Case report: palmar herpetic whitlow and forearm lymphangitis in a 10-year-old female.

BACKGROUND: Herpetic whitlow is a viral infection caused by the herpes simplex virus (HSV) types 1 or 2, and occurs in the pediatric population primarily on the fingers and toes due to autoinoculation from oral secretions. Because of this cited prevalence, other locations of herpetic whitlow may go unrecognized. CASE PRESENTATION: We present an atypical presentation of palmar herpetic whitlow with delayed recognition and associated viral lymphangitis. The patient presented as a transfer from an outside hospital with a progressive, three-day history of a suspected left hand abscess preceded by left hand pain and itching. She was initially evaluated by Orthopedic Surgery, who described an erythematous, edematous, tender, left palmar abscess with associated erythematous streaking up her forearm. The lesion was surgically managed with an incision and drainage. Wound cultures were obtained during which "minimal drainage" was noted. After admission to the General Pediatrics Hospital service, the lesion was noted to appear vesicular and subsequently obtained PCR samples were positive for HSV type 1, confirming her diagnosis of herpetic whitlow. Although she remained afebrile with negative wound cultures throughout her hospitalization, a secondary bacterial infection could not be conclusively excluded due to the accompanying lymphangitis. Thus, she was discharged with oral antibiotics and anticipatory guidance of potential recurrence of palmar lesions. CONCLUSIONS: Herpetic whitlow should be included in the differential diagnosis of palmar lesions that appear vesicular or abscess-like to ensure appropriate treatment. Additionally, these palmar lesions may present with associated lymphangitis without evidence of bacterial infection.

Structure-Activity Relationships of Benzenesulfonamide-Based Inhibitors towards Carbonic Anhydrase Isoform Specificity.

Carbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease-implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer-associated isoforms and reduce side effects. Four benzenesulfonamide-based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active-site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active-site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors.

The Structure of Carbonic Anhydrase IX Is Adapted for Low-pH Catalysis.

Human carbonic anhydrase IX (hCA IX) expression in many cancers is associated with hypoxic tumors and poor patient outcome. Inhibitors of hCA IX have been used as anticancer agents with some entering Phase I clinical trials. hCA IX is transmembrane protein whose catalytic domain faces the extracellular tumor milieu, which is typically associated with an acidic microenvironment. Here, we show that the catalytic domain of hCA IX (hCA IX-c) exhibits the necessary biochemical and biophysical properties that allow for low pH stability and activity. Furthermore, the unfolding process of hCA IX-c appears to be reversible, and its catalytic efficiency is thought to be correlated directly with its stability between pH 3.0 and 8.0 but not above pH 8.0. To rationalize this, we determined the X-ray crystal structure of hCA IX-c to 1.6 Å resolution. Insights from this study suggest an understanding of hCA IX-c stability and activity in low-pH tumor microenvironments and may be applicable to determining pH-related effects on enzymes.

Specific binding of a naturally occurring amyloidogenic fragment of Streptococcus mutans adhesin P1 to intact P1 on the cell surface characterized by solid state NMR spectroscopy.

The P1 adhesin (aka Antigen I/II or PAc) of the cariogenic bacterium Streptococcus mutans is a cell surface-localized protein involved in sucrose-independent adhesion and colonization of the tooth surface. The immunoreactive and adhesive properties of S. mutans suggest an unusual functional quaternary ultrastructure comprised of intact P1 covalently attached to the cell wall and interacting with non-covalently associated proteolytic fragments thereof, particularly the ~57-kDa C-terminal fragment C123 previously identified as Antigen II. S. mutans is capable of amyloid formation when grown in a biofilm and P1 is among its amyloidogenic proteins. The C123 fragment of P1 readily forms amyloid fibers in vitro suggesting it may play a role in the formation of functional amyloid during biofilm development. Using wild-type and P1-deficient strains of S. mutans, we demonstrate that solid state NMR (ssNMR) spectroscopy can be used to (1) globally characterize cell walls isolated from a Gram-positive bacterium and (2) characterize the specific binding of heterologously expressed, isotopically-enriched C123 to cell wall-anchored P1. Our results lay the groundwork for future high-resolution characterization of the C123/P1 ultrastructure and subsequent steps in biofilm formation via ssNMR spectroscopy, and they support an emerging model of S. mutans colonization whereby quaternary P1-C123 interactions confer adhesive properties important to binding to immobilized human salivary agglutinin.

Sulfonamide inhibition studies of the α-carbonic anhydrase from the gammaproteobacterium Thiomicrospira crunogena XCL-2, TcruCA.

We report a sulfonamide/sulfamate inhibition study of the α-carbonic anhydrase (CA, EC 4.2.1.1) present in the gammaproteobacterium Thiomicrospira crunogena XCL-2, a mesophilic hydrothermal vent-isolate organism, TcruCA. As Thiomicrospira crunogena is one of thousands of marine organisms that uses CA for metabolic regulation, the effect of sulfonamide inhibition has been considered. Sulfonamide-based drugs have been widely used in a variety of antibiotics, and bioelimination of these compounds results in exposure of these compounds to marine life. The enzyme was highly inhibited, with Ki values ranging from 2.5 to 40.7nM by a variety of sulfonamides including acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide and benzenesulfonamides incorporating 4-hydroxyalkyl moieties. Less effective inhibitors were topiramate, zonisamide, celecoxib, saccharin and hydrochlorothiazide as well as simple benzenesulfonamides incorporating amino, halogeno, alkyl, aminoalkyl and other moieties in the ortho- or para-positions of the aromatic ring (Kis of 202-933nM). The active site interactions between TcruCA and three clinically-used CA inhibitors, acetazolamide (Diamox®), dorzolamide (Trusopt®), and brinzolamide (Azopt®) are studied using molecular docking to provide insight into the reported Ki values. Comparison between various enzymes belonging to this family may also bring interesting hints in these fascinating phenomena.

Novel scoring tool of hypoxemic respiratory failure and pulmonary hypertension for defining severity of persistent pulmonary hypertension of newborn.

OBJECTIVE: To obtain preliminary validity data for a hypoxemic respiratory failure/pulmonary hypertension (HRF/PH) score for classifying persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: Retrospective chart review of 100 consecutive neonates admitted to a Children's hospital from 2016-2021 with PPHN, gestational age ≥34 weeks, and echocardiograms in the first week. We assessed the correlation between HRF/PH score and short-term outcomes using linear and logistic regressions. RESULTS: HRF/PH scores ranged 2-12 (mean 8.5), and were classified mild (0-5), moderate (6-10), and severe (11-15), with 6%, 77% and 17% infants in respective categories. HRF/PH score category correlated with invasive ventilation, nitric oxide, high frequency ventilation, vasoactive infusions, extracorporeal life support and death. HRF/PH score category did not correlate with duration of support or length of stay. CONCLUSION: The HRF/PH score offers a promising representation of disease severity for PPHN. The tool requires further validation in prospective studies and evaluation for long-term outcomes.

Factors to Consider to Study Preductal Oxygen Saturation Targets in Neonatal Pulmonary Hypertension.

There are potential benefits and risks to the infant with higher and lower oxygen saturation (SpO2) targets, and the ideal range for infants with pulmonary hypertension (PH) remains unknown. Targeting high SpO2 can promote pulmonary vasodilation but cause oxygen toxicity. Targeting lower SpO2 may increase pulmonary vascular resistance, especially in the presence of acidosis and hypothermia. We will conduct a randomized pilot trial to compare two ranges of target preductal SpO2 in late-preterm and term infants with hypoxic respiratory failure (HRF) and acute pulmonary hypertension (aPH) of the newborn. We will assess the reliability of a newly created HRF/PH score that could be used in larger trials. We will assess trial feasibility and obtain preliminary estimates of outcomes. Our primary hypothesis is that in neonates with PH and HRF, targeting preductal SpO2 of 95-99% (intervention) will result in lower pulmonary vascular resistance and pulmonary arterial pressures, and lower the need for pulmonary vasodilators (inhaled nitric oxide-iNO, milrinone and sildenafil) compared to targeting SpO2 at 91-95% (standard). We also speculate that a higher SpO2 target can potentially induce oxidative stress and decrease response to iNO (oxygenation and pulmonary vasodilation) for those patients that still require iNO in this range. We present considerations in planning this trial as well as some of the details of the protocol design (Clinicaltrials.gov (NCT04938167)).

Telemedicine in Pediatric Training: A National Needs Assessment of the Current State of Telemedicine Education in Pediatric Training.

PURPOSE: To describe the current state of telemedicine within pediatric training programs to inform development of a national telemedicine training curriculum for pediatric trainees. METHODS: We conducted an anonymous cross-sectional survey of pediatric residency (Fall 2020) and fellowship program directors (Spring 2021) on their current telemedicine practices in pediatric post-graduate training. RESULTS: Forty-eight US pediatric residency programs (n = 48/198, 24%) and 422 fellowship programs completed the survey (n = 422/872, 48%); combined response rate 44% (n = 470/1070). Pre-COVID-19, 12% (n = 57/470) of programs surveyed reported using telemedicine in their training program, but during the pandemic 71% (n = 334/470) reported telemedicine use with trainees. Over 71% (n = 334/470) agreed that a formalized curriculum is important, yet 69% (n = 262/380) of programs reporting telemedicine use either did not have a curriculum or were unsure if one existed at their program. Respondents who were unsure/not likely to add a telemedicine curriculum and/or indicated that a telemedicine curriculum would not be important (52% n = 243/470), cited "time" (55%, n = 136/243) most frequently as a barrier. CONCLUSIONS: Our needs assessment indicates marked increase in use of telemedicine with trainees by respondent pediatric training programs, with fewer than 50% reporting a formalized training curriculum and most agreeing that a curriculum is important.

17-Month-Old Girl With Severe, Prolonged Lethargy and Somnolence.

A 17-month-old girl arrived at the pediatric ED with decreased responsiveness. She was lethargic, localizing only to noxious stimuli with vital signs significant for fever of 103.8 °F, heart rate of 185 beats/min, respiratory rate of 12 breaths/min, blood pressure of 100/59 mmHg, and oxygen saturation level of 88% on room air. She was admitted to the pediatric intensive care unit (PICU) due to concerns of septic meningitis with altered mental status and respiratory distress, and was treated with antibiotics. A respiratory viral panel (RVP) was positive for adenovirus, resulting in all antibiotics being discontinued. She remained lethargic until day nine of illness, when she had improved almost completely to her baseline. Polymerase chain reaction (PCR) of her cerebral spinal fluid returned positive for adenovirus serotype A, thus confirming our case of transient adenovirus encephalopathy. This case illustrates the importance of keeping adenovirus in the differential for encephalopathy versus a neurologic abnormality or other malignant or infectious etiology.

An Unusual Visit from an Old Foe: Oral Presentation of Syphilis in a Teenage Patient.

The authors report an atypical case of secondary syphilis in an adolescent female presenting to a tertiary-care center with fever, weight loss, oral sores, painful inguinal lymphadenopathy, and transient macular rash. Given the lower prevalence of syphilis in adolescent females, this infection was not included on the initial differential diagnosis. The evolving presentation of syphilis over time complicates the diagnosis and management of these infections, as it did for the patient in this report. The authors provide a detailed discussion of the patient's clinical findings, including the protean features of syphilis infection. This case is particularly relevant to the fields of general pediatrics and pediatric hospital medicine.

Hypercalcemia from hypervitaminosis A in a child with autism.

Objectives Vitamin A is essential for normal cellular physiology and is often taken as a dietary supplement. Hypervitaminosis A can lead to hypercalcemia by increasing osteoclasts and subsequent bone resporption. Dietary supplements including vitamin A are new popular treatment stategies for autism. Case presentation We report a five-year old boy with autism spectrum disorder presenting with severe abdominal pain and bilateral lower extremity pain, who was found to have persistent hypercalcemia due to hypervitaminosis A. The patient ingested over 700 times the recommended intake of Vitamin A per day for age. Retention of vitamin A in the liver and adipose tissue causes toxic levels of retinoids and hypercalcemia. Conclusions Acute treatment included intravenous rehydration, furosemide, and calcitonin. Pamidronate was the definitive treatment for hypercalcemia from hypervitaminosis A due to its osteoclast inhibition and long biologic half-life. Parents should be counseled on risks of toxicity and absence of evidence showing benefits of vitamin A therapy for autism.

Renin-Angiotensin-Aldosterone System Optimization for Acute Decompensated Heart Failure Patients (ROAD-HF): Rationale and Design.

INTRODUCTION: The long-term benefits of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on outcomes in patients with chronic congestive heart failure are well-known, making them one of the most widely prescribed medications. However, the administration of ACEIs/ARBs in acute decompensated heart failure (ADHF) can increase the risk of morbidity and mortality secondary to worsening renal function (WRF). A decrease in estimated glomerular filtration rate (eGFR) during the treatment of ADHF has been associated with an increase in mortality proportional to the degree of WRF. AIM: The aim of our study is to determine whether withholding ACEIs/ARBs during the initial 72 h of admission in patients with ADHF will prevent WRF and allow more effective diuresis. METHODS: Four hundred and thirty patients will be randomized to the intervention (withholding ACEIs/ARBs) or control (continue/start ACEIs/ARBs) arms for 72 h. Primary outcomes include rates of acute kidney injury (AKI), patient global assessment, and change in kinetic eGFR over 72 h, while secondary outcomes include change in weight, fluid balance, change in signs and symptoms of congestion, change in renal function, change in urinary biomarkers (tissue inhibitor of metalloproteinases 2 [TIMP-2] × insulin-like growth factor-binding protein 7 [IGFBP7]), patients experiencing treatment failure, hospital length of stay (LOS), cost analysis, mortality within 30 days, and hospital readmissions over 30 days and 1 year. CONCLUSION: This prospective clinical trial will prove if withholding ACEIs/ARBs will prevent AKI in ADHF. It will help us understand the complex interactions between the heart and kidney, and delineate the best treatment strategy for ADHF. Holding ACEIs/ARBs might help preserve renal function, and decrease hospital LOS, readmission rates, and cost of care in ADHF. REGISTRATION: ClinicalTrials.gov identifier: NCT03695120.

Crystal Structure of Carbonic Anhydrase II in Complex with an Activating Ligand: Implications in Neuronal Function.

Carbonic anhydrase (CA) plays a key role in neuronal signaling, providing bicarbonate and proton ions for GABAergic and glutamatergic neuronal function. Activation of CA isoforms expressed in neurons have been shown to have implications in the prognosis of Alzheimer's disease and dementia, while inhibitors of CAs are clinically used in the treatment of epilepsy, emphasizing the importance of this family of enzymes in both disease and normal neuronal function. Previously, compounds have been reported to enhance activity of CAs in an aging rat model, but their mechanism of action was not known. We report the 1.6 Å resolution structure of an imidazole-based CA activator in complex with the ubiquitously-expressed human CA II. Based on the structure, a proposed mechanism of CA activation by the compound and its potential applications in the neurobiology of aging are discussed.

Entropic Anomaly Observed in Lipid Polymorphisms Induced by Surfactant Peptide SP-B(1-25).

The N-terminal 25 amino-acid residues of pulmonary surfactant protein B (SP-B1-25) induces unusual lipid polymorphisms in a model lipid system, 4:1 DPPC/POPG, mirroring the lipid composition of native pulmonary surfactant. It is widely suggested that SP-B1-25-induced lipid polymorphisms within the alveolar aqueous subphase provide a structural platform for rapid lipid adsorption to the air-water interface. Here, we characterize in detail the phase behavior of DPPC and POPG in hydrated lipid assemblies containing therapeutic levels of SP-B1-25 using 2H and 31P solid state NMR spectroscopy. The appearance of a previously observed isotropic lipid phase is found to be highly dependent on the thermal cycling of the samples. Slow heating of frozen samples leads to phase separation of DPPC into a lamellar phase whereas POPG lipids interact with the peptide to form an isotropic phase at physiologic temperature. Rapid heating of frozen samples to room temperature leads to strongly isotropic phase behavior for both DPPC and POPG lipids, with DPPC in exchange between isotropic and interdigitated phases. 31P T2 relaxation times confirm the isotropic phase to be consistent with a lipid cubic phase. The observed phases exhibit thermal stability up to physiologic temperature (37 °C) and are consistent with the formation of a ripple phase containing a large number of peptide-induced membrane structural defects enabling rapid transit of lipids between lipid lamellae. The coexistance of a lipid cubic phase with interdigitated lipids suggests a specific role for the highly conserved N-terminus of SP-B in stabilizing this unusual lipid polymorphism.