with a punch biopsy is reported. Pseudocyst of the ear is considered to be a benign, asymptomatic condition seen infrequently in clinical practice. Our patient is a 45-year-old white man who presented with a 5-month history of a painless nodule on his left auricle without any preceding history of trauma. Although many treatments have been reported, none appear satisfactory, and many surgical treatment modalities are cumbersome. This is the first report, to our knowledge, of a case of a pseudocyst of the ear confirmed and treated with a 3-mm punch biopsy of the inferior border of the pseudocyst, followed by a pressure bolster.

Topical alprostadil in the treatment of Female Sexual Arousal Disorder: a pilot study.

This study evaluated the efficacy and safety of three doses of topical alprostadil USP (prostaglandin E1) cream in 8 patients with Female Sexual Arousal Disorder (FSAD). Each patient was administered a single intravaginal dose of placebo followed by escalating intravaginal doses of the active drug at 2-week intervals. Alprostadil's effectiveness in enhancing subjective and physiological arousal during visual sexual stimulation was supported by patient ratings and physician assessments of vaginal erythema and transudate volume. Photoplethysmography measurement of vaginal pulse amplitude was not able to demonstrate treatment sensitivity in the present study. Adverse events included mild cases of vaginal itching and burning. The data support further investigation of the use of alprostadil for FSAD.

Fixed drug eruptions to human immunodeficiency virus-1 protease inhibitor.

Despite numerous drug interactions that occur with human immunodeficiency virus-1 protease inhibitors, there are relatively few drug reactions. We present two patients receiving saquinavir who developed fixed drug reactions. Both reactions cleared while patients received a therapeutic dose of the medication, and in one patient a flare was seen when the patient later stopped and then restarted the medication. Although fixed drug reactions are relatively inconsequential, it is important to know that these eruptions may clear when the patient is given uninterrupted therapy of a human immunodeficiency virus-1 protease inhibitor, with only post-inflammatory hyperpigmentation.

Microbiology of infected poison ivy dermatitis.

We report the aerobic and anaerobic microbiology of secondarily infected poison ivy dermatitis. The study involved retrospective review of clinical and microbiology laboratory records of patients with secondarily infected poison ivy lesions. Bacterial growth was noted in 33 specimens. Aerobic or facultative anaerobic bacteria only were present in 18 (55%) patients, anaerobic bacteria only in seven (21%), and mixed anaerobic-aerobic bacteria in eight (24%). Forty-five isolates were recovered (1.4 per specimen): 27 aerobic or facultative anaerobic bacteria, and 18 strict anaerobes. The predominant aerobic and facultative anaerobic bacteria were Staphylococcus aureus (13 isolates) and group A beta-haemolytic streptococci (six). The predominant anaerobes were Peptostreptococcus spp. (seven isolates), pigmented Prevotella and Porphyromonas spp. (four) and Fusobacterium spp. (two). Single bacterial isolates were recovered in 18 (55%) patients, eight of which were S. aureus. Nineteen of the organisms isolated from 16 (48%) patients produced the enzyme beta-lactamase. Organisms that resided in the mucous membranes close to the lesions predominated in those infections. Enteric gram-negative rods and Bacteroides fragilis group predominated in leg and buttock lesions. Group A beta-haemolytic streptococci, pigmented Prevotella and Porphyromonas and Fusobacterium spp. were most frequently recovered from lesions of the finger, face and neck. The polymicrobial aetiology of secondarily infected poison ivy lesions, and the association of bacterial flora with the anatomical site of the lesions, are demonstrated.

Micrococcus folliculitis in HIV-1 disease.

Organisms with little pathogenic potential in immunocompetent hosts may produce disease in HIV-1 + patients. We describe three HIV-1 + patients in late disease who presented with pruritic papules with central ulceration over the face and arms. In all the patients the eruptions had been present for months, and the patients did not develop sepsis. Biopsy specimens in all the patients showed large Gram-positive cocci, forming tetrads. Colony morphology, catalase positivity and coagulase negativity, and resistance to nitrofurantoin were used to separate micrococci from staphylococci. Micrococcus species are usually considered normal inhabitants of the skin; however, in patients with HIV-1 disease, Micrococcus species can produce localized cutaneous infections.

Microbiology of infected pustular psoriasis lesions.

BACKGROUND: Bacterial infections can occur in lesions of pustular psoriasis (PP). The objective of this study was to establish the aerobic and anaerobic microbiology of secondarily infected PP. METHODS: A retrospective 10-year review was carried out of clinical and microbiology laboratory records from patients with secondarily infected PP lesions, whose specimens of infected sites were processed for the presence of aerobic and anaerobic bacteria. RESULTS: Bacterial growth was noted in 23 specimens. Aerobic or facultative anaerobic bacteria only were present in 12 patients (52%), anaerobic bacteria only in four (17%), and mixed anaerobic-aerobic flora was present in seven (30%). Thirty-six isolates were recovered (1.6 per specimen), 23 aerobic or facultative bacteria and 13 strict anaerobes. The predominant aerobic and facultative bacteria were Staphylococcus aureus (15 isolates), Group D Enterococcus (two isolates), and Escherichia coli (two isolates). The predominant anaerobes were Peptostreptococcus spp. (six isolates) and Bacteroides fragilis group, Propionibacterium acnes, and pigmented Prevotella spp. in two each. Single bacterial isolates were recovered in 14 patients (61%), 11 of which were S. aureus. Nineteen of the organisms isolated from 18 patients (78%) produced the enzyme beta-lactamase. S. aureus was isolated from all body sites. Organisms that resided in the mucous membranes close to the lesions predominated in these infections. Enteric Gram-negative rods and Bacteroides fragilis group predominated in lesions on the legs and buttocks. Group A beta-hemolytic streptococci, pigmented Prevotella, and Fusobacterium spp. were most frequently recovered in lesions of the hand. CONCLUSIONS: The polymicrobial etiology of secondarily infected PP lesions and the association of bacterial flora with the anatomic site of the lesions were demonstrated.

Increased soft tissue in the posterior cervical and upper back area of patients on HIV-1 protease inhibitors.

BACKGROUND: Corticosteroids as well as sex hormones affect the redistribution of subcutaneous fat and the percentage of lean body mass. In addition, some stromal cells express steroid receptors, and the quantity and distribution of these receptors vary at different body sites and between sexes. Inhibitors of HIV-1 protease may affect steroid hormone metabolism through their effect on cytochrome P450. OBJECTIVES: To determine the changes in the tissue of the back in three HIV-1+ patients who developed increased soft tissue in posterior cervical and upper back areas while on HIV-1 protease inhibitors. METHODS: Punch biopsies of the involved posterior cervical and upper back areas were done. These included subcutaneous adipose tissue. Routine hematoxylin and eosin-stained sections, along with special stains for elastic and stromal mucin, and immunohistochemical stains for CD34 (HPCA-1 and Factor XIIIa) were evaluated. RESULTS: Histologically all three patients showed identical features. There was expansion of the dermis with decreased periadnexal fat and marked widening of the fibrous septa within the expanded subcutaneous fat. CONCLUSIONS: The posterior cervical and upper back area appears to be a common site for localization of mesenchymal tumours that show some fat differentiation and produce an increase in stromal matrix material. Mesenchymal cell populations within this area are also affected by systemic diseases. A male predominance pattern occurs with these conditions, and steroid receptors are expressed on some mesenchymal cells, that vary with the body location. Thus, this observation may be related to the effects of protease inhibitors on steroid hormone metabolism through their inhibition of cytochrome P-450.

The effect of decreasing digital image resolution on teledermatology diagnosis.

OBJECTIVE: To determine the effect of degraded digital image resolution (as viewed on a monitor) on the accuracy and confidence of dermatologic interpretation. MATERIALS AND METHODS: Eight dermatologists interpreted 180 clinical cases divided into three Logical Competitor Sets (LCS) (pigmented lesions, non-pigmented lesions, and inflammatory dermatoses). Each case was digitized at three different resolutions. The images were randomized and divided into (9) 60-image sessions. The physicians were completely blinded concerning the image resolution. After 60 seconds per image, the viewer recorded a diagnosis and level of confidence. The resultant ROC curves compared the effect of LCS, level of clinical difficulty, and resolution of the digital image. One-way analysis of variance (ANOVA) compared the curves. RESULTS: The areas beneath the ROC curves did not demonstrate any consistently significant difference between the digital image resolutions for all LCS and levels of difficulty. The only significant effect observed was amongst pigmented lesions (LCS-A) where the ROC curve area was significantly smaller in the easy images at high resolution compared to low and medium resolutions. For all other ROC curve comparisons within LCS-A, at all other levels of difficulty, as well as within the other LCS at all levels of difficulty, none of the differences was significant. CONCLUSION: A 720 x 500 pixel image can be considered equivalent to a 1490 x 1000 pixel image for most store-and-forward teledermatology consultations.