The patient was a 45-year-old woman who first presented to our center due to abdominal pain 7 years prior to transplantation. At initial presentation, she had cryptogenic cirrhosis requiring large-volume paracentesis. She had undergone no procedures except paracentesis on presentation to our center. Initial magnetic resonance imagining (MRI) demonstrated possible bowel ischemia as well as thrombosis of her portal, splenic, and superior mesenteric veins. Approximately 190 cm of ischemic small bowel was resected over multiple operations. Liver biopsy at this time showed central lobular ischemic injury and early fibrosis.
She next underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for continued ascites after thrombolysis of her portomesenteric clot, which allowed for performance of the procedure. She required multiple TIPS revisions due to thrombosis in spite of systemic anticoagulation. Hypercoagulable workup revealed a weakly positive lupus anticoagulant antibody, heterozygosity for the prothrombin G20210A polymorphism, heterozygosity for the JAK2 V617F mutation, and elevated platelet counts, consistent with essential thrombocytosis.
She was maintained on hydroxyurea for some time before she was admitted to the hospital for TIPS occlusion with ascites. She also had occlusion of her hepatic veins, cavernous transformation of the portal vein, and multifocal intrahepatic and extrahepatic portal venous thromboses and associated regenerative nodules (). Due to recurrent TIPS occlusion, she was evaluated for and underwent a combined liver, pancreas small bowel transplant 7 years after her initial presentation. Her calculated MELD-Na at that time was 22. Of note, her only pretransplant comorbidities not related to her hypercoagulable state were prior melanoma and squamous cell carcinoma treated and cured as well as situational migraines and anxiety.
During the transplant, a large volume of chylous ascites was encountered. Due to significant collateral vessels obscuring the planes for dissection around the head of the pancreas and the fact that she had few esophagogastric varices (likely indicative of sufficient venous drainage of the bowel), the decision was made to defer complete removal of the native organs (stomach, pancreas, spleen) draining into the clotted native portomesenteric system.
The multivisceral graft was implanted using a conduit of donor thoracic aorta for inflow, anastomosed to the native supraceliac aorta. Venous drainage was via the vena cava above the level of clot. Ultimately, the recipient jejunum and ileum were resected, and an ileocolostomy with a Santulli (“Chimney”) ileostomy was created. The patient received a total of 4 units of packed red blood cells, 4 units of fresh frozen plasma, and 3 units of platelets.
Postoperatively, the patient experienced difficulty resuming enteral nutrition due to chylous ascites. Therefore, she was discharged on total parenteral nutrition (TPN). Explant pathology of the native liver showed severe parenchymal congestion and nodular regenerative hyperplasia with centrilobular perisinusoidal fibrosis.
Her postoperative course was complicated by multiple readmissions secondary to refractory chylous ascites. Postoperative computed tomography (CT) scan redemonstrated massive splenomegaly and large varices (). She underwent Denver shunt placement 4 months after transplant. Though this provided some relief, she required a total of four revisions of her shunt over the course of 1.5 years. Due to the fact that her shunt was only ever patent for a short period of time, lymphangiography was pursued and a chyle leak was identified and embolized (). However, the procedure did not appreciably improve her symptoms. She next underwent surgical exploration; however, the ascites at this time was unexpectedly nonchylous and no direct lymphatic leak was identified.
Given the negative exploration and the nonchylous and persistent nature of her ascites, consideration was given to residual portomesenteric hypertension as the potential cause of her ascites. Three years after her initial transplant, the decision was made to proceed with surgical resection of her the native organs draining into the native obstructed portomesenteric system. In preparation for this procedure, her native spleen was embolized. She then underwent explant of her native distal stomach, duodenum, pancreas, and spleen. The native proximal superior mesenteric artery was ligated (supplying the duodenal, pancreatic, and proximal jejunal arterial branches). The common hepatic artery distal to the left gastric artery was also ligated in order to preserve blood supply to the proximal native stomach. Thereafter, mobilization of the markedly enlarged spleen and transection of the mid gastric body allowed for excision of the duodenum, pancreas, (including the retropancreatic thrombosed portal and splenic veins), spleen, distal stomach, proximal jejunum, and a short length of the native transverse colon. Gastrointestinal continuity was restored by the creation of a roux-en-y gastrojejunostomy utilizing the transplanted small bowel and new ileocolostomy.
The patient recovered well from this operation with complete resolution of her now nonchylous ascites and was discharged on postoperative day 16. Since this operation, the patient has been admitted to the hospital only briefly for choledocholithiasis requiring endoscopic retrograde cholangiopancreatogram (ERCP) and an episode of malaise and cramping abdominal pain with diarrhea that improved with conservative management.


A 58-year-old man with bilateral essential tremor received bilateral VIM-DBS with directional leads (Model DB-2202-45; Boston Scientific). Due to his asymmetrical anatomy, also highlighted by the surgical planning software, the right trajectory was adjusted by 2 mm in the anterior direction (). The patient experienced excellent tremor control on both sides, with no side effects on his latest stimulation settings. Six months postoperatively, he participated in this study to test tremor control and side effects in a double-blinded fashion.


In December 2014, a 50-year-old male never-smoker showed up at a medical examination with increasing cough over the last five months. The cough had recently become productive, and the sputum was occasionally red. Chest CT scan, bronchoscopy and positron emission tomography–computed tomography (PET-CT) confirmed stage III lung adenocarcinoma in the left lower lobe with mediastinal and hilar lymph node involvement on both sides (T3N3M0, stage III/B) (c). Below the affected region he developed atelectasis. In January 2015, the patient underwent mediastinoscopy. Pathology test results showed that the lymph node metastasis was negative for EGFR (Epidermal growth factor receptor) and KRAS (GTPase KRas (Kirsten rat sarcoma)) mutations and ALK rearrangement.
In February, treatment with cisplatin and docetaxel (75 mg/m2 each) was commenced, but due to an allergic reaction to taxol, they were switched to cisplatin (75 mg/m2) + gemcitabine (1200 mg/m2)/pemetrexed (500 mg/m2). In March 2015, sampling of the primary tumor was successful with explorative thoracotomy and the tumor turned out to be inoperable. Histopathologic examination of formalin-fixed paraffin-embedded (FFPE) block section of the tissue revealed positivity for ALK in 56% of cells (63/113) using two channels of the ZytoLight SPEC ALK/EML4 TriCheck Probe specific for ALK (b). The fusion partner has not been determined. Fluorescence in situ hybridization (FISH) was negative for HER2 (Receptor tyrosine-protein kinase erbB-2 (human epidermal growth factor receptor 2)), MET (Hepatocyte growth factor receptor), FGFR1 (Fibroblast growth factor receptor 1), and PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform) amplification and ROS1 rearrangement. Next-generation sequencing of 50 genes (50-gene Cancer HotSpot Ampliseq panel, Thermo Fisher) detected two missense mutations: R273H (c.818G > A) in exon #7/10 of TP53, which hits the DNA-binding domain of p53, and Q472H (c.1416A > T) in exon #11/30 of KDR (encoding vascular endothelial growth factor receptor 2 (VEGFR-2)), which hits the immunoglobulin-like C2-type 5 domain within the extracellular region of VEGFR-2.
In the light of the findings, from May 2015, crizotinib (first generation ALK inhibitor) therapy was started (2 × 250 mg (MD 250 mg)). After five months on crizotinib, PET-CT demonstrated progression on the primary left lower lobe tumor and on the mediastino-hilar lymph nodes (c). Novel metastatic mass was not detected. Due to progression, in November 2015, his treatment was changed to the second-generation ALK inhibitor ceritinib (450 mg/day) plus nivolumab (240 mg biweekly). Two months after the second administration of nivolumab, the patient was hospitalized with severe liver failure demonstrated by subicterus and elevated liver enzymes (alkaline phosphatase (AP) values over 3000 U/L) and a C-reactive protein (CRP) value of 175 mg/L. Endoscopic retrograde cholangiopancreatography (ERCP) revealed cholelithiasis and immune-related hepatitis. Nivolumab was held. Ceritinib therapy (450 mg/day) was continued and resulted in stable disease for over 2.5 years without metastatic lesions. In June 2018, PET-CT revealed morphometabolic progression of the mediastino-hilar lymph nodes (c).
Therefore, in July 2018, therapy was switched to the third-generation ALK inhibitor, lorlatinib (100 mg/day), which stabilized the disease (c). ALK inhibitor resistance mutations (C1156Y, I1171N, L1196M, G1202R, or G1269A) were not detected by droplet digital PCR (ddPCR) on liquid biopsy. After showing no signs of progression or metastatic lesions for 17 months on lorlatinib, the patient arbitrarily discontinued medication without informing his physician. One month later, in January 2020, he was hospitalized with severe liver failure, which turned out to be the consequence of multiple liver metastases. The patient’s health condition and organ function could not be improved due to the advanced tumor stage and he succumbed to the disease one week after admission to the hospital.


Case 1: A 56-year-old male farmer presented with radioscaphoid and capitolunate osteoarthritis of the right wrist following a fall 5 years prior. The GS was 74% and the QuickDASH score was 29.5. Due to wrist pain and arthritis, the patient was diagnosed as having SNAC stage III (Fig. a, b, c, d), as evaluated by an X-ray, computed tomography (CT) scan, and bone scintigram. The four corners were fixed using a circle-shaped BAP. After fixation, the joint capsule was sutured onto the BAP. The patient was assessed radiographically directly post operation (Fig. a, b), and 1 year postoperatively via a three-dimensional CT scan (Fig. a, b, c). Five years after the operation, the four corners had united, and the plate had almost disappeared (Fig. a, b, c). At that stage, the active ROM was VF, 50°; DF, 40°; pronation, 85°; and supination, 90° (Fig. a, b, c, d). Radial bending was 25°, ulnar bending was 30°, GS was 25 kg (67%), the QuickDASH score was zero, and the level of pain was none.


Case 2: A 61-year-old female with no obvious history of trauma presented with a SNAC stage III right wrist (Fig. a, b, c, d). Her GS was 78% and MRI results showed obvious scaphoid advanced collapse. In this case, as part of preoperative planning, a stereo model of the wrist was created using a three-dimensional printer. This was done to understand the appropriate shape of the BAP required for the surgery (Fig. a, b). In practice, the BAP is created during the surgery based on the results of the preoperative planning (Fig. ). At 1.5 years post operation, the four corners were fully united (Fig. a, b); her GS was 21.9 kg (87%), QuickDASH score was 6.82, and the level of pain was none.


A 47-year-old male with a past medical history of IV heroin abuse, untreated hepatitis C, and Crohn's disease presented with a one-week history of left lower back pain. The pain was sharp, rated 5/10, nonradiating, without known relieving or exacerbating factors. Further history taking revealed five to six bags of IV heroin use per day for an unknown period, including on the morning of admission. Additional history and review of systems were noncontributory. Objectively, the patient was febrile at 102.6°F, had leukocytosis, prominent lactic acidosis, and an unremarkable chest X-ray. Empiric antibiotic therapy was initiated using vancomycin, ceftriaxone, and gentamicin. On day 2 of admission, the patient became hemodynamically unstable, refractory to IV fluid therapy, and received escalated care using vasopressor support.
Blood cultures on admission grew Streptococcus mitis, sensitive to ceftriaxone; therefore, antibiotics were appropriately narrowed. The patient subsequently developed angina symptoms, where additional workup revealed troponin elevation to 0.82 without electrocardiogram changes, for which heparin was initiated. Transthoracic echocardiography (TTE) was remarkable only for aortic valve thickening, suspicious for vegetation, and moderate to severe aortic regurgitation. Transesophageal echocardiography was recommended for further investigation; however, after discussing the risks and benefits, the patient refused. Interval changes on a chest X-ray revealed new pulmonary edema. Repeat TTE showed an left ventricular ejection fraction (LVEF) of 60%-65% with a 1 cm x 1 cm aortic valve vegetation, severe aortic regurgitation, and valve leaflet perforation (Figures -). The results, plan, and prognosis were discussed with the patient. After hemodynamic stabilization, the patient refused surgical intervention and left against medical advice with the prescribed antibiotic therapy. A month later, the patient was readmitted and reported that he received an aortic valve replacement two weeks after leaving the hospital. A subsequent TTE was performed and showed an LVEF of 55%-60% with a bioprosthetic aortic valve.


A 72-year-old female with a medical history of primary hypothyroidism presented to the emergency department for progressively worsening confusion for three days. Her husband reported that her oral intake had been getting slowly poor over a period of few months and for past few weeks she has been eating very less. He had also noticed difficulty maintaining balance while ambulating for the past few weeks. He confirmed he had been giving her thyroid medicine. Initial workup in the emergency department revealed hypothermia with a rectal temperature of 93.7°F, an irregularly irregular heart rate at 55 beats per minute, blood pressure of 160/108 mmHg, respiratory rate was 8 breaths per minute, oxygen saturation of 100% on ambient air, and a body mass index (BMI) of 19. On physical exam, the patient was ill appearing with marked macroglossia. Bowel sounds and breath sounds were decreased. The neurologic exam revealed diffuse hypertonicity of all four extremities. Deep tendon reflexes were reduced to 1+ globally. Glasgow Coma Score was 12/15. The complete blood count was unremarkable. The comprehensive metabolic panel was significant for hyperkalemia with a potassium of 5.7 mmol/L, albumin level of 1.8 g/dL, as well as acute kidney injury with blood urea nitrogen (BUN) 34 mg/dL and creatinine 1.86 mg/dL. The blood glucose level was 89 mg/dL. The arterial blood gas revealed a pH of 7.36, pO2 64.5, and pCO2 of 38.8. Troponin was <0.015 ng/mL. Electrocardiography (EKG) revealed new-onset atrial fibrillation at a rate of 65 per minute without peaked T waves. A plain CT scan of the head and CT angiogram of the head and neck revealed no acute intracranial bleeding, ischemia, or significant stenosis in major neck vessels. Urinalysis was not suggestive of infection and a urine drug screen was negative. TSH was significantly elevated at 402.0 µU/L and the free thyroxine (T4) was low at 0.22 ng/dL. Cortisol level was 16.1 µg/dL but it was not a morning cortisol level since the patient presented in the evening. Further inquired history later on revealed that the patient’s primary hypothyroidism had been very difficult to control even with compliance and follow up for the past few months. The most recent TSH two months prior to the admission was 180 µU/L, so her levothyroxine regimen was increased to 112 mcg/daily from 100 mcg/daily by her primary care physician.
A diagnosis of MC was made. The patient was admitted to the step-down unit for the management of MC. She was given intravenous loading doses of intravenous hydrocortisone 100 mg, levothyroxine 100 mcg, and liothyronine 10 mcg by the admission team, and then started on intravenous levothyroxine 100 mcg daily, liothyronine 2.5 mcg every eight hours, and hydrocortisone 100 mg every eight hours. Hyperkalemia was resolved with IV insulin and glucose and oral polystyrene sulfonate. Calcium gluconate was also given in the emergency department for cardioprotection.
Her clinical condition improved over the next two days, and the patient gradually regained the ability to speak and interact with hospital staff appropriately. Given elevated morning cortisol level 76.9 µg/dL and neurological improvement, IV hydrocortisone was reduced to 50 mg every eight hours. However, she continued to be hypothermic with a temperature of 94.7°F. Blood cultures obtained on the admission day returned positive for gram-positive cocci in clusters in both bottles. Concerning for sepsis, she was started on intravenous vancomycin for suspected bacteremia; a warming blanket was applied to raise her body temperature. On hospital day 3, she suddenly became irritable, uncooperative, and continually attempted to get up from bed throughout the night despite repeated requests by the nursing staff to remain in bed. She was unsteady, and she pulled out all her peripheral intravenous lines. She ultimately had to be restrained with a vest and soft mitts. This was also thought to be the continuum of MC. On hospital day 4, the patient’s cognition improved significantly. Laboratory results revealed improved free triiodothyronine (T3), free T4, and morning cortisol level. The patient was deescalated from the step-down unit to a regular medicine floor. The thyroid replacement regimen transitioned to oral levothyroxine 200 mcg daily, while IV cortisone was continued. On hospital day 5, the previous blood cultures ultimately identified the organisms mixed with alpha-hemolytic Streptococcus and coagulase-negative Staphylococcus, consistent with culture contamination. Also, repeat blood cultures revealed negative results. Therefore, vancomycin was discontinued.
The patient continued to exhibit poor appetite and low blood sugar despite treatment with dronabinol for appetite stimulation and scheduled oral glucose tablets for hypoglycemia. Adrenal insufficiency was ruled out given a repeat normalized morning cortisol, for which IV hydrocortisone was discontinued on hospital day 11. Due to the patient’s continuing refusal to eat, a percutaneous endoscopic gastrostomy (PEG) tube was placed. She tolerated regular tube feeds and her hypoglycemia resolved. Ultimately, the patient was discharged in stable condition with the improvement of her mental status to the baseline to a skilled nursing facility, with a regimen of oral levothyroxine 112 mcg daily. At one-month follow-up upon discharge, she continued to improve clinically. She was self-ambulatory and tolerated oral feeds well. The plan for removing the PEG tube had been made. Her TSH was reported to be 12.5 µU/L.


A 42-year-old female with a past medical history of SLE on hydroxychloroquine 200 mg daily and prednisone 10 mg daily for six months, APS on warfarin, valvular heart disease with myxomatous aortic valve with bioprosthetic aortic valve repair, hypertension, hyperlipidemia, cerebrovascular accident and stage II chronic kidney disease presented to the hospital with epistaxis, hemoptysis, menorrhagia, worsening shortness of breath, and weakness along with nausea and vomiting for three days. She was diagnosed with APS seven years prior to admission with triple-positive APLA and lupus anticoagulant positive.
On day 1, after switching warfarin to enoxaparin for an elective cardiac catheterization, she developed epistaxis and hemoptysis. The patient was initially hemodynamically stable, and her relevant labs from admission are displayed in Table .
Her bleeding was attributed supratherapeutic international normalized ratio (INR) and so the anticoagulation medications were discontinued and she was given 10 mg PO vitamin K for reversal of warfarin. The hemolytic panel revealed low haptoglobin, elevated lactate dehydrogenase (LDH), indirect hyperbilirubinemia, and negative coombs test. A preliminary diagnosis of CAPS was made due to positive APS serology, multiorgan failure, and development of manifestations in less than a week.
On day 3, she was started on intravenous methylprednisolone 60 mg daily and hydroxychloroquine was continued. Atovaquone was started for Pneumocystis pneumonia (PCP) prophylaxis. On day 7, she was transferred to the intensive care unit due to renal failure and the need for dialysis and plasma exchange. A renal biopsy was done to discern the etiology behind rapidly deteriorating renal function. It was reported as early membranoproliferative glomerulonephritis (MPGN)-like picture with positive staining for C3, C4, immunoglobulin A (IgA), negative for complement component 1Q (C1q) with interstitial fibrosis, and intact integrity of the tubule-capillary architecture. It was consistent with features of chronic APS nephropathy, probable class II lupus nephritis, and moderate interstitial fibrosis with tubular atrophy. She was continued on plasmapheresis every 48 hours for a total of 14 days (starting on day 7). Due to a lack of improvement after plasmapheresis, concomitant treatment with rituximab was started on day 12 and she received a total of four infusions of rituximab over the course of the next two weeks, however, due to low cluster of differentiation (CD)19 and CD20 values, further rituximab was not indicated. On day 16, the patient endorsed right upper extremity pain and was found to have bilateral superficial venous thrombosis and heparin drip was initiated.
During her third week of hospitalization, her thrombocytopenia and APLA levels worsened on the days she did not receive plasma exchange (every 48 hours) which suggested that it was a resistant disease despite aggressive measures, and hence the patient was administered eculizumab 600 mg. She was on prophylactic ceftriaxone 1g/24 hours when on eculizumab therapy which was switched to piperacillin-tazobactam when urinalysis (sent prior to eculizumab therapy) came back positive for pyuria. Urine culture was positive for Candida dubliniensis and blood cultures remained sterile. On day 25, the patient started getting hypotensive and lethargic and was found to have lactic acidosis, however, she was clinically worsening with massive volume overload and altered mentation. The patient had initially received three sessions of alternate day hemodialysis after which her renal function improved with improving urine output, however, it did not sustain. Aggressive diuresis and albumin infusions were tried for volume overload without improvement. The deterioration was thought to be due to pre-renal acute kidney injury due to decreased intravascular volume secondary to third spacing in the setting of CAPS and cardiorenal syndrome secondary to her defective aortic valve. The patient was initiated on continuous venovenous hemodialysis. The patient continued to by hypotensive requiring pressor support with norepinephrine (40 mcg/min) and epinephrine (2 mcg/min). Sodium bicarbonate drip was initiated due to worsening acidosis and antibiotics were escalated to meropenem to cover extended-spectrum beta-lactamases (ESBL) and nosocomial gram negatives with the addition of micafungin due to prolonged hospitalization, immunocompromised status, and multiple indwelling lines. The patient was not able to tolerate plasmapheresis due to hemodynamic instability.
By the fifth week, the patient’s condition then continued to deteriorate with lethargy, right gaze preference, bilateral plantar extensor response. She also started having increased work of breathing. Given worsening respiratory and mental status, a possible need for intubation was discussed with the patient’s health care proxy who voiced that the patient would have wished to be a 'do not resuscitate and intubate' (DNR-DNI). The patient eventually passed away. The patient’s family declined autopsy after discussion.


A 40-year-old male patient was brought to R. L. Jalappa Hospital & Research Centre affiliated to Sri Devaraj Urs Medical College, Kolar, Karnataka, South India. The patient presented with an alleged history of road traffic accident, sustaining an open injury to his right foot. It involved the bipolar dislocation of the proximal phalanx of the third toe with extensor digitorum longus tendon injury and fracture of the neck of the fourth proximal phalanx of the right foot. Range of motion of the metatarsophalangeal joint of the third and fourth digits was painful and restricted. Active first, second, and fifth toe movements were present. No distal neurovascular deficits were noted. All other bones and joints were clinically normal. It was an isolated injury with no evidence of intracranial, thoracic, abdominal, or pelvic injury on clinical or radiographic examination. A focused assessment with sonography in trauma showed no signs of hemorrhage.
On arrival, tetanus prophylaxis was administered to the patient. Triple antibiotic prophylaxis consisting of amoxicillin-potassium clavulanate 1.2 g, amikacin sulfate 500 mg, and metronidazole 100 mL were administered in the emergency department. A brief bedside irrigation with 6 L of sterile saline was given, and the wound site was dressed with moist gauze. The patient was then provisionally stabilized with a short leg splint and sent for preoperative imaging. Clinical image and preoperative radiographs are provided in Figures , , respectively. After imaging was completed, a trial closed manipulation failed as expected, as shown in Figure . The patient was operated under spinal anesthesia. Three liters of sterile saline was then used to irrigate the wound. Gross wound contaminants were removed. The patient underwent wound debridement with extensor digitorum longus tendon repair of the fourth digit, and internal fixation with K-wire fixation for the third and fourth digit was performed. Post-operative image is shown in Figure . The post-operative period went uneventful. The superficial and deep wound infection never occurred at any point of time. This included physical signs (erythema, malodor, gross purulence, etc.) and hematological signs (rising of white blood cell count, erythrocyte sedimentation rate, C-reactive protein etc.). Post-operatively, the patient stayed in the hospital for seven days for wound monitoring. Daily physical and occupational therapy was routinely performed by the patient. The surgical site healed well. Active toe movements of the first to fifth digits were present.
Hospital course
Post-operatively, the patient received intravenous amoxicillin-potassium clavulanate 1.2 g twice daily for seven days, amikacin sulfate 500 mg twice daily for five days, and metronidazole 100 ml thrice daily for three days followed by oral amoxicillin-potassium clavulanate 625 mg twice daily for seven days. Analgesics and anti-edema measures were given. Protein-rich supplements along with personal hygiene measures were provided. A below-knee slab and strict non-weight bearing ambulation for six weeks were recommended. The K-wires were removed after six weeks, and partial weight-bearing was started with the help of a walker. Full weight-bearing was permitted after six months. The patient was being followed up at regular intervals. The patient returned to his work with no limitations on the activity or complications after his final follow-up.


An 11-year-old female patient came to the orthodontic clinic concerned about her appearance. An extraoral examination showed the distinct posterior position of the mandible with the substantially turned up lower lip and deepened mentolabial sulcus. An intraoral examination and analysis of diagnostic models revealed a bilateral tendency to Angle's class II, increased overjet up to 8 mm (standard 2-3 mm), and slight crowding in the lower dental arch. The cephalometric analysis showed an ANB angle of 7.1° and a WITS of 6.8 mm. The incisors were positioned correctly, and the maxillary base angle suggests a harmonic growth. A Metzelder removable appliance was used to treat the patient.
During the one-year period of treatment with the Metzelder appliance, the progress in treatment was monitored, dentition replacement was supervised, and the appliance was adapted to constantly changing occlusal conditions.
During the treatment with the Metzelder functional appliance, a correction of the bone base position towards the skeletal class I is expected. The key measurements, in this case, are the ANB angle and the WITS. After one year of treatment, the ANB angle was reduced by 1°. The WITS measurement was improved by 2.7 mm. Although the results still indicate the skeletal class II, correction towards Angle's dental class I was observed. The position of incisors has not changed significantly, which suggests more dentoalveolar than skeletal changes.
To illustrate these changes, superimposition of lateral cephalograms along the anterior part of the cranial base was performed as it is proved to be reliable after the age of 6 by de Coster [], Ford [], and most recently by Afrand et al. []. Cephalometric radiograms taken before the treatment—in blue—and after one year of treatment—in red—were superimposed.
Based on the analysis of , a considerable vertical growth of the mandible and its slight anterior growth were observed. Since the growth of the mandibular ramus occurs mainly within the condylar process, it is concluded that the “backward” and “upward” growth of the process was observed in the treated patient. An important observation is also a change in the angle of inclination of the occlusal plane (this explains the improvement in the WITS value at the virtually unchanged ANB angle).
3D models of mandibular condyles were generated and compared using data from CBCT images (). According to the values in , there is a considerable increase in the volume of the processes, which can then be visualized in the CloudCompare software. The colorful map shown in was created by superimposition of solids of the right mandibular ramus (before and after one year of treatment) and the left mandibular ramus (before and after one year of treatment). Elements that were unchanged were marked in blue, while changes up to 2 mm were shown in red. Most of them were located on the upper and posterior part of the condylar process—this is confirmed by the conclusions drawn from the analysis of lateral cephalograms regarding the growth of this element. In this particular case, the change in shape of the condylar process and its growth definitely had a positive effect on the anteroposterior relations.


The case was a 56-year-old Chinese man with a 1-month soreness in the left waist that worsened in the last 2 days. On May 8, 2018, he was admitted to the hospital, while during hospital admission, the symptoms were not alleviated or treated. The patient had no family history of a malignant tumor. He was the administrator of a financial institution without any history of smoking and alcohol abuse.
Physical examination showed that the angles of bilateral ribs were symmetrical, and there was no protuberance in the bilateral kidney area. There was negative bilateral renal tenderness and discomfort in tapping. The tumor makers, routine urine, blood tests, and other relevant laboratory tests did not show any significant findings. The abdominal computed tomography (CT) scan revealed a circular mixed density of about 4.5 cm in diameter in the left kidney. CT value had a calcification margin of about 34 to 37 HU, shown in Fig. A. A CT-enhanced scan revealed a slight enhancement that is lower than that of the renal parenchyma (Fig. B–D). However, the distinction between the lesion and fatty tissue of the renal sinus was not clear (Fig. E–F). Surgical resection was advised when the diagnosis of a malignant tumor could not be avoided. Laparoscopic radical nephrectomy was performed on May 12, 2018, under general anesthesia.
Postoperative pathology (Fig. A) has shown that mitosis was normal in the differentiated mesenchymal areas (haematoxylin and eosin, HE, magnification = 400×). The results of immunohistochemical findings (Fig. B–H) were as follows: 34βE12 (Epithelium+, 200×), Bcl-2(+, 200×), CD99 (+, 200×), CK-pan((Epithelium+, 200×), EMA(Epithelium+, 200×), Ki-67(+60%, 200×), and Vimentin(+, 200×). Histopathological findings indicated an ultimate diagnosis of PRSS with necrosis. The patient was discharged 10 days after surgery (May 22, 2018) without any complications. He was advised to go in for further treatment at the Cancer Center. The patient was re-examined 3 months after surgery. An abdominal and pulmonary CT found no recurrence or metastasis. The patient was recommended to do a once-in-3-month review and long-term follow-up.


A 2-month-old baby girl was admitted to the hospital with recurrent laryngeal stridor and dyspnea lasting for more than 20 days. Before admission, she had undergone tracheal intubation for respiration support and received an anti-infective treatment from a local secondary level hospital. The patient’s dyspnea improved, but it was difficult to perform tracheal extubation. A computed tomography (CT) scan of the chest revealed pneumonia, consolidation in the right lung field, and a space occupying lesion in the thyroid. Due to difficulty of diagnosis and treatment at the local hospital, the patient was transferred to our first level hospital on Apr 28, 2019. The child was born at the second trimester with a gestational age of 41 + 3 weeks. Birth weight was 3.4 kg. The patient had no birth asphyxia, history of pathological jaundice, or any other family history of note. On physical examination after admission, heart rate was110–180 beats/min, blood pressure was67–104/38-61 mmHg, percutaneous oxygen saturation was95–98% (ventilator-supported breathing),no cervical or supraclavicular lymph nodes were palpated. The neck was symmetrical, without bulging in the anterior neck area; the overlying skin was not erythematous. The trachea was centered, the three depression signs of inspiration were observed, and coarse breath sounds without rales were noted on pulmonary auscultation. Laboratory investigations found that thyroid stimulating hormone (TSH) was 5.070uIU/mL (reference value 0.870–6.150uIU/mL), free triiodothyronine (FT3) was 4.700 pmol/L (reference value 3.800–6.000 pmol/L), free thyroxine (FT4)was13.900 pmol/L (referencevalue12.100–18.600 pmol/L),triiodothyronine(T3)was2.161 nmol/L (reference value1.34–2.70 nmol/L), thyroxine(T4)was97.4 nmol/L (reference value95 ~ 195 nmol/L), thyroglobulin antibody (TG-AB)was0.20Iu/ml (reference value was negative), thyroid peroxidase antibody(TPO-Ab)was12.1Iu/ml, alpha fetoprotein (AFP)was99.16μg/L (reference value was lessthan25ug/L), chorionic gonadotropinβ(B-HCG) was <1.20mIU/ml (reference value 0 ~ 3mIU/ml),ferritin (Fer) was 204.80μg/L (reference value194-238μg/L), specific neuronal enolase (NSE) was 150.50 ng/ml (reference value< 16.3 ng/ml). Arterial blood gas: PH 7.32,PCO2 43 mmHg,PO2 58 mmHg,P/F (PaO2/FiO2) 193 mmHg.An ultrasound scan of the thyroid (Fig. ) revealed a hypoechoic lesion measuring 3.6 × 1.7 × 4.8 cm in diameter at the lower pole of the bilateral thyroid with an abundant blood supply. The boundary was clear, and a chord-like hyperechoic lesion was observed inside. The remaining thyroid gland showed a regular morphology, with a complete capsule and an even internal echo. The nature of the hypoechoic lesions remains to be determined. CT scanning of the thyroid with and without contrast (Fig. ) revealed that the thyroid gland was enlarged and a part of the left lobe had stretched into the superior mediastinum. The thyroid parenchymal enhancement was inhomogeneous with multiple nodules. Chest CT revealed inflammation in the lower lobe of the left lung. No abnormality was found in abdominal ultrasound and cardiac ultrasound. The patient was given anti-infection treatment for pneumonia for 14 days after admission, pneumonia improved, however, an attempt to wean the patient off the invasive ventilator failed again (Arterial blood gas analysis under non-invasive ventilator assistance: PH 7.21,PCO2 74 mmHg,PO2 66 mmHg,P/F 165 mmHg). A multidisciplinary discussion led to a decision on surgical treatment. After completing the preoperative examination, the child underwent a total resection of the left thyroid gland and mass on May 8th.The size of the left thyroid and mass was about 3.0 × 3.0 × 1.0 cm.
Postoperative heart rate was 110–160 times/min, blood pressure was 67–89/38-53 mmHg, percutaneous oxygen saturation was 98–100%.Based on a postoperative pathological examination, infantile thyroid capillary hemangioma was diagnosed (Fig. ). Then propranolol was administered orally (2.5 mg tid). There were no side effects of bradycardia, hypoglycemia, bronchospasm, or hyperkalemia during medication. A postoperative review showed that the thyroid function was normal, No recurrence of hemangioma was found by thyroid ultrasound (Fig. ), the child’s respiration was smooth, and there was no laryngeal ringing after she was weaned from the ventilator 6 days after the operation. Arterial blood gas analysis after extubation: PH 7.38, PCO2 44 mmHg, PO2 176 mmHg,P/F 606 mmHg. The patient only had a small amount of hoarseness and low voice tone after stitch removal and extubation, possibly due to damage of the recurrent laryngeal nerve during the operation. The baby was discharged from hospital on May 20. During the subsequent six-month follow-up, the thyroid function remained normal and the tumor gradually shrank without recurrence; the hoarseness and low voice tone have also improved.


A 37-year-old African-American female presented to the emergency department (ED) complaining of abdominal pain, nausea, vomiting, diaphoresis, chills, and burning with urination. The patient stated she had dysuria and “bubbles in her urine”. She also stated that the pain was 10 (on a scale of 1-10) and described the quality as “crampy”. The patient had a past medical history of diabetes mellitus, gastritis, hypertension, and kidney stone. She also had a past surgical history of a Caesarian section. Additionally, the patient was a regular cigarette smoker, marijuana user, and alcohol drinker.
Physical exam revealed a blood pressure of 173/80 mmHg, a body temperature of 36.6 degrees Celsius, a respiratory rate of 20/min, and a pulse rate of 100/min. The patient was six feet tall and weighed 125 pounds; this was a significant decrease from her weight of 187 pounds less than eight months ago.
Urine analysis was performed, which revealed hematuria, bacteria, and an elevated leukocyte esterase; this suggested a possible urinary tract infection. Complete cell count revealed a white blood cell (WBC) count of 8.0 cells/mcL, hemoglobin of 15.6 gm/DL, red blood cell (RBC) count of 4.28 cells/mcL, and platelet count of 214,000 cells/mcL. The basic metabolic profile revealed a low potassium level of 3.3mMol/L, and an elevated glucose level at 392 mg/dL with an anion gap of 15.
An abdominal X-ray was performed to evaluate ileus or obstruction, and it revealed curvilinear lucencies in the pelvis (Figure ). Computed tomography (CT) scan was recommended to evaluate for EC. A CT scan of the pelvis and abdomen without contrast indicated that the patient had abnormal bladder wall thickening that contained air (Figure ). The diagnosis of acute emphysematous cystitis was made after these multiple indications.
The patient was started on intravenous fluid hydration and admitted to the hospital. The patient was started on vancomycin, cefepime, metronidazole, and a foley catheter was recommended but refused by the patient. A urine culture was ordered to determine the pathogen and the appropriate antibiotic regimen. However, the patient left against medical advice prior to the results.


A 6.6-year-old boy, who sustained an electric cautery circumcision-related penile injury, was transferred from the urology department to the burns and plastic surgery department 10 days after injury. The defect area measured 1.5 × 2.5 cm. After debridement, a thick STSG was performed (
).


A 12.5-year-old boy, who suffered a traffic accident-related penile injury, received primary suturing at another hospital. The penile skin necrosis area measured 2.2 × 3.1 cm, and the left thigh necrosis skin area measured 38 × 15 cm. He was transferred to our department 10 days after injury, and he received debridement and an artificial dermis implant (acellular dermal matrix) during the primary surgery. After 14 days, the acellular dermal matrix was removed, and a 0.2-mm STSG was placed on the granulation tissue wound (
).
This STSG was harvested from the scalp using a Zimmer electric dermatome. The donor site was covered with antibiotic dressing and healed naturally after 2 weeks. The penile dressing and the catheter were removed 7 days after STSG placement.
A Foley catheter was inserted and retained throughout the treatment. We used the dressing for hypospadias surgery as a reference to design the skin graft dressing. On the inner side, a mesh-like lipid hydrogel dressing (UrgoTul, Laboratories URGO, France) was evenly applied to the grafted skin so as to form a moderately tight sheath and to avoid dressing adhesion. An antibiotic ointment (mupirocin) was applied to the second layer, and the outer layer was wrapped with an elastic dressing. The graft was applied tightly to the wound surface, and the absence of dissolution or scabbing was considered to indicate good skin graft survival. The Vancouver scar scale (VSS; Baryza and Baryza, 1995) was used to evaluate the scar quality in all patients. The scale consists of the following variables: vascularity, pliability, height, and pigmentation (
).
The three thick STSGs survived completely, with no signs of dissolution or scabbing (
,
, and
). The FTSG survived almost completely, with a small area of skin necrosis healing remaining after the dressing was changed (
). The 12.5-year-old boy gradually developed lymphedema of the distal foreskin (
), and he received prepuce plastic surgery 6 months after skin grafting (
). He reported that he could achieve an erection and experienced no pain during urination. All patients were able to urinate easily. The VSS scores of these four patients are presented in
. Scar vascularity and pliability in all four patients were close to those of normal skin. The scars after STSG were hypopigmented and flat, whereas the scar after the FTSG was hyperpigmented, showing slight hyperplasia (< 2 mm). All parents were satisfied with the appearance and function of the penis.


A 45-year-old male, from the Midwestern region of Nepal, presented in the emergency with the weakness of bilateral upper and lower limb for 4 months. He gave a history of fall from the tree (approximately 20 m height) and sustained injury over the neck and managed by the nearby hospital conservatively but he gradually developed weakness. On neurological examination, he had American Spinal Injury Association Impairment Scale (ASIA-C) neurology. Preoperative CT-Scan (A) shows the fracture of 7thcervical vertebrae with bilateral facet dislocation at the C6-C7 level and Magnetic Resonance Imaging (MRI) shows significant cord compression (B). He was diagnosed as a neglected fracture-dislocation of the C6-7 level with ASIA-C neurology. The patient admitted and kept on skull traction for one week but the reduction could not be achieved.
Anterior decompression by partial corpectomy of C7 vertebrae, posterior reduction by partial facetectomy, stabilization, and fusion by using lateral mass screws and bone graft, anterior cervical fusion by using a mesh cage, cancellous bone graft, and anterior cervical plating was done by combined Anterior-Posterior-Anterior (APA) approach. Immediately after surgery neurology was deteriorated to ASIA-B. Postoperative CT-Scan (C) confirmed the adequate decompression and proper placement of hardwires. The patient was followed up to 6 months at a monthly interval and found that neurology was gradually recovered to normal by the end of three months.


A 59-year-old male, from the western region of Nepal, presented in the emergency with complain of pain and stiffness of neck and weakness of bilateral upper and lower limbs for 3 months. He had a history of falls from the tree and sustained neck injury 3 months back followed by the gradual development of weakness. On examination, he had ASIA-C neurology and a decreased neck range of motion. Pre-operative X-ray (Figure-2A) shows bilateral facet dislocation at the C6-C7 level and MRI (B) shows significant cord compression at the same level. He was diagnosed as a neglected bilateral facet dislocation of the C6-7 level with ASIA-C neurology. The patient was admitted and kept on skull traction for 1 week and operated by the APA approach. Anterior cervical decompression, posterior reduction, stabilization and fusion, anterior cervical fusion by using tri-cortical iliac crest bone graft, and anterior cervical plating was done (C). The patient developed acute renal failure postoperatively, which was managed by the nephrology team. Follow up was done at a monthly interval, by the end of 6 months, neurology was improved to ASIA-D with some myelopathic changes (Japanese Orthopedics Association Score = 15).


A seventy-six years old lady presented to our Emergency Department with complaints of progressive worsening of headache eleven days in duration and acute onset of several episodes of vomiting since the past two days. She was referred from another center where she was treated symptomatically with no relief of either pain or vomiting. She reported no weakness or numbness of upper and lower limbs. There was no history of fever, abnormal body movements and loss of consciousness. She reported decreased appetite and alteration of sleep habit. She did not give any history of recent trauma or falls. She however gave a history of head surgery 20 years back for a subdural hematoma that she had due to a fall and a leg fracture 7 years ago which was fixed with plates. An interesting revelation was that the patient had remained unconscious for three months following her previous surgery for SDH evacuation.
On examination, she was ill-looking. Her vitals were normal. Cardiovascular, respiratory and abdominal examination were normal with a blood pressure of 140/80 mm Hg , pulse rate of 80 beats per minute, a respiratory rate of 20 breaths per minute and oxygen saturation (Sp02) of 98%. She was afebrile, conscious with a Glasgow Coma Scale of 15 and normal neurologic exam, including that of cranial nerves. Tone, power and reflexes were normal in both upper as well as lower limbs. Sensations to all four limbs were also preserved. Palpation of spine revealed no tenderness or steps.
Initial laboratory investigations including random blood glucose, hematological profile including that of clotting, liver and renal function tests and other basic tests were normal. A non-contrast CT scan of the head was ordered in the ER which revealed a small hyperdense area surrounded by hypodense areas indicating acute on chronic, right subdural hematoma with a small acute bleed around the temporal lobe and a chronic bleed around the temporoparietal region. The CT also showed a massive hypodense area indicating a large subdural hematoma on the left temporoparietal region, with a very slight midline shift to the right, to go along with a previous burr hole mark on the left temporal bone ().
A neurosurgical referral was made. She was monitored intensively and treated conservatively with no improvement of her symptoms. Surgery was then planned. A left parietal burr-hole craniostomy was done under local anaesthesia, the following day with aspiration of “machinery-oil” blood under pressure. The headache resolved. The next day after the surgery, the patient complained of headache on the side opposite to which the procedure was performed. The patient was closely monitored in the neurosurgical Intensive Care Unit. After the pain persisted for a day more, a repeat head CT was ordered. It revealed isodense to slightly hyperdense areas in the right temporo-parietal region with a slight midline shift to the left ().
A right parietal burr-hole craniostomy was performed under local anaesthesia which led to aspiration of dark brown blood under pressure. A repeat CT of the head showed resolution of the hematoma ().
Three days after the second procedure, the patient complained of frontal headache and nausea. The patient was febrile as well. Repeat CT showed a large bi-frontal pneumocephalus ().
A chest radiograph showed bilateral infiltrates. These problems were managed medically with high flow oxygen therapy and intravenous antibiotics and the patient recovered eventually (). She was discharged after 13 days of in-hospital stay.


A 28 years old primigravida at 40 weeks 1 day of gestation was admitted with a diagnosis of false labour pain and labour induced the next day. She underwent emergency LSCS for non-progress of labour and delivered a live male baby weighing 4.3kg. She had received intravenous Cefazoline 1 gm first dose preoperatively and 3 doses thereafter 8 hourly, intravenous Metronidazole 2gm single dose postoperatively, prophylactically as per hospital protocol. Her intraoperative period was uneventful. She was perfectly alright till 2nd postoperative day.
On 3rd postoperative day she developed fever. Initially it was low grade later on it became high grade (up to 104°F). On her 4th postoperative day, blood, urine, high vaginal swab culture tests were sent. Her total count was 20,600 with 91% neutrophil. Then she was given intravenous ceftriaxone 2gm once a day and an antipyretic. On 5th postoperative day, despite of medications, she continued to have high grade fever. She developed pustular rashes on her neck which progressed to the trunk, abdomen, back and upper thigh with burning sensation().
Dermatology and medicine consultation were done. Intravenous Ceftriaxone was stopped and Tab. Cefadroxil 500mg twice a day; Tab. Loratidine 10mg once at night; Fusidic acid 2% + Betamethasone Valerate 0.1% cream were started. On 6th postoperative day she developed hypotension, tachycardia and tachypnea along with generalized pustular exanthematous rashes and high grade fever. Injection Hydrocortisone 100mg was added. All the above mentioned drugs were held. Same day at the evening, she suddenly developed shortness of breath with increasing tachycardia, hypotension and tachypnea. On auscultation, crepitations were heard over bilateral basal areas. She was shifted to ICU. Femoral venous line was inserted and was kept under continuous positive airway pressure (CPAP). Also ionotropes, subcutaneous Enoxaparin Sodium 40mg once a day and Intravenous clindamycin 600mg 8 hourly were started. On 7th postoperative day, her total count raised to 30,400 along with deranged LFT reports. Dermatology consultation was done again. Provisional diagnosis of Toxic Epidermal Necrolysis with drug induced fever and lukemoid reaction was made. All antibiotics were stopped and intravenous Dexamethasone 8 mg once a day, Vancomycin 500 mg twice a day and Thiamine 200 mg twice a day were started.
On the next day patient improved dramatically and became afebrile. Skin rashes started to desquamate (Fig. 2) along with a decrease in burning sensation. On 9th postoperative day all symptoms improved and ionotropes was stopped. Her pus culture, urine culture and blood culture reports were sterile. Tab. Prednisolone 40 mg once a day was started and injection vancomycin was continued. She was shifted to ward on her 13th postoperative day. Later on, the patient developed wound infection and wound debridement and re-suturing were done. She recovered completely and was discharged on 25th postoperative day.


A 51-year-old woman presented to our Emergency Department with acute severe abdominal pain, nausea, vomiting, sudden-onset of bilateral leg weakness with diffuse sensory loss, and paresthesias on the trunk and legs. After 1 hour, she developed chest tightness with acute urinary retention requiring catheterization. Sensorimotor disturbances reached a plateau after 6 hours. On neurological examination, she showed severe paraparesis and a D6 sensory level. Deep tendon reflexes were absent in the lower limbs and the plantar response was silent bilaterally. Abdominal reflexes were absent. Light touch, pinprick, temperature, and position sense were decreased in the trunk and lower limbs circumferentially.
The patient denied recent traumatic injuries, strenuous physical exertion, or Valsalva maneuver before symptom onset, scuba diving, exposure to radiation or toxic substances, recent infections, and vaccinations. She had a negative history of hypertension, diabetes, smoke, drug abuse, hypercholesterolemia, heart arrhythmias, and recent cardiac or aortic surgery interventions.
In the Emergency Department, complete blood count, coagulation tests, and comprehensive metabolic panel were within normal limits; toxicological screening was negative for recent drug abuse. EKG showed normal sinus rhythm. An aortic computed tomography angiography showed no sign of acute aortic/artery dissection. A 3T spinal cord MRI with gadolinium, ADC maps, and DWI performed at 9 hours after symptom onset did not detect spinal cord alterations. Neuroimaging ruled out the possibilities of disc extrusion, spinal tumors, arachnoiditis, or arteriovenous shunts. Brain MRI was unremarkable. Cerebral spinal fluid (CSF) analysis yielded normal opening pressure, white cell count (3 cells/mL), protein (32 mg/dL), and glucose levels (67 mg/dL). CSF was negative for comprehensive viral Polymerase Chain Reaction panel, bacterial culture, cytology, and oligoclonal bands.
The patient was admitted to our Neurology Unit and she developed paresthesia and weakness in her left hand and forearm and an ipsilateral Horner's syndrome (ptosis, enophthalmos, and miosis).
Due to the persistence of a clinical picture suggestive of an acute myelopathy, a 3T MRI of the spine was repeated after 72 hours. MRI showed a hyperintense “pencil-like” signal mainly involving the grey matter from T1 to T6 on T2 sequence, mildly hypointense on T1, and with restricted diffusion. The spinal cord showed a mild tumefaction; vertebral marrows from C7 to T4 were hyperintense on T2, presented gadolinium enhancement on post-contrast T1 and restricted diffusion (Fig. ).
Serologic screening for syphilis, human T-lymphotropic virus 1, varicella-zoster virus, HIV, aquaporin-4, and myelin oligodendrocyte glycoprotein antibodies resulted negative. Other unremarkable blood tests included serum protein electrophoresis, angiotensin-converting enzyme, copper levels, vitamin B12, and erythrocyte sedimentation rate. Analysis of inherited and acquired prothrombotic states comprehensive of antiphospholipid antibodies was negative. Cancer and systemic vasculitis were ruled out by appropriate diagnostic workup. Visual evoked potentials were normal bilaterally.
On the first day of admission, empirical treatment with intravenous acyclovir (10 mg/kg 3 times daily), dexamethasone (8 mg twice daily), and salicylic acid (100 mg/d) was started. We suspended corticosteroid and antiviral therapy once infectious and inflammatory causes were ruled out. In addition, the patient was given prophylactic low-molecular-weight heparin and began neuromotor rehabilitation.
Two months later, a follow-up neurological examination revealed a severe spastic paraparesis, no evident sensory level, and poor sphincteric control with distended bladder.


A 14-year-old male patient, referred to a referral hospital service in Curitiba City,
Paraná State, Brazil, for investigation. He was born at 38 weeks, weighing 3,500 g,
measuring 52 cm, and head circumference not informed. Mother denied consanguinity.
The child sustained his head at 4 months old, sat without support at 6, crawled at
9, walked at 1 year and 4 months old and spoke at 2 years old. Until then, the
patient had an appropriate development for his age.
The earliest sign of developmental change was speech regression, which started after
2 years of age. Speech was completely lost at 3 years and 6 months old. During this
period, frequent falls occurred, and the worsening of balance was progressive. The
loss of balance became more constant, making mobility very difficult.
Subsequently, the patient presented psychomotor agitation, hyperactivity, insomnia,
and loss of urinary and anal sphincter control. He evolved with a progressive
worsening of behavior, with crises of psychomotor agitation increasingly serious and
frequent, accompanied by obstinacy, periods of aggression, restlessness and a rapid
decrease in attentional capacity. It demonstrated stereotypes, such as cutting paper
and hitting cans over and over again. At 7 years of age, he presented coprophagia
and spread feces on his own body. He was diagnosed with ASD at the age of 6 and, at
the age of 8, he started to be monitored in a special school. He was administered
risperidone, amitriptyline, clonazepam, fluoxetine and periciazine, but with no
adequate response. At the special school, he attended occupational therapy and
speech therapy, both of which were unsuccessful.
At the beginning of the case, despite the falls, he was able to walk with the aid of
crutches, but at 12 years and 11 months old he suffered a complete loss of function.
There was also a decrease in his swallowing capacity, until the point in which he
needed assistance from a nasogastric tube for nutrition. At the age of 13,
gastrostomy was inserted to give him food. As his condition evolved, the behaviors
of hyperactivity and aggressiveness decreased, with a gradual and progressive
transition to drowsiness since the age of 9, and the intense drowsiness occurred
around 12 years of age.
In the previous morbid history, there are reports of recurrent respiratory tract
infections. However, there is no history of fainting or seizures, nor a family
history of genetic, neurological, psychiatric or cardiovascular diseases.
On the physical examination, his weight was 25 kg (Z score: -3.81), his height, 125
cm (Z score: -4.05), body mass index of 16 (Z score: -1.26) and head circumference
of 53 cm (Z score: -1.33); coarse facial features, saddle nose, thick lips,
sinophris, short neck, macroglossia, prominent forehead, dry and thinning hair; and
osteotendinous reflexes 3+/4+, claw hands, spasticity in lower limbs and joint
stiffness. Ophthalmological examination as normal, extrinsic eye movement apparently
preserved, with bilateral positive red reflex, fundoscopy/retinal mapping without
abnormalities.
Magnetic resonance imaging of the skull showed slight dilation of the lateral
ventricles and the third ventricle, with diffuse thickening of the diploe and
volumetric decrease in the cerebral hemispheres. Magnetic resonance imaging of the
total spine showed an inversion of the physiological cervical curvature, diffuse
morphostructural alteration of the vertebral bodies and wedging of their plateaus,
promoting the radiological aspect of the bullet-shaped vertebra. Diffuse disc
dehydration associated with a slight reduction in intervertebral spaces and small
intrasomatic disc herniations (Schmorl’s nodules) of chronic aspect in the
contiguous plateaus.
The echocardiogram identified hypertrophic cardiomyopathy, with significant left
ventricular hypertrophy and moderate diastolic dysfunction, mild double aortic
lesion and moderate aortic insufficiency. The electrocardiogram showed left
ventricular overload. Abdominal ultrasound revealed liver with normal contours,
regular echogenicity, and echotexture, but enlarged dimensions.
The patient had increased urinary glycosaminoglycan excretion, with elimination of
heparan sulfate. Laboratory tests showed glycosaminoglycans=127 µg/mg creatinine
(reference value 44-106). The diagnosis was confirmed by evidence of deficiency of
the alpha-N-acetylglucosaminidase enzyme. Laboratory tests showed:
N-acetyl-glucosaminidase dosage: not detected (reference
value=10-34). Acetyl-CoA glucosamine-N-acetyltransferase: 11 nmol/17 h/mg protein
(reference value=14-81).


A 45-year-old woman, farmer by occupation, presented to our center with fever, swollen lymph nodes in the neck, and painful rash in the lower extremities. She was apparently well until before 15 days when she developed a fever and sore throat followed by a painful rash on her legs three days later. She visited a primary care center where she was prescribed a seven-day course of intramuscular ceftriaxone with a provisional diagnosis of streptococcal pharyngitis, which resolved the sore throat and fever but not the rash. When her fever relapsed several days later, this time accompanied by swelling of cervical nodes, the patient was referred to Nork Infectious Clinical Hospital in Yerevan for further evaluation and management. At presentation, her blood pressure was measured 115/70 mmHg, the temperature was 102˚F, pulse rate was 102 beats per minute, and the respiratory rate was 18 per minute. General examination revealed few enlarged tender cervical nodes on the left side of her neck and multiple red, firm, and tender lump-like rash (erythema nodosum) on both her legs (Figure ).
Systemic examination was unremarkable. Blood workup revealed leukocytosis with relative lymphocytosis, raised erythrocyte sedimentation rate of 55 mm per hour, and C-reactive protein of 35 mg/L. We admitted her for a thorough evaluation. Serology for Streptococcus, Epstein-Barr virus, HIV, hepatitis B and C virus, Cytomegalovirus, Brucella, and leptospirosis were all negative. With unremarkable chest X ray and negative tuberculin test, we also eliminated sarcoidosis and tuberculosis as possible infectious causes of the erythema nodosum. She was diagnosed with tularemia based on latex agglutination testing, which came positive. A 14-day course of intramuscular streptomycin two grams daily divided into two doses was prescribed. Five days into treatment, the patient’s fever subsided, the buboes shrank, and the erythema nodosum resolved. The patient was discharged on the eighth day of admission with subsequent follow-up. Potentially exposed persons, particularly the family members, were advised to be vigilant about the symptoms, especially the development of fever for two weeks. They were informed about the water and food hygiene, which might have been the possible source of infection. The incidence was reported to the local health authority as a part of the standard protocol. The patient was doing better on the follow-up visit at three weeks with complete resolution of symptoms and return to a normal routine.


A 33-year-old male, on hemodialysis for 4 years, was admitted to our institution for kidney transplantation from a brain-dead 33-year-old male donor. The donor was involved in a road traffic accident. The recipient's primary disease was focal segmental glomerulosclerosis (FSGS), and he also had hypertension. He had undergone living donor kidney transplantation from his brother in the right iliac fossa 11 years ago. His postoperative course after the living donor kidney transplantation was marked by angioplasty for renal artery stenosis and sessions of plasmapheresis for suspected recurrent FSGS. There was no history of hematuria or urinary tract infections. A micturating cystourethrogram (MCUG) showed a grade 2 reflux into the failed allograft. The deceased donor kidney transplantation into the left iliac fossa went uneventfully. The cold ischemia time was 8 hours, and the warm ischemia time was 22 minutes. During the transplantation, the bladder was found to have multiple small polypoid lesions which were biopsied. The histopathology showed features of NA (). The patient has been under follow-up for five years with a functional graft. He has no urinary symptoms. Recent cystoscopy revealed mucosal polypoid lesions () which histologically showed features of NA. There were no signs of malignancy.


A 61-year-old male, previously well, was diagnosed with localized ileocaecal adenocarcinoma in September 2016 after presenting with a positive faecal immunochemical test on routine screening. He underwent a right hemicolectomy in December 2016, and the 15 dissected lymph nodes did not reveal metastatic involvement. He did not require adjuvant chemotherapy or radiation and was deemed in remission. The resected bowel included a portion of small bowel that incidentally demonstrated pathological changes consistent with coeliac disease; however, he was negative for anti-tissue transglutaminase antibodies with a normal immunoglobulin (Ig) A level. He underwent an oesophagogastroduodenoscopy that revealed duodenal inflammation and ulceration, villous atrophy, and intraepithelial lymphocytes, consistent with coeliac disease. He commenced a gluten-free diet.
He was well until August 2017, when he was referred to our Respirology Department with a four-month history of fever, productive cough, and intermittent haemoptysis despite four courses of antibiotics. HRCT revealed a 5-cm dominant right lower lobe cavitary lesion, multifocal consolidation, and nodular infiltrates (Fig. ). He underwent a bronchoscopy with radial endobronchial ultrasound-guided transbronchial biopsies (TBBs) and one computed tomography (CT)-guided transthoracic biopsy (TTB) of the mass. TBB revealed acute inflammation and TTB revealed organizing fibrous plugs with inflammatory cells, consistent with OP (Fig. ). All biopsies, lymph node aspirates, bronchoalveolar lavages, and washes were negative for malignancy, granulomas, vasculitis, or infection, including Ziehl–Neelsen stains for acid-fast bacilli and mycobacterial culture. Autoimmune serology was negative. He was started on prednisone 50 mg daily in October 2017, and due to symptomatic improvement and undesirable side effects such as insomnia, a taper was commenced after seven weeks on this dose. Unfortunately, in December 2017, he developed worsening cough, dyspnoea, and haemoptysis while on prednisone 20 mg daily. Repeat CT in December 2017 demonstrated improvement in multifocal consolidation and nodular infiltrates, and minimal change in the dominant right lower lobe lesion (Fig. ). He underwent a bronchoscopy with biopsy of a mucosal lesion that demonstrated acute and chronic inflammation with small areas of necrotic debris. He was assessed for a surgical lung biopsy; however, the depth of the lesion would have required a large resection and this was thought not warranted given three prior biopsies with similar histological findings. Ultimately, he restarted prednisone 50 mg in January 2018. A post-mortem review of the mucosal biopsy revealed atypical CD8+ lymphocytes with some phenotypic aberrations, suggestive of but insufficient for a diagnosis of malignancy.
In February 2018, despite being on a proton pump inhibitor, the patient was admitted with a massive upper gastrointestinal bleed. He underwent three more oesophagogastroduodenoscopies in one month with biopsies of duodenal ulcers, the pathological examination of which showed findings similar to previous, but now with a T-cell population with aberrant phenotype. This was thought to be consistent with refractory coeliac disease type II (RCDII).
He subsequently developed fevers, splenomegaly, pancytopenia, hypertriglyceridaemia, and marked hyperferritinaemia that peaked at 14,957 μg/L (normal: 12–300 μg/L). Bone marrow biopsy showed evidence of haemophagocytosis and a monoclonal T-cell population not conclusively diagnostic of T-cell lymphoma. Positron emission tomography/CT did not demonstrate definitive evidence of malignancy. He was discharged after a one-month hospitalization with haematology follow-up, but was re-admitted three months later with ongoing fevers, significant constitutional symptoms, and persistent features of haemophagocytic lymphohistiocytosis (HLH). He was started on etoposide for treatment of HLH, and repeat bone marrow biopsies were consistent with T-cell lymphoma, likely EATL given his clinical history. Unfortunately, he continued to decline and became too unwell for chemotherapy, and passed away in the critical care unit.


A 6-year-old boy, fully immunized for age, was referred to us from a general hospital due to a palpable purpuric skin rash with trouser-like distribution, arthralgias, abdominal pain, and bloody stools. He was afebrile and with the exception of moderate leukocytosis (leukocytes 23,610 μL), mild thrombocytosis (platelets 414,000 μL), and slightly elevated CRP (1.32 mg/dL, normal <0.5), he had normal hemoglobin, 13.7 g/dL; hematocrit, 38.5%; urea, 11 mg/dL; creatinine, 0.4 mg/dL; sodium, 136 mmol/L; potassium, 3.5 mmol/L; AST, 38 U/L; ALT, 31 U/L; prothrombin time (PT), 12.9 sec; activated partial thromboplastin time (aPTT), 24.4 sec; fibrinogen, 312 mg/dL; IgG, 924 mg/dL; IgA, 190 mg/dL; IgM, 102 mg/dL; C3, 138 mg/dL; C4, 29.1 mg/dL; and negative antinuclear antibodies (ANA). Microscopic stool examination demonstrated 50–70 erythrocytes per HPF.


An afebrile 3-year-old girl, fully immunized for age, was admitted because of typical IgA vasculitis with purpuric skin rash over the lower extremities. Fewer purpuric lesions were also found on both forearms. In addition, her ankles and elbows were edematous and slightly erythematous, while she had intense abdominal pain and bloody stools. Baseline laboratory studies showed leukocytes, 18,110 μL; hemoglobin, 13.4 g/dL; hematocrit, 39.4%; platelets, 451,000 μL; CRP, 4.7 mg/dL; urea, 24 mg/dL; creatinine, 0.4 mg/dL; sodium, 133 mmoL/L; potassium, 4.5 mmol/L; AST, 26 U/L; ALT, 11 U/L; PT, 14.4 sec; aPTT, 26.9 sec; fibrinogen, 381 mg/dL; IgG, 891 mg/dL; IgA, 210 mg/dL; IgM, 71.4 mg/dL; C3, 125 mg/dL; C4, 33.7 mg/dL; and negative ANA.
In both children, meticulous and repeated physical examinations and abdominal ultrasounds ruled out intussusception, while repeated urinalyses were negative for hematuria and substantial proteinuria. No child was subjected to skin biopsy for immunofluorescence in order to demonstrate dermal IgA staining because their skin lesions were very typical of IgA vasculitis, i.e., both had palpable purpuric rash with typical trouser-like distribution.
In the first child, methylprednisolone was started intravenously at 0.5 mg/kg twice daily. After a period of two days with no symptoms, recurrent and severe abdominal pain occurred to the point that the child was unable to sleep at nighttime without waking up with stabbing periumbilical pain. On the 8th day of hospitalization, he received a single infusion of IVIg at 1 g/kg over 8 hours. He tolerated treatment well. Within a few hours after the administration of IVIg, he had no further recurrences of abdominal pain, which allowed us to gradually taper and finally discontinue the corticosteroids on the 14th day of hospitalization.
The second child initially received intravenous methylprednisolone at 0.5 mg/kg twice daily, while she continued to develop new skin lesions on both shins. Despite the normalization of her bowel movements, on the 9th day of hospitalization due to intractable abdominal pain, she received a single infusion of IVIg at 1 g/kg over 8 hours. After the administration of IVIg, the abdominal pain was relieved within less than a day, and methylprednisolone was gradually tapered and finally discontinued on the 14th day of hospitalization.
Both children were discharged home one day after the discontinuation of corticosteroids, with resolving skin rash and instructions for repeated urinalyses at regular intervals to check for hematuria. They remain asymptomatic, six and four months, respectively, after the described events.


We report the case of a 31-year-old nulliparous woman diagnosed with stage 1C ovarian cancer in 2019. She initially presented with bilateral complex ovarian cysts and a significantly elevated cancer antigen 125 (CA-125) of 526 U/mL. She underwent bilateral laparoscopic ovarian cystectomies with pathology significant for endometroid ovarian carcinoma arising in bilateral endometrioid borderline tumors. Her medical history was unremarkable except for daily tobacco use (two cigarettes per day). The patient was counseled for bilateral salpingo-oophorectomy, lymphadenectomy, and omentectomy followed by three cycles of carboplatin/paclitaxel. Testing for Lynch Syndrome was pending at the time of consultation for fertility preservation, but eventually returned negative.
Evaluation revealed an anti-mullerian hormone (AMH) level of 0.39 ng/mL and an antral follicle count of 3 by ultrasound, along with moderate free fluid due to recent bilateral ovarian cystectomy. Her 34-year-old partner’s semen analysis was poor with a low concentration (4.7 million/mL), low motility (16%), and no morphologically normal sperm (0%). He was referred to urology for further evaluation, which is ongoing.
She then underwent three cycles of controlled ovarian stimulation spanning 42 days. Her first cycle began just 3 weeks after bilateral ovarian cystectomy as a random start in the luteal phase; a gonadotropin-releasing hormone antagonist (GnRH-antagonist) protocol was utilized with 450 units of gonadotropins per day []. Letrozole (aromatase antagonist, 5 mg) was prescribed due to theoretical concern for estrogen receptors in her gynecologic cancer, but was discontinued after five days due to side effects. She was stimulated for eleven days, reached a peak estradiol (E2) of 261 pg/mL, and triggered with human chorionic gonadotropin (hCG) once two lead follicles reached a diameter of at least 18 mm. One metaphase II (MII) oocyte was retrieved, fertilized by intracytoplasmic sperm injection (ICSI), and frozen at the two pro-nuclear (2PN) stage.
Her second cycle with the same protocol was initiated six days after retrieval; following nine days of stimulation and a peak E2 of 2072 pg/mL, eight oocytes (6 MII) were retrieved, and three fertilized and were frozen at the 2PN stage. An immature oocyte (MI) underwent in vitro maturation (IVM) overnight, fertilized, and was frozen as a 2PN. Immature oocytes that did not respond to in vitro maturation were not cryopreserved. Her third cycle was initiated six days after her second retrieval. After ten days of stimulation with a peak estradiol of 1543 pg/mL, seven oocytes (6 MII) were retrieved with four fertilized and frozen as 2PNs. The six day interval between stimulations was due to the patient’s schedule, including other medical appointments.
With multiple embryos cryopreserved, she underwent a laparoscopic bilateral salpingo-oophorectomy, lymph node dissection, and omentectomy with pathology significant for a small residual focus of endometrioid borderline tumor. The patient declined chemotherapy and is being monitored with frequent laboratory testing and imaging. She has been advised by her gynecologic oncologist to wait at least one year after definitive surgery prior to embryo transfer.


A 53-year-old African American female with a past psychiatric history of schizoaffective disorder, bipolar subtype, amphetamine use disorder, cannabis use disorder and multiple involuntary psychiatric hospitalizations, was admitted to the behavioral health unit on an involuntary legal hold after making grandiose and bizarre statements, and being no longer able to appropriately utilize food, clothing and shelter. Her home medications (daily dose) on admission were valproic acid 1,000 milligrams (mg), fluphenazine 20 mg, magnesium oxide 400 mg for migraine prophylaxis, diazepam 15 mg, diphenhydramine 50 mg, and trazodone 100 mg for insomnia. Past medical history was significant for conservatively managed hypertension, hypercholesterolemia, and diverticulosis. She has no known allergies to medications.
During week one of hospitalization, the patient's fluphenazine was replaced with olanzapine 30 mg due to persistent psychosis. Valproic acid was increased to 1,500 mg due to unstable mood and a sub-therapeutic serum level of 36 L (μg/ml). During week four of hospitalization the patient's psychosis remained refractory and clozapine titration was initiated while tapering off olanzapine. Complete blood count (CBC) was monitored closely during initial clozapine titration, with no signs of blood dyscrasias through day 9 of titration. On day 11 of clozapine titration (dose: 250 mg daily) the patient acutely developed sepsis like symptoms. The patient complained of chills and chest pain. The patient had a fever of 38.9°C; systolic and diastolic blood pressures ranging in the 90's and 60's respectively [mmHg]; tachycardia (140–160 beats per minute); tachypnea (up to 29 respirations per minute); and oxygen saturation on room air of 80%. On physical exam the appeared patient appeared diaphoretic, lungs were clear to auscultation, no abnormal heart sounds were heard, and no muscular rigidity, dystonia or other dyskinesias were present. Neurologic physical exam was grossly normal, no mental status change (patients orientation was unchanged from baseline psychosis), cranial nerves II-XII tested and intact, motor exam 5/5 throughout with no abnormal movements noted, sensory exam normal throughout. Initial laboratory studies were significant for white blood cell count (WBC) of 15.0 × 103 (μL), absolute neutrophil count (ANC) of 13.3 × 103 (μL), with no eosinophilia, and lactic acid level of 4.2 (mmol/L). Creatinine kinase (CK) was within normal limits at 65.0 μ/L. Other laboratory studies include a valproic acid level of 101.0 (μg/mL), unremarkable urinalysis, normal electrolytes, troponins and liver function tests. Eighteen-lead electrocardiogram was negative for signs of acute coronary syndrome.
Chest x-ray revealed peribronchial vascular opacities in the left lung base and perihilar region, raising concern for a developing pneumonia (). Given the patient's septic presentation, intravenous (IV) vancomycin and piperacillin/tazobactam was started, along with acetaminophen for pyrexia. Although the patient had no evidence of neutropenia, clozapine was still discontinued out of concern for putting the patient at risk for neutropenia in the setting of a possible acute infection. After 24 h of holding clozapine and initiating treatment with broad spectrum antibiotics, the patient's vital signs stabilized, and leukocytosis resolved. The patient continued levofloxacin with presumed resolving pneumonia and restarted on clozapine 200 mg for her treatment resistant schizophrenia.
Within hours of restarting clozapine, the patient once again complained of chills and chest pain, but this time also had sialorrhea. Heart rate was 154, temperature of 39.3°C, respiration rate of 29 and oxygen saturation of 88%. The remainder of the physical exam was otherwise unchanged from the previous presentation, including no dyskinesias or muscle rigidity. The patient received nitroglycerin but had no symptomatic improvement and repeat electrocardiogram was still negative for signs of acute coronary syndrome. Blood and urine cultures continued to show no growth. Complete blood count was within normal limits, including WBC count of 7.2 × 103 (μL) and ANC of 4.8 × 103 (μL) with no eosinophilia. Repeat CK was not done as no neurologic and muscular abnormalities were noted and neuroleptic malignant syndrome was not suspected. Clozapine was held and the patient's symptoms resolved within 24 h without additional medical intervention.
A repeat chest x-ray 48 h after withholding clozapine showed markedly improved lungs almost completely clear of prior opacities (). The patient was started on risperidone 2 mg and eventually paliperidone palmitate before being discharged, with no recurrence of fever or other signs of sepsis.


The patient is a 70-year-old Caucasian male with no known past medical history who presented to the emergency department (ED) by rescue with syncope and appeared acutely ill. He had not seen a physician for over 15 years. He has a smoking history of 50 pack year. During initial assessment in the ED, he was found to have a large, bleeding, ulcerative wound posterior to his left ear. However, diagnostic evaluation for his presenting complaint was notable for ischemic ST depressions in the inferior and anterolateral electrocardiogram leads and up trending serum troponins, resulting in the diagnosis of acute coronary syndrome. He was admitted to the hospital and treated for a non-ST elevation myocardial infarction with subsequent percutaneous coronary intervention and stent placement. When his condition stabilized from a cardiac perspective, additional history revealed that a “red rash” initially developed adjacent to his left ear about 15 years ago. The rash grew slowly and ultimately became ulcerated with purulent discharge. His wound care at home consisted of washing the area with soap and water and letting it air dry. Physical exam revealed 7.5 x 6.0 cm ulcerated plaque with rolled borders, peripheral hemorrhagic crust, and purulent drainage on the left postauricular area and upper neck (Figures , ).
Also, the examination of his left upper eyelid revealed a waxy, pink plaque with telangiectasia. A punch biopsy of both lesions confirmed basal cell carcinoma. CT of the neck with contrast showed invasion of the ulcerated lesion into the distal left sternocleidomastoid muscle and its insertion, and loss of the fat plane between the ulcerative lesion and upper left trapezius muscle. Surgical resection was recommended with the possibility of adjuvant hedgehog inhibitor therapy with vismodegib treatment conditional on lymph node involvement. His surgery date was delayed due to repeated hospitalizations for complications of ischemic cardiomyopathy and ultimately, he expired prior to intervention five months following index presentation.


A 57-year-old Caucasian female presented with a 4-day history of worsening left ear pain. Her symptoms began with left otalgia and otorrhea which progressed to helical erythema, prompting a visit to the emergency department (ED). The ED physician noted erythema of her left auricle and swelling of the left auditory meatus. The tympanic membrane was not visualized due to stenosis of the external auditory canal (EAC). The patient was initiated on intravenous (IV) levofloxacin and otic ofloxacin. Our otolaryngology service observed erythema of the auricle with sparing of the lobule (Fig. ). We amended the diagnosis to be otitis externa with perichondritis and recommended otic ciprofloxacin-hydrocortisone, IV vancomycin, and ciprofloxacin. The patient had marked improvement and was discharged on an oral and otic fluoroquinolone. This clinical image was approved by the IRB at the Philadelphia College of Osteopathic Medicine.


A 35-year-old Hindu woman presented to our dermatology outpatient department with complaints of painful depigmented lesions of 1½ years’ duration. On examination, the lesions were porcelain white atrophic papules with surrounding erythema present over the trunk, upper limbs, thighs, and chest (Figure a-d). The lesions were associated with mild tenderness. She had a history of joint pain for the last 7–8 years and a history of headache, giddiness, and ocular pain for the last 3 months. She had no history of proximal muscle weakness or skin tightening. Her menstrual cycles were regular. She had a history of irregular bowel habits (constipation). She had no history of hypertension or diabetes/any other medication. Results of her laboratory tests for antinuclear antibody, lupus anticoagulant, cardiolipin antibody, and β2-glycoprotein were all negative. Ultrasonography of the abdomen was unremarkable. Ophthalmological examination of bilateral eyes showed myopic astigmatism. The result of stool occult testing of the patient’s blood was negative.
A skin punch biopsy was taken from the porcelain white lesion over the trunk. Histopathological examination of the sections showed atrophic epidermis with mild hyperkeratosis and flattened rete ridges focally. The underlying papillary was showing a band-like mucin deposit along with focal sclerosis. The middle and deep dermis had patchy mucin along with focal fibrosis. Cuffing of mild to moderate lymphomononuclear infiltrate was observed around perivascular areas in the dermis. Few of the blood vessels were showing endothelial cell proliferation (Figure a-c). Scant subcutaneous tissue was available in the biopsy. The result of Alcian blue staining for dermal mucin was positive (Fig. d). Owing to the absence of systemic complications, the patient was diagnosed with benign cutaneous Degos disease.
She was prescribed antiplatelet agents (aspirin 75 mg and clopidogrel 75 mg once daily). New lesions stopped appearing within 1 month of starting this therapy. Patient’s follow-up after 3 months, the lesions had started flattening, the erythema had decreased, and her pain was completely subsided (Figure a-d). The patient is under regular follow-up with us, and her condition is improving.


A previously healthy 35-year-old black male was referred to our service due to new onset of hypertension and lower-limb edema, followed by progression to anasarca within an eight-month period. He had been recently diagnosed with schistosomiasis by serological test (ELISA) (immunoglobulin G: 5; normal range: less than 1.1). An upper abdomen ultrasound revealed liver with increased dimensions and a heterogeneous parenchyma due to diffuse periportal hyperechogenicity (consistent with periportal fibrosis) as well as signs of portal hypertension, including splenomegaly, increased portal vein caliber, and detection of hepatofugal portal venous flow by Doppler ultrasound. These findings were strengthened by the identification of esophageal and gastric varices at upper digestive endoscopy. The patient referred no other systemic complaints or previously diagnosed comorbidities. He reported a brother also recently diagnosed with schistosomiasis but denied family history of renal diseases. His physical examination disclosed systemic hypertension (blood pressure of 157/106mmHg), anasarca, semiology consistent with bilateral pleural effusion and ascitis, and +4/+4 edema in lower limbs.
Laboratory tests revealed serum creatinine of 1.89mg/dL (normal range [NR]: 0.7–1.2 mg/dL), estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 54 mL/min per 1.73 m2, blood urea nitrogen (BUN) of 24 mg/dL (NR: 4.5–24 mg/dL), electrolyte and acid-base parameters within the normal ranges, total serum protein 4.6 g/dL (NR: 6.6–8.7 g/dL), serum albumin 1.9 g/dL (NR: 3.4–4.8 g/dL), total cholesterol 531 mg/dL (NR: less than 200 mg/dL), low-density lipoprotein 426 mg/dL (NR: less than 100 mg/dL), high-density lipoprotein 56 mg/dL (NR: more than 40 mg/dL), triglycerides 202 mg/dL (NR: less than 150 mg/dL), serum glucose 89 mg/dL (NR: 70–99 mg/dL), glycosylated hemoglobin 5.5% (NR: 4.5%–5.6%), hemoglobin 13.8 g/dL (NR: 13–18 g/dL), leucocytes 6440 per mm3 (NR: 4,000–11,000 per mm3), platelets 115.000 per mm3 (NR: 140,000–450,000 per mm3), C3 155 mg/dL (NR: 90–180 mg/dL) and C4 38 mg/dL (NR: 10–40 mg/dL), hepatitis B surface antigen (HBsAg) negative and total hepatitis B core antibody (AntiHBc) immunoglobulin G positive, urinalysis with no leukocyturia or hematuria, and 24 hour proteinuria 6.56 g (NR: less than 150 mg per 24 hours). Autoantibody test results (antinuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibodies), serologies for HCV and HIV, and serum cryoglobulins were negative, and no monoclonal protein was detected. His chest X-ray displayed signs of congestion and bilateral pleural effusion. Echocardiogram evidenced mild pericardial effusion with no hemodynamic repercussion, with the other parameters within the normal range. Ultrasound of the kidneys and urinary tract showed kidneys with normal size and appearance, with preserved corticomedullary differentiation.
In the setting of nephrotic syndrome, a kidney biopsy was performed. Light microscopy evinced 16 glomeruli, two of which were globally sclerotic, some of them with normal features and other ones with mesangial hypercellularity and capillary wall collapse, associated with marked podocyte hypertrophy and hyperplasia as well as cystic tubule dilatation (). Diffuse interstitial fibrosis and arteriolar hyalinosis were also observed. Immunofluorescence staining showed glomerular deposition of immunoglobulin M (+2/+3) and C3 (+3/+3) with a granular pattern and focal and segmental distribution. Electron microscopy revealed collapse of capillary walls, vacuolization of podocyte cytoplasm (), and global effacement of foot processes, without images consistent with viral particles, fibrillar deposits, or deposits of other nature (). Based on the described histological, immunofluorescence, and ultrastructural findings, the diagnosis of CG was established. Although the identification of SM antigens in the biopsy would definitely establish the cause-effect relationship between SM infection and CG, the biopsy fixation process precluded the performance of immunomicroscospy, therefore hindering this possibility.
The patient was treated with praziquantel (50 mg/kg divided into three doses and administered for one day) and enalapril (5 mg twice daily from the time of diagnosis to the start of hemodialysis), reaching partial remission of proteinuria. Such a response, however, was followed by relapse of nephrotic syndrome. In this scenario, he was started on prednisone 1 mg/kg per day for 5 months, but no therapeutic response was observed. The patient was then tested for the G1 and G2 high-risk APOL1 alleles and found to carry a high-risk APOL1 genotype (G1/G2). Given the lack of response to immunosuppressive therapy, he underwent a fast and progressive decrease of renal function, reaching chronic hemodialysis 19 months after the diagnosis ().
S. mansoni schistosomiasis, an endemic disease in some Brazilian regions, is most often manifested by gastrointestinal symptoms and signs. Renal involvement, however, is also within the pathological spectrum of this disorder. [,] While glomeruli constitute the main target for kidney lesions in SM infection, glomerulopathies can be associated with the hepatosplenic or hepatointestinal forms of the disease. [,] The pathogenesis of such glomerulopathies, however, is still largely unknown. It has been postulated that the parasite may stimulate the immune system, leading to production of immune complexes and their subsequent deposition in glomeruli or, alternatively, it may lead to direct lesion of podocytes likely through the production of cytokines. []
A clinicopathological classification of SM-associated glomerulopathies was proposed by the African Society of Nephrology [], defining five classes: class I: mesangial proliferative glomerulonephritis, representing the most frequent form; class II: exsudative glomerulonephritis; class III: MPGN; class IV: FSGS; and Class V: amyloidosis. Of note, classes III and IV are associated with progressive disease. Interestingly, in Brazilian series of patients with glomerulopathies associated with schistosomiasis, MPGN and FSGS are the most common forms. These studies also include cases of membranous nephropathy [,,] not contemplated in the classification, whereas they do not report cases of amyloidosis.
A previous Brazilian study [] analyzed the distribution of primary FSGS subtypes according to the Columbia classification. This report found a frequency of CG significantly higher than other studies worldwide, reaching a 36.6% rate, whereas in other epidemiological studies it varied from 4% to 12% [,]. Given the high degree of African ancestry present in the Brazilian population, epidemiological data on APOL1 are very important to understand more broadly the kidney disease scenario in this country. Studies addressing the prevalence of HRG in Brazil and its distribution among the different regions are, however, scarce. A recent report, nevertheless, showed a 6% G1 allele frequency and 1.4% G2 allele prevalence in a healthy Brazilian population. [] The potential impact of such frequencies upon the Brazilian chronic kidney disease (CKD) reality is, therefore, significant, although this same study revealed that APOL1 risk variants were less frequent in dialysis patients of African ancestry in Brazil than in the United States. Remarkably, carriers of an HRG had a 10-fold higher probability to reach end-stage kidney disease (ESKD) and started dialysis substantially earlier than other CKD patients. Another Brazilian feature potentially relevant to the development of CG is the increased risk of exposure to environmental factors, particularly tropical infectious agents, which might serve as triggers to CG.
Prior experimental studies showed that podocytes containing APOL1 risk alleles overexpress the corresponding protein when submitted to increased endogenous production of Th1 cytokines, such as interferon and Toll-like receptor agonists. This increased APOL1 protein expression, often observed in infections and autoimmune disorders, is thought to favor the development of CG. [] Acting in line, the proposed susceptibility and triggering mechanisms support a two-hit model for the genesis of CG. Interestingly, this model has also been supported in the clinical setting, in which patients with an HRG have been reported to develop CG following viral infections, such as HIV and parvovirus, and autoimmune diseases, such as systemic lupus erythematosus. In agreement with this mechanism, transplant recipients without an HRG who received an HRG kidney developed de novo CG after cytomegalovirus or poliomavirus infection or antibody-mediated rejection. [,] Immune profile analysis of patients with SM revealed a role for the Th1, Th2, and Th17 lymphocytic subpopulations in the disease pathogenesis. Notably, the Th1 and Th2 profiles remain chronically activated throughout the disease process. [,] Taken together, the aforementioned concepts and observations strongly suggest that SM may also serve as an amplifier of mutated APOL1 protein expression in an HRG patient, triggering the development of CG.
CG is associated with a worse outcome than the histological variants that remain under the FSGS designation, even following immunosuppressive therapy and treatment of associated conditions. [] This behavior can be appreciated in the current case, in which the patient presented partial remission after treating the parasitosis; however, nephrotic syndrome relapsed with no response to steroids and progressed to ESKD within a short time period after the diagnosis.
To our knowledge, this is the first case of CG associated with schistosomiasis mansoni in a patient with a high-risk APOL1 genotype. This case corroborates the interactive role between genetic and environmental factors in the development of CG, highlighting the proposed two-hit model as a mechanism for its pathogenesis. Our case, therefore, not only allowed the identification of SM infection as an additional trigger for the development of CG but, also, strengthened the concept that a high-risk APOL1 genotype exerts a susceptibility role in this glomerulopathy.


A 53-year-old man presented to the hospital with bilateral leg weakness, repeated falls, and general paresthesia with bilateral numbness in upper and lower extremities (worse in lower extremities). His past medical history was significant for uncomplicated type 2 diabetes mellitus, essential hypertension, and chronic pain. The patient reported using N2O recreationally every day, multiple times per day for one month prior to symptom onset. The patient also reported having abused N2O intermittently since adolescence. N2O Quantification: the patient inhaled one box of 25 N2O-containing steel cartridges each containing 8g (4.37L) of compressed N2O for a total of 200g (109.23L) of inhaled N2O daily for three weeks, then increased consumption to approximately 15 boxes daily containing a total of 3,000g (1,638.5L) of compressed N2O for five days prior to symptom onset.
Neurologic examination was performed upon admission. Motor examination was significant for 4/5 strength in bilateral upper and lower extremities - more pronounced in the left upper and lower extremities. Coordination examination was significant for decreased bilateral finger to nose test - more pronounced on left - and decreased bilateral heel to shin test - more pronounced on left. Reflex examination was significant for 3+ bilateral patellar reflexes with greater hyperreflexia on the left. Sensory examination was significant for impaired vibratory sense up to his knees and loss of proprioception in his bilateral lower extremities. His gait examination was significant for positive Romberg test, wide-based stance, and the patient was unable to make small steps without falling - secondary to loss of proprioception. The patient was awake, alert, and oriented to person, place, time, and circumstance throughout his admission; therefore, a mini mental examination was not deemed clinically necessary.
Laboratory tests and diagnostic imaging modalities were performed throughout the patient’s seven-day hospital course. Work-up revealed neurologic abnormalities consistent with SCD, normal B12 levels, increased homocysteine and methylmalonic acid, positive intrinsic-factor-blocking (IFB) antibodies, and sensorimotor polyneuropathy without major demyelination features (Tables , ). A peripheral blood smear was not performed. T2-weighted imaging revealed increased dorsal column signal attenuation (Figure ).
Treatment consisted of a seven-day course of daily vitamin B12 intramuscular injections at a dose of 1,000 µg, followed by once weekly injections at the same dose. At one-week office follow-up, the patient reported symptomatic improvement. There was persistence of ataxia and peripheral neuropathy associated with loss of vibratory sense and proprioception, but reflexes were 2+ throughout. At one-month office follow-up, the patient reported overall symptomatic persistence with improvement. Upon two-month telephone follow-up, the patient reported overall improvement in mobility and paresthesia; however, symptoms persisted. He had difficulty ambulating (using a cane for assistance) and performing activities of daily living due to ataxia. Symptoms were fluctuating daily, subjectively ranging from 30%-70% of baseline functionality, which was improved from almost no functionality upon admission. The patient had been supplementing his diet with 750 mg of vitamin B12 daily, as well as vitamin B6, vitamin D3, nitric oxide, and Omega-3 fatty acid since discharge. He has not been using N2O since prior to hospital admission. No further patient follow-up was reported.