Pedunculated Osteochondroma Presenting as Verruca Vulgaris: A Diagnosis Requiring a High Index of Suspicion: Case Report.

Introduction: Osteochondromas are the most common benign tumors of the bone and can be sessile or pedunculated. Although osteochondromas are typically seen in the long bones, they are rarely seen in the small bones of the hand or foot. Verruca vulgaris, also known as the common wart, is one of the most common skin conditions presenting to physicians and must be distinguished either clinically or histologically from other hyperkeratotic conditions, including bone conditions such as bone tumors that can place pressure on the skin and cause callus formation that can mimic a wart or create skin deformity. A high index of suspicion for underlying bone mass or tumor should be entertained when evaluating patients for skin conditions, particularly of the hand or foot, with failure to improve with treatment. Case Report: This case report presents a 20-year-old male with a pedunculated osteochondroma of the left fourth distal phalanx with hyperkeratotic skin overlying the mass at the end of the toe. He was initially treated by a family doctor and podiatrist for verruca vulgaris for over 5 years with two treatments of liquid nitrogen cryotherapy and surgical excision of the mass when the treating podiatrist encountered bone and recommended radiographs. The family requested follow-up with our practice several days later after they were told the patient had a bone tumor. The patient requested surgical excision of the osteochondroma secondary to pain with activities and difficulties with his vocation as a pilot. Conclusion: All physicians must be mindful of an underlying bone tumor or mass in patients presenting with skin changes, particularly about the foot or hand. Knowledge that an underlying bone tumor can present as a verruca vulgaris may prevent a delay in diagnosis or unnecessary treatment when evaluating and treating a patient with a skin lesion. Fortunately, our case was a benign osteochondroma; a malignant tumor with a delay in diagnosis could lead to loss of limb or life.

Double Squeeze Reduction Clamp Technique for Fracture Stabilization: A Case Report.

Introduction: The double squeeze technique for fracture stabilization is a technique in which the surgeon uses a second reduction clamp to hold and stabilize a smaller reduction clamp that reduces a fracture or plate yet is too small to hold by itself. This technique greatly assists anatomic fracture reduction and stabilization and allows the surgeon to complete the operation when there is limited reduction instrumentation available, or the surgeon needs more excursion on a small clamp holding a fracture and does not want to change instruments and possibly lose a reduction. We present a case of the double squeeze clamp technique, which to our knowledge has not been reported, to facilitate limited open reduction percutaneous plate stabilization in a distal tibia fracture. Case Report: This case report presents an 18-year-old male with a closed, oblique, displaced right distal tibia fracture following a crush injury to the extremity with a tree while using a chainsaw. He was initially seen in the emergency room and was discharged home in a splint to follow-up with the orthopedic surgeon on call. The family requested follow-up with our practice 3 days later and requested surgery at their rural local hospital secondary to insurance reasons. Patient requested plate fixation to treat his fracture. Due to limited reduction instrumentation in the facility, a double squeeze reduction clamp technique using a pointed reduction clamp on a serrated reduction clamp that was too small to hold the plate on the reduced fracture accomplished stabilization of the plate on the fracture while screws were placed. Conclusion: The double squeeze reduction clamp technique using one reduction clamp on a smaller reduction clamp greatly increases the ability to successfully reduce and stabilize multiple variations of different fractures whether secondary to differences in sizes of the bones, different types of bones, or in our case limited fracture reduction tools available.

COVID-19 Exposure Assessment Tool (CEAT): Exposure quantification based on ventilation, infection prevalence, group characteristics, and behavior.

The coronavirus disease 2019 (COVID-19) Exposure Assessment Tool (CEAT) allows users to compare respiratory relative risk to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for various scenarios, providing understanding of how combinations of protective measures affect risk. CEAT incorporates mechanistic, stochastic, and epidemiological factors including the (i) emission rate of virus, (ii) viral aerosol degradation and removal, (iii) duration of activity/exposure, (iv) inhalation rates, (v) ventilation rates (indoors/outdoors), (vi) volume of indoor space, (vii) filtration, (viii) mask use and effectiveness, (ix) distance between people (taking into account both near-field and far-field effects of proximity), (x) group size, (xi) current infection rates by variant, (xii) prevalence of infection and immunity in the community, (xiii) vaccination rates, and (xiv) implementation of COVID-19 testing procedures. CEAT applied to published studies of COVID-19 transmission events demonstrates the model's accuracy. We also show how health and safety professionals at NASA Ames Research Center used CEAT to manage potential risks posed by SARS-CoV-2 exposures.

Covid-19 Exposure Assessment Tool (CEAT): Easy-to-use tool to quantify exposure based on airflow, group behavior, and infection prevalence in the community.

The COVID-19 Exposure Assessment Tool (CEAT) allows users to compare respiratory relative risk to SARS-CoV-2 for various scenarios, providing understanding of how combinations of protective measures affect exposure, dose, and risk. CEAT incorporates mechanistic, stochastic and epidemiological factors including the: 1) emission rate of virus, 2) viral aerosol degradation and removal, 3) duration of activity/exposure, 4) inhalation rates, 5) ventilation rates (indoors/outdoors), 6) volume of indoor space, 7) filtration, 8) mask use and effectiveness, 9) distance between people, 10) group size, 11) current infection rates by variant, 12) prevalence of infection and immunity in the community, 13) vaccination rates of the community, and 14) implementation of COVID-19 testing procedures. Demonstration of CEAT, from published studies of COVID-19 transmission events, shows the model accurately predicts transmission. We also show how health and safety professionals at NASA Ames Research Center used CEAT to manage potential risks posed by SARS-CoV-2 exposures. Given its accuracy and flexibility, the wide use of CEAT will have a long lasting beneficial impact in managing both the current COVID-19 pandemic as well as a variety of other scenarios.

Synthesis and Evaluation of PPARδ Agonists That Promote Osteogenesis in a Human Mesenchymal Stem Cell Culture and in a Mouse Model of Human Osteoporosis.

We synthesized a directed library of compounds to explore the structure-activity relationships of peroxisome proliferator-activated receptor δ (PPARδ) activation relative to mesenchymal stem cell (MSC) osteogenesis. Our scaffold used para-substituted cinnamic acids as a polar headgroup, a heteroatom and heterocycle core connecting units, and substituted phenyl groups for the lipophilic tail. Compounds were screened for their ability to increase osteogenesis in MSCs, and the most promising were examined for subunit specificity using a quantitative PPAR transactivation assay. Six compounds were selected for in vivo studies in an ovariectomized mouse model of human postmenopausal osteoporosis. Four compounds improved bone density in vivo, with two (12d and 31a) having activity comparable to that of GW0742, a well-studied PPARδ-selective agonist. 31a (2-methyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamic acid) had the highest selectivity for PPARδ compared to other subtypes, its selectivity far exceeding that of GW0742. Our results confirm that PPARδ is a new drug target for possible treatment of osteoporosis via in situ manipulation of MSCs.

Template-assisted design of monomeric polyQ models to unravel the unique role of glutamine side chains in disease-related aggregation.

Expanded polyglutamine (polyQ) sequences cause numerous neurodegenerative diseases which are accompanied by the formation of polyQ fibrils. The unique role of glutamines in the aggregation onset is undoubtedly accepted and a lot structural data of the fibrils have been acquired, however side-chain specific structural dynamics inducing oligomerization are not well understood yet. To analyze spectroscopically the nucleation process, we designed various template-assisted glutamine-rich ß-hairpin monomers mimicking the structural motif of a polyQ fibril. In a top-down strategy, we use a template which forms a well-defined stable hairpin in solution, insert polyQ-rich sequences into each strand and monitor the effects of individual glutamines by NMR, CD and IR spectroscopic approaches. The design was further advanced by alternating glutamines with other amino acids (T, W, E, K), thereby enhancing the solubility and increasing the number of cross-strand interacting glutamine side chains. Our spectroscopic studies reveal a decreasing hairpin stability with increased glutamine content and demonstrate the enormous impact of only a few glutamines - far below the disease threshold - to destabilize structure. Furthermore, we could access sub-ms conformational dynamics of monomeric polyQ-rich peptides by laser-excited temperature-jump IR spectroscopy. Both, the increased number of interacting glutamines and higher concentrations are key parameters to induce oligomerization. Concentration-dependent time-resolved IR measurements indicate an additional slower kinetic phase upon oligomer formation. The here presented peptide models enable spectroscopic molecular analyses to distinguish between monomer and oligomer dynamics in the early steps of polyQ fibril formation and in a side-chain specific manner.

Biomolecular dynamics studied with IR-spectroscopy using quantum cascade lasers combined with nanosecond perturbation techniques.

Early events of protein folding can be studied with fast perturbation techniques triggering non-equilibrium relaxation dynamics. A nanosecond laser-excited pH-jump or temperature-jump (T-jump) was applied to initiate helix folding or unfolding of poly-l-glutamic acid (PGA). PGA is a homopolypeptide with titratable carboxyl side-chains whose protonation degree determines the PGA conformation. A pH-jump was realized by the photochemical release of protons and induces PGA folding due to protonation of the side-chains. Otherwise, the helical conformation can be unfolded by a T-jump. We operated under conditions where PGA does not aggregate and temperature and pH are the regulatory properties of its conformation. The experiments were performed in such a manner that the folding/unfolding jump proceeded to the same PGA conformation. We quantified the increase/decrease in helicity induced by the pH-/T-jump and demonstrated that the T-jump results in a relatively small change in helical content in contrast to the pH-jump. This is caused by the strong pH-dependence of the PGA conformation. The conformational changes were detected by time-resolved single wavelength IR-spectroscopy using quantum cascade lasers (QCL). We could independently observe the kinetics for α-helix folding and unfolding in PGA by using different perturbation techniques and demonstrate the high sensitivity of time-resolved IR-spectroscopy to study protein folding mechanisms.

Prevalence of Café-au-Lait Spots in children with solid tumors.

Cafe-au-lait maculae (CALM) are frequently observed in humans, and usually are present as a solitary spot. Multiple CALMs are present in a smaller fraction of the population and are usually associated with other congenital anomalies as part of many syndromes. Most of these syndromes carry an increased risk of cancer development. Previous studies have indicated that minor congenital anomalies may be more prevalent in children with cancer. We investigated the prevalence of CALMs in two samples of Brazilian patients with childhood solid tumors, totaling 307 individuals. Additionally, 176 school children without diagnosis of cancer, or of a cancer predisposing syndrome, were investigated for the presence of CALMs. The prevalence of solitary CALM was similar in both study groups (18% and 19%) and also in the group of children without cancer. Multiple CALMs were more frequently observed in one of the study groups (Z = 2.1). However, when both groups were analyzed together, the significance disappeared (Z = 1.5). The additional morphological abnormalities in children with multiple CALMs were analyzed and compared to the findings observed in the literature. The nosologic entities associated with CALMs are reviewed.

Large germline copy number variations as predisposing factor in childhood neoplasms.

AIMS: Constitutive genetic factors are believed to predispose to cancer in children. This study investigated the role of rare germline copy number variations (CNVs) in pediatric cancer predisposition. PATIENTS & METHODS: A total of 54 patients who developed cancer in infancy were screened by array-CGH for germline CNVs. RESULTS: In total, 12 rare CNVs were detected, including a Xq27.2 triplication, and two >1.8 Mb deletions: one of them at 13q31, containing only RNA genes, and another at 3q26.33-q27.1, in a patient with congenital malformations. Detected rare CNVs are significantly larger than those identified in controls, and encompass genes never implicated in cancer predisposition. CONCLUSION: Our results suggest that constitutive CNVs contribute to the etiology of pediatric neoplasms, revealing new candidate genes for tumorigenesis.

Length-dependent conformational transitions of polyglutamine repeats as molecular origin of fibril initiation.

Polyglutamine (polyQ) sequences are found in a variety of proteins with normal function. However, their repeat expansion is associated with a number of neurodegenerative diseases, also called polyQ diseases. The length of the polyQ sequence, varying in the number of consecutive glutamines among different diseases, is critical for inducing fibril formation. We performed a systematic spectroscopic study to analyze the conformation of polyQ model peptides in dependence of the glutamine sequence lengths (K2QnK2 with n=10, 20, 30). Complementary FTIR- and CD-spectra were measured in a wide concentration range and repeated heating and cooling cycles revealed the thermal stability of formed ß-sheets. The shortest glutamine sequence K2Q10K2 shows solely random structure for concentrations up to 10 mg/ml. By increasing the peptide length to K2Q20K2, a significant fraction of ß-sheet is observed even at low concentrations of 0.01 mg/ml. The higher the concentration, the more the structural composition is dominated by the intermolecular ß-sheet. The formation of highly thermostable ß-sheet is much more pronounced in K2Q30K2. K2Q30K2 precipitates at a concentration of 0.3 mg/ml. Our spectroscopic study shows that the aggregation tendency is enhanced with increased glutamine repeat expansion and that the concentration plays another critical factor in the ß-sheet formation.

Interplay of pH and binding of multivalent metal ions: charge inversion and reentrant condensation in protein solutions.

Tuning of protein surface charge is a fundamental mechanism in biological systems. Protein charge is regulated in a physiological context by pH and interaction with counterions. We report on charge inversion and the related reentrant condensation in solutions of globular proteins with different multivalent metal cations. In particular, we focus on the changes in phase behavior and charge regulation due to pH effects caused by hydrolysis of metal ions. For several proteins and metal salts, charge inversion as measured by electrophoretic light scattering is found to be a universal phenomenon, the extent of which is dependent on the specific protein-salt combination. Reentrant phase diagrams show a much narrower phase-separated regime for acidic salts such as AlCl3 and FeCl3 compared to neutral salts such as YCl3 or LaCl3. The differences between acidic and neutral salts can be explained by the interplay of pH effects and binding of the multivalent counterions. The experimental findings are reproduced with good agreement by an analytical model for protein charging taking into account ion condensation, metal ion hydrolysis, and interaction with charged amino acid side chains on the protein surface. Finally, the relationship of charge inversion and reentrant condensation is discussed, suggesting that pH variation in combination with multivalent cations provides control over both attractive and repulsive interactions between proteins.

A de novo em ~1.3 Mb microdeletion at 17q11.2 associated with Neurofibromatosis-Noonan syndrome

Introduction: Neurofibromatosis-Noonan syndrome is a clinical entity considered an extended Neurofibromatosis phenotype generally caused by different types of intragenic mutations at the NF1 gene. About 5%-10% of patients with neurofibromatosis diagnosis carry chromosomal microdeletions involving NF1, often presenting with a more severe phenotype than that observedin the patients carrying intragenic mutations; however, anticipating the presence of a deletion based only in the phenotype is not straightforward. Patient and Methods: Here we investigated by oligoarray-CGH (aCGH) the presence of a submicroscopic genomic rearrangement in a patientwith a clinical picture of Neurofibromatosis, and other characteristics compatible with Noonansyndrome. Results: The aCGH analysis revealed a germline de novo ~1.3 Mb microdeletion at 17q11.2 encompassing other coding genes besides the NF1 gene. Discussion: Up to now, thenumber of reported patients with Neurofibromatosis-Noonan syndrome carrying NF1 microdeletions is quite small. The continuous identification of patients carrying 17q11.2 deletions canhelp to establish a reliable genotype-phenotype relationship in this syndrome

Universality of protein reentrant condensation in solution induced by multivalent metal ions.

The effective interactions and phase behavior of protein solutions under strong electrostatic coupling conditions are difficult to understand due to the complex charge pattern and irregular geometry of protein surfaces. This distinguishes them from related systems such as DNA or conventional colloids. In this work, we discuss the question of universality of the reentrant condensation (RC) of proteins in solution induced by multivalent counterions, i.e., redissolution on adding further salts after phase separation, as recently discovered (Zhang et al., Phys Rev Lett 2008; 101:148101). The discussion is based on a systematic investigation of five different proteins with different charge patterns and five different multivalent counterions. Zeta potential measurements confirm the effective charge inversion of proteins in the reentrant regime via binding of multivalent counterions, which is supported by Monte Carlo simulations. Charge inversion by trivalent cations requires an overall negative net charge of the protein. Statistical analysis of a representative set of protein sequences reveals that, in theory, this effect could be possible for about half of all proteins. Our results can be exploited for the control of the phase behavior of proteins, in particular facilitating protein crystallization.

A rare case of trisomy 15pter-q21.2 due to a de novo marker chromosome.

Supernumerary marker chromosomes (sSMC) may or may not be associated with an abnormal phenotype, depending on the presence of euchromatin, on their chromosomal origin and whether they are inherited. Over 80% of sSMCs are derived from acrocentric chromosomes and half of them include the short arm of chromosome 15. Generally, they appear as bisatellited isodicentric marker chromosomes, most of them are symmetric. These chromosomes are normally originated de novo and are associated with mild to severe intellectual disability but not with physical abnormalities. We report on a patient with an SMC studied using classical and molecular cytogenetic procedures (G and C banding, NOR staining, painting and centromeric fluorescent in situ hybridization (FISH), BAC-FISH, and SKY). The MLPA technique and DNA polymorphic markers were used in order to identify its parental origin. The marker chromosome, monosatellited and monocentric, was found to be derived from a maternal chromosome 15 and was defined as 15pter-q21.2. This is the report of the largest de novo monosatellited 15q marker chromosome ever published presenting detailed cytogenetic and clinical data. It was associated with a phenotype including cardiac defect, absence of septum pellucidum, and dysplasia of the corpus callosum.

Two new Brazilian patients with Gómez-López-Hernández syndrome: reviewing the expanded phenotype with molecular insights.

Gómez-López-Hernández (GLH) syndrome or cerebello-trigeminal dysplasia is a neurocutaneous syndrome whose etiology is unknown at the present time. We report two additional Brazilian patients, including the oldest one known to date (age 29). Here, we review the expanded phenotype in four patients with new clinical, psychiatric, radiological, and molecular investigations. One patient may have hypomania within the bipolar spectrum disorder with onset in childhood and adolescence. Primary growth hormone (GH) deficiency was ruled out in all patients, although one of them might have developed secondary GH deficiency due to partial hypopituitarism following severe hydrocephalus. Brain magnetic resonance angiography disclosed no azygous anterior cerebral artery (ACA) but only normal variants. Molecular analysis of the lysosomal acid phosphatase gene (ACP2) was performed, but no pathogenic mutations were identified. We present an overview of the phenotypic features of all patients described to date. There are currently 12 unrelated patients reported in the literature, 5 of whom are Brazilian. We discuss new molecular insights and speculate about the pathogenesis of GLH syndrome.

Comparison of embryo implantation in Wistar rats that underwent ovarian stimulation using exogenous gonadotropins associated with cetrorelix acetate or leuprolide acetate.

OBJECTIVE: To compare embryo implantation in Wistar rats submitted to ovarian stimulation using recombinant FSH (rFSH) with cetrorelix acetate or leuprolide acetate. DESIGN: Experimental study. SETTING: Faculty of medicine animal facility. PATIENT(S): Fifty-six female Wistar rats with normal estrus cycles and 30 male. INTERVENTION(S): Ovarian stimulation and laparotomy (by the day 13 of gestation). MAIN OUTCOME MEASURE(S): Embryo implantation. RESULT(S): The female rats were subdivided into four groups: group 1, medicated with rFSH, hCG, and cetrorelix acetate; group 2, medicated with rFSH, hCG, and leuprolide acetate; group 3, medicated with rFSH and hCG; and group 4, in which only saline solution was administered. The female rats were mated with fertile male rats on the day of hCG administration with copulation confirmed through cytologic vaginal analysis. The females were killed on the 13th day of gestation. After laparotomy, comparison and identification was done regarding the numbers of corpora lutea and embryo implantations and gestation rates. Group 1 presented lower numbers of corpora lutea and embryo implantations in comparison to the other groups (P<.05). A difference was not found in the gestation rates between the groups. CONCLUSION(S): The number of embryo implantations in Wistar rats medicated with rFSH and cetrorelix acetate is lower than that of rats medicated with rFSH and leuprolide acetate.

Acute monocytic leukemia and multiple abnormalities in a child with duplication of 1q detected by GTG-banding and SKY.

Patients with 1q duplication have demonstrated a wide range of multiple congenital abnormalities. Alterations involving this chromosomal region have being described in hematopoietic malignancies and a series of candidate genes that may be associated with neoplasias have been mapped in this region. We describe a case of partial trisomy 1q "syndrome" and acute monocytic leukemia. Cytogenetic study of the bone marrow cells by GTG-banding and spectral karyotyping (SKY) showed dup(1)(q23q44) in all cells analyzed. The dismorphological features with the dup(1q) suggest a constitutional chromosome alteration and the first, in our knowledge, association of a trisomy 1q "syndrome" with AML.