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**Abstract:**



Aching Adipose: Shedding Light on Dercum’s Disease

Brugada syndrome is characterized by coved-type ST-segment elevations in the precordial leads associated with syncope, life-threatening ventricular tachyarrhythmias and sudden cardiac death. When typical ECG findings are present in the absence of symptoms, it is called Brugada pattern. About 25% of cases are associated with loss-of-function mutation of the cardiac sodium channel SCN5A while others may be triggered by drugs with sodium channel-blocking effects, electrolyte abnormalities, febrile states, or autonomic dysfunction.

A 33-year-old man presented with a 3-day history of intermittent substernal chest pressure. On hospital admission, ECG showed normal sinus rhythm without ST-segment changes and serial cardiac enzymes were normal. Given persistent symptoms and unremarkable recent exercise ECG-stress testing, cardiac CT-angiography was performed which revealed anomalous origin of the right coronary artery (RCA) with approximately 50% luminal narrowing. The patient underwent successful surgical reimplantation of the RCA. Cardiopulmonary bypass was weaned
off and the patient rewarmed from therapeutic hypothermia. Once normothermia was achieved, the patient developed ventricular fibrillation (VF). Following successful resuscitation, ECG revealed ST-segment elevations in V1 and V2 consistent with type 1 Brugada, which completely resolved spontaneously in the subsequent hours and was not reproducible with ajmaline challenge.

It is well known that hyperthermia may trigger Brugada syndrome in predisposed individuals. Studies have shown that mutated sodium channels result in temperature-dependent ionic changes. In febrile states, delayed sodium influx results in heterogeneous depolarization predisposing to VF. On the contrary, severe hypothermia (28.5C) causes sinus bradycardia, QT prolongation, widening of the QRS complex and the pathognomonic Osborn wave. Typical Brugada pattern has been rarely described in hypothermic states. Nonetheless, this pattern has been reproduced in animal models with cooling of the epicardium. Therapeutic hypothermia is targeted in the range of mild hypothermia (32-34C), where VF occurs only rarely, mainly in patients with primary arrhythmic disorders. Tan et al. described a case of transient typical Brugada ECG pattern upon rewarming from therapeutic hypothermia after sudden cardiac death of unknown etiology, with complete resolution with normothermia. These authors proposed that the Brugada pattern was hidden during the hypothermic state. In our patient, however, VF occurred only during the rewarming phase when normothermia was
achieved. We hypothesize that temperature increments, not necessarily hyperthermia, may be associated with increased risk of Brugada syndrome in susceptible patients. Although further research is needed, rewarming from therapeutic hypothermia requires careful monitoring for potentially lethal arrhythmogenic disorders.

A Warming Surprise: Brugada Syndrome After Rewarming from Therapeutic
Hypothermia

Background
A post-dural puncture headache (PDPH) is a common complication following trauma from spinal or epidural procedures. While the gold standard of treatment is an epidural blood patch (EBP), numerous pharmaceuticals have been investigated to prevent and manage symptoms with varying results. In some studies, gabapentin has been shown to decrease the incidence and severity of PDPH and opioid consumption without significant adverse effects.
Case Presentation
A 22-year-old female presented with an intractable headache after a recent lumbar puncture (LP). She was receiving treatment with REPOCH and intrathecal (IT) methotrexate for Burkitt’s Lymphoma and had end-stage renal disease status-post a remote kidney transplant complicated by post-transplant lymphoproliferative disorder. At presentation, her associated symptoms included nausea, vomiting, and severe pain that improved with lying flat, consistent with a PDPH. Initial treatment included fluids, opioids, anti-emetics, and caffeine. However, the patient required hospitalization due to her symptoms for which Anesthesiology and Palliative
Medicine were consulted. Since the patient had future cycles of IT chemotherapy and was a high infectious risk due to her immunocompromised state, an EBP was not recommended. Steroids, acetaminophen, and NSAIDs were contraindicated given her neutropenic fever and renal dysfunction, respectively. Gabapentin 100mg TID was then recommended based on limited evidence. The patient experienced significant symptom relief with gabapentin, decreasing her opioid utilization from over 100 oral morphine equivalents to zero within 24 hours. Gabapentin was prescribed for the patient’s future LP schedule that included three days of prophylactic treatment followed by three days of therapeutic treatment. The patient’s last chemotherapy was completed a few months later without recurrence of her headache.
Discussion
Management of PDPH includes a wide variety of treatment options in the literature with new non-opioid medications undergoing ongoing investigation. Clinicians should consider the use of gabapentin in the treatment and prevention of PDPH for patients who fail standard therapies.

The Use of Gabapentin for Relief of Post-Dural Puncture Headache

Lip and face lesions are recognized in dermatology as significantly distressing for patients. There are stereotypes associated with different lesions in this area that affect patients deeply, motivating them to seek care immediately. The average population or clinician is aware of common lip lesions, the most diagnosed of which is herpes simplex virus. Dermatologists must continue to be aware of unique lip and face lesions as they may grow rapidly, be worrisome, and affect the patient’s perception of themselves and psychological well-being. We present the case of neutrophilic sebaceous adenitis, which is an incredibly rare condition that has been reported minimally in the literature. Recognition of rapidly growing lesions, like our patients, is vital for proper diagnosis and treatment.
A 74-year-old female presented to the dermatology clinic with a 5-day history of a rapidly progressive lower lip lesion. Valacyclovir and Carmex only minimally improved her condition. Examination was significant for tenderness to palpation. The patient had no other lesions, no preceding trauma or bites, and no systemic symptoms. Histopathology showed a somewhat dense, superficial and deep, perivascular and periadnexal infiltrate composed predominantly of lymphocytes. The overlying epidermis showed some interface changes with a few necrotic keratinocytes as well as a focal but prominent neutrophilic infiltrate involving a sebaceous gland lobule. No increased dermal mucin was identified on Alcian blue stain. The patient discontinued valacyclovir and treated the lesion with triamcinolone 0.1% twice a day for a few weeks until it cleared. 
Neutrophilic sebaceous adenitis is a very rare condition. Pathogenesis is unknown but triggers such as sun exposure, antibiotics, and febrile illness have been reported. Lesions can progress over days to months and are typically asymptomatic. Recognition of this lesion around the lips and face is imperative as a differential diagnosis for providers to be aware of. Histopathology typically shows an inflammatory infiltrate, particularly of neutrophils and lymphocytes, around sebaceous glands. Sebocytes may be necrosed and further inflammatory infiltrates may be noted around the dermis. There are no current dermatologic guidelines on management although case reports have shown successful treatment with topical or oral steroids, metronidazole, or isotretinoin.

Looking Beyond the Ordinary Lip Lesion: A Rapidly Progressive Case of Neutrophilic Sebaceous Adenitis

Dermatofibromas are benign cutaneous soft-tissue tumors characterized by solitary or multiple, firm red-brown to black dermal nodules found on the trunk or extremities. Dermatofibromas most frequently affect middle-aged adults and have a slight preponderance in females. Variants of dermatofibroma include hemosiderotic, aneurysmal, epithelioid and deep fibrous histiocytomas, cellular, lipidized, lichenoid, keloidal, atrophic, and atypical. 

Diagnosis of the classical type of dermatofibroma is made clinically and based on dermoscopic patterns; however, the clinical and histologic heterogeneity observed in dermatofibroma variants can pose a diagnostic challenge and may be difficult to distinguish from potentially aggressive malignancies. Notably, hemosiderotic dermatofibroma has been reported to clinically simulate melanoma, while atypical dermatofibroma, is often mistaken histologically for sarcoma. 

Herein, we report a unique presentation of a patient with a recurrent atypical melanocytic nevus and multiple benign dermatofibromas masquerading as potentially malignant counterparts.

Dermatological Deception: Massive Dermatofibroma and Atypical Melanocytic Nevus Mimicking Malignancy

Lymphomatoid papulosis (LyP) is a chronic cutaneous CD30-positive lymphoproliferative disorder that is characterized by red-to-violaceous crops of papulonodular skin lesions. Although LyP carries a positive prognosis, there is consensus that LyP is associated with a history of or subsequent development of lymphoma. Herein, we present a case of LyP in a patient with a history of cutaneous B-cell lymphoma. The patient is a 67-year-old male with a history of treated cutaneous B-cell lymphoma two years prior to presentation, currently in remission, presenting with a two week history of painful hemorrhagic papules on his hands. Biopsy revealed a dense lymphomatoid infiltrate with admixed histiocytes and dermal hemorrhage. Tumor cells expressed CD3 and CD4, with marked loss of CD7. Small clusters of CD30+ cells were noted. There was no significant expression of CD20, CD56, or myeloperoxidase. At subsequent follow up, his original lesions were healing, but he had developed a new crop of lesions on the foot and both hands. Given the patient’s clinical course and histopathologic findings, a diagnosis of LyP subtype C was favored. The patient’s presentation was notable due to antecedent history of cutaneous B cell lymphoma, in addition to confinement to acral sites.

Lymphomatoid Papulosis Type C in Patient with History of Cutaneous B-Cell Lymphoma

Background
Scleroderma is a rare, chronic autoimmune disease that is characterized by thickening of the skin and other connective tissues in the body. Nodular scleroderma (NS) is a rare cutaneous form of scleroderma that can occur primarily with systemic sclerosis. Due to the rarity of NS, it is important to recognize these lesions, if presenting early in disease progression, as a sign of underlying scleroderma before internal organ damage becomes apparent. 

Case Presentation
A 42-year-old female with a history of systemic sclerosis presented with an enlarging left supraclavicular nodule. Upon physical exam, a 1.1cm erythematous nodule was found. The patient had clinical findings consistent with systemic sclerosis, including Raynaud’s phenomenon, gastroesophageal reflux disease, sclerodactyly, dyspnea on exertion, and skin tightening. The patient had been treated with CellCept 1500mg twice daily and responded very well to therapy. Pertinent laboratory data included speckled antinuclear antibodies (1:320 titer) and positive anti-RNA polymerase III antibodies (>80 units). 

The lesion was initially excised to rule out diagnosis of a cyst. However, histopathological analysis demonstrated a nodular proliferation of dense fibrotic collagen with scattered bland fibroblasts. A sparse perivascular and periadnexal lymphocytic infiltrate in the dermis was present with notable eccrine coil trapping. A CD34 stain showed markedly diminished dermal dendritic cells within the fibrotic nodule. Considering the patient’s known history of anti-RNA polymerase III-positive systemic sclerosis and histopathological findings, the focal lesion was consistent with nodular scleroderma. No subsequent treatments were performed.

Discussion
Nodular scleroderma is an atypical cutaneous presentation of systemic sclerosis and patients who are well-controlled on immunosuppressive therapy with few to no signs of internal organ disease are still susceptible to developing these lesions. Thus, diagnosis and treatment of NS remains a challenge. NS usually presents as 2 mm - 3 cm firm nodules or plaques resembling keloid or morphea, usually distributed on the trunk, neck, proximal extremities, and face. The pathogenesis of NS is also not well understood. Previous reports have shown that there may be a role for increased expression of connective tissue growth factor, tenascin, epidermal growth factor, or transforming growth factor beta in the formation of NS. 

Furthermore, treatment of NS is difficult as these lesions are resistant to many non-surgical interventions and remain stable over time. As in our case, surgical excision of NS has been the only treatment reported so far that results in full removal of NS, but not necessarily prevention of NS recurrence.


Systemic Sclerosis with a Rare Presentation of Nodular Scleroderma

Background
Drug-induced hypersensitivity syndrome (DIHS) is a severe, potentially life-threatening drug reaction with cutaneous and internal organ involvement. DIHS can lead to various autoimmune conditions, occurring in about 10% of patients, including thyroiditis. This case highlights the need for post-DIHS thyroiditis screening.

Case Presentation
A 32-year-old woman presented to the emergency department with fever, morbilliform eruption, facial swelling, lymphadenopathy, and laboratory studies notable for atypical lymphocytes (4%), eosinophilia (1400), and aminotransferase abnormalities (AST 61, ALT 265). Two weeks prior, she initiated a course of oral trimethoprim-sulfamethoxazole. History, clinical exam, and laboratory findings were consistent with DIHS. She was treated with high-dose corticosteroids with a resolution of the eruption and stabilization of hepatic enzymes. At follow-up in an outpatient dermatology clinic four weeks after discharge, she was noted to have clinically painful thyromegaly, fever, tachycardia, and palpitations. She was referred to the ED to expedite workup for suspected symptomatic hyperthyroidism. Workup revealed TSH of 0.01 (L), FT4 >7.7 (H), TSI <0.10, TRAb negative, and TPO Ab 202 (H). Thyroid ultrasound showed enlarged thyroid with heterogenous echotexture. Endocrinology diagnosed her with thyroiditis and prescribed atenolol for symptom management. She continued to have heat intolerance, palpitations, and faint pink macules on her lower legs. She initiated low-dose methimazole with a resolution of symptoms.

Discussion

One of the most common drug classes to cause post-DIHS autoimmune thyroiditis are sulfa drugs and antiepileptics. The most commonly seen issues that arise in the thyroid post-DIHS are Hashimoto’s thyroiditis and Graves’ disease, which have been observed to occur between 2 months and 3 years after the diagnosis of DIHS. As seen in this case, the patient experienced debilitating symptoms of thyroiditis within 1 month, which could have been minimized with early screening and recognition. This case emphasizes the importance of dermatologic follow-up for patients diagnosed with DIHS and the role of post-DIHS screening for autoimmune thyroid disease, as missed diagnosis of delayed sequelae can lead to significant morbidity.

Importance of Post-Drug Induced Hypersensitivity Syndrome Thyroiditis Screening

Computer-aided drug discovery of novel anti-malarial drugs

New quinoline-based leads in chemical therapy of Neglected Tropical Diseases

Rationale. WNT/β-catenin signaling and particularly the WNT receptor FZD4 are downregulated in chronic obstructive pulmonary disease (COPD). FzM1, a negative allosteric modulator for FZD4, and FzM1.8, an allosteric agonist, can be used to assess the role of FZD4 in activating β-catenin-dependent transcription in COPD, and to investigate FZD4 as a potential therapeutic target in COPD.
Methods. We tested modulation of β-catenin-dependent transcription by FzM1 and FzM1.8 with a luciferase reporter assay (TOP/FOPflash assay) in A549 adenocarcinoma epithelial cells. Mouse organoids were obtained co-culturing EpCAM+ cells isolated from mice lungs and CCL206 mouse fibroblasts in Matrigel in a Transwell system. Organoids were treated with FzM1 and FzM1.8 every other day until day 14, when number and phenotype (alveolar, airway, bronchioalveolar) were assessed. Precision-cut lung slices (PCLS) were obtained from mice lungs filled with warm agarose and cut with a vibratome into slices that were treated with the ligands for 48 hours and 5 days. Gene expression of β-catenin target genes, proliferation and alveolar markers was assessed through qRT-PCR.
Results. TOP/FOPflash assay confirmed dose-dependent β-catenin inhibition by FzM1 and activation by FzM1.8. FzM1 caused a drastic and significant reduction in organoids number at day 14, while FzM1.8 did not have a significant effect on organoids number or phenotype. In PCLS we observed an increased expression of pro-SPC (alveolar type II) and T1α (alveolar type I) genes after treatment with FzM1.8 for 5 days, suggesting an effect on cell fate in the alveolar compartment.
Discussion. We confirmed that these compounds modulate FZD4 and β-catenin activity in in vitro and ex-vivo lung models. We show that blocking FZD4-dependent β-catenin activation impairs organoids formation, therefore FZD4 signaling may be vital to proliferation and differentiation of alveolar progenitor cells. Targeting FZD4 could be an important strategy to rescue tissue repair in COPD. Further experiments are needed to clarify the role of FZD4 activation with FzM1.8.

Two novel allosteric ligands of FZD4 regulate the WNT/β-catenin pathway in COPD

Effect of intravenous alpha-1-antitrypsin augmentation therapy on a proteinase-3-generated AαVal541 in deficient patients

Iris G. M. Schouten, Richard A. Mumford, Abraham C. van der Linden, Dirk Jan A. R. Moes, Pieter S. Hiemstra, Jan Stolk

Background. In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as proteinase 3 (PR3) and elastase are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived footprint peptide AαVal541, compared to healthy controls (Newby et al, ERJ Open Res. 2019).
Aim and objectives. To analyse the course of AαVal541 in plasma over 4 weeks after a single iv dose of 240 mg/kg AAT in patients with genotype Z/Rare or Rare/Rare. 
Methods We developed a competitive immunoassay to measure AαVal541 in plasma. We assessed AaVal541 levels in healthy controls (n=20) and in patients before/after AAT augmentation (n=10).
Results. The average AαVal541 plasma level before treatment was 535.4 nM (range 46.9 - 4017.8 nM), and in all patients the level decreased within 1 day after receiving iv AAT. 
In the 5 patients who received AAT for the first time, the AαVal541 decreased to 42.0 nM (range 5.1 - 141.1 nM), 89.7% (SD 6.4%) of the baseline AαVal541 value. In the patients (n=5) who already received multiple infusions before, the AαVal541 decreased to 28.1 nM (range 21.9 - 38.0 nM), 68% (SD 13.8%) of baseline. In 9 of 10 patients, AαVal541 levels were reduced to the average level of healthy controls (27.9 nM ± 17.9 SD). At 7-14 days after treatment, AαVal541 levels started to increase again in all patients, reaching on average a level of 202.0 nM (range 15.3 - 1237.0 nM) at about 4 weeks after the AAT dose.
Conclusion. Fibrinopeptide AαVal541 may serve as a biochemical footprint to assess efficacy of in vivo inhibition of proteinase 3 activity in patients receiving intravenous AAT augmentation therapy. This opens opportunities for personalized tailored dosing.

Underline digital video library

Aching Adipose: Shedding Light on Dercum’s Disease

A Warming Surprise: Brugada Syndrome After Rewarming from Therapeutic Hypothermia

The Use of Gabapentin for Relief of Post-Dural Puncture Headache

Looking Beyond the Ordinary Lip Lesion: A Rapidly Progressive Case of Neutrophilic Sebaceous Adenitis

Dermatological Deception: Massive Dermatofibroma and Atypical Melanocytic Nevus Mimicking Malignancy

Lymphomatoid Papulosis Type C in Patient with History of Cutaneous B-Cell Lymphoma

Systemic Sclerosis with a Rare Presentation of Nodular Scleroderma

Importance of Post-Drug Induced Hypersensitivity Syndrome Thyroiditis Screening

Computer-aided drug discovery of novel anti-malarial drugs

New quinoline-based leads in chemical therapy of Neglected Tropical Diseases

Two novel allosteric ligands of FZD4 regulate the WNT/β-catenin pathway in COPD

Effect of intravenous alpha-1-antitrypsin augmentation therapy onproteinase-3-generated AαVal541 in deficient patients

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