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Polymyxins [colistin and polymyxin B (PMB)] comprise an important class of natural product lipopeptide antibiotics used to treat multidrug-resistant Gram-negative bacterial infections. These positively charged lipopeptides interact with lipopolysaccharide (LPS) located in the outer membrane and disrupt the permeability barrier, leading to increased uptake and bacterial cell death. Many bacteria counter polymyxins by upregulating genes involved in the biosynthesis and transfer of amine-containing moieties to increase positively charged residues on LPS. Although 4-deoxy-l-aminoarabinose (Ara4N) and phosphoethanolamine (PEtN) are highly conserved LPS modifications in Escherichia coli, different lineages exhibit variable PMB susceptibilities and frequencies of resistance for reasons that are poorly understood. Herein, we describe a mechanism prevalent in E. coli B strains that depends on specific insertion sequence 1 (IS1) elements that flank genes involved in the biosynthesis and transfer of Ara4N to LPS. Spontaneous and transient chromosomal amplifications mediated by IS1 raise the frequency of PMB resistance by 10- to 100-fold in comparison to strains where a single IS1 element located 90 kb away from the end of the arn operon has been deleted. Amplification involving IS1 becomes the dominant resistance mechanism in the absence of PEtN modification. Isolates with amplified arn operons gradually lose their PMB-resistant phenotype with passaging, consistent with classical PMB heteroresistance behavior. Analysis of the whole genome transcriptome profile showed altered expression of genes residing both within and outside of the duplicated chromosomal segment, suggesting complex phenotypes including PMB resistance can result from tandem amplification events.IMPORTANCEPhenotypic variation in susceptibility and the emergence of resistant subpopulations are major challenges to the clinical use of polymyxins. While a large database of genes and alleles that can confer polymyxin resistance has been compiled, this report demonstrates that the chromosomal insertion sequence (IS) content and distribution warrant consideration as well. Amplification of large chromosomal segments containing the arn operon by IS1 increases the Ara4N content of the lipopolysaccharide layer in Escherichia coli B lineages using a mechanism that is orthogonal to transcriptional upregulation through two-component regulatory systems. Altogether, our work highlights the importance of IS elements in modulating gene expression and generating diverse subpopulations that can contribute to phenotypic polymyxin B heteroresistance.

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Magee Equations™ (ME) are multivariable models that can estimate oncotype DX® recurrence score. One of the equations, Magee Equation 3 (ME3) which utilizes only semi-quantitative receptor results has been shown to provide chemopredictive value in the neoadjuvant setting in a single institutional study. This multi-institutional study (seven institutions contributed cases) was undertaken to examine the validity of ME3 in predicting response to neoadjuvant chemotherapy in estrogen receptor positive, HER2-negative breast cancers. Stage IV cases were excluded. The primary endpoint was the pathologic complete response (pCR) rate in different categories of ME3 scores calculated based on receptor results in the pre-therapy core biopsy. A total of 166 cases met the inclusion criteria. The patient age ranged from 24 to 83 years (median 53 years). The average pre-therapy tumor size was 3.9 cm, and axillary lymph nodes were confirmed positive by pre-therapy core biopsy in 85 of 166 cases (51%). The pCR rate according to ME3 scores was 0% (0 of 64) in ME3 < 18, 0% (0 of 46) in ME3 18-25, 14% (3 of 21) in ME3 > 25 to <31, and 40% (14 of 35) in ME3 score 31 or higher (p value: <0.0001). There were no distant recurrences and no deaths in the 17 patients with pCR. In the remaining 149 cases with residual disease, ME3 score of >25 was significantly associated with shorter distant recurrence-free survival and showed a trend for shorter breast cancer-specific survival. The results of this multi-institutional study are similar to previously published data from a single institution (PMID: 28548119) and confirm the chemo-predictive value of ME3 in the neoadjuvant setting. In addition, ME3 may provide prognostic information in patients with residual disease which should be further evaluated.

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The data regarding radial scar (RS) as a risk factor for breast cancer are conflicting, and it is unclear whether an excision is warranted for patients with RS identified on core needle biopsy (CNB). In this study, we investigated the follow-up excisional results for patients with RS on CNB with no history of or concurrent breast cancer or atypical proliferative lesions. The study cohort was composed of 403 such cases, and follow-up excision (FUE) was performed in 220 (54.6%). There was no significant difference in the radiologic findings in cases with and without FUE. Of the 220 cases with FUE, only 2 (0.9%) were upgraded to malignancy (1 invasive carcinoma and 1 ductal carcinoma in situ), whereas 44 cases (20.0%) were upgraded to atypical ductal hyperplasia and 13 cases (5.9%) to lobular neoplasia. Upgrades were associated with greater age but not with any other variable. This is one of the largest studies to evaluate excisional findings in patients with RS identified on CNB but no history of or concurrent breast cancer or atypical proliferative lesions, and the extremely low malignancy-upgrade rate indicates that conservative follow-up with imaging rather than surgical excisions may be more appropriate for these patients.

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We present here a case of an asymptomatic end-stage renal disease (ESRD) patient, who had an unexplained persistent mild leukocytosis in the setting of an extremely high ferritin level (8,997 ng/ml; reference range: 12 - 300 ng/ml) 3 weeks after she suffered from a myocardial infarction (MI). Infection as the cause of these laboratory abnormalities was ruled out. A week later, the patient was noted to have asymptomatic hypotension (100/60 mmHg; her baseline blood pressure was 120/70 mmHg) during a maintenance hemodialysis session. An echocardiography revealed an interval development of moderate pericardial effusion when compared to her previous echocardiography 4 weeks before. In the setting of a recent MI with other laboratory markers suggesting an ongoing inflammatory process, a tentative diagnosis of Dressler's syndrome was made. A pericardial tap yielded exudative (bloody) fluid, thus, confirming our suspicion. Dressler's syndrome results from an inflammation of the pericardium as a consequence of an underlying autoimmune process few weeks to months after a myocardial infarction or post-cardiac surgery. Although it typically presents with pleuritic chest pain, fever, leukocytosis, and a friction rub; our case illustrates that the initial presentation may be asymptomatic in ESRD patients. For the same reason, it is likely an under-recognized entity in such patients. An unexplained elevated ferritin in an ESRD patient with recent history of MI should prompt an investigation for Dressler's syndrome. In those with associated significant pericardial effusion, daily HD should be initiated and anticoagulation should be avoided. Unlike other ESRD associated pericarditis, steroids and NSAIDs should be avoided in Dressler's syndrome as they may hamper cardiac remodeling in the immediate post-MI period. Colchicine may offer some benefit in patients with associated chest pain. For those failing medical management or manifesting overt signs of tamponade, surgical drainage should be preferred.

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Abdominal compartment syndrome (ACS) is defined as an organ dysfunction caused by intra-abdominal hypertension (IAH). Up to 4.2% of the patients in intensive care unit may develop IAH with it being an independent predictor of mortality. However, overall, it still remains a relatively underdiagnosed condition, part in because physical examination alone is very unreliable. Acute kidney injury is one of the most consistently described organ dysfunctions with oliguria being one of the earliest clinical signs of IAH. We recommend that any patient with evidence of new onset oliguria in the setting of distended abdomen, unexplained respiratory failure, with or without hypotension should be suspected of having IAH/ACS. Intravesicular pressure measurement represents a safe, rapid, and cost-effective method of diagnosing IAH. We hereby review the pathophysiology, diagnosis, and management of ACS and its association with acute kidney injury.

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Calciphylaxis, or calcific uremic arteriopathy (CUA), is characterized by metastatic calcification in the media of small arteries and arterioles leading to cutaneous necrosis. It is most commonly seen in patients with end stage renal disease who have elevated serum calcium × phosphorus (Ca × P) product. Normalization of Ca × P product is considered paramount in the prevention and treatment of CUA. We describe a novel presentation of CUA in which a Stage-5 CKD patient developed signs and symptoms of CUA immediately after initiation of hemodialysis (HD). We postulate that an influx of calcium from the dialysate into the patient's blood, in addition to correction of her acidosis, led to abundant substrate in a favorable milieu for Ca-P complex formation at the time of her first HD session. Our case is the first reported case of HD associated iatrogenic acute CUA. To avoid this complication, we should maintain adequate hydration,use lower calcium dialysate, and avoid vitamin D analogues and calcium-containing medications when initiating HD in patients with high Ca-P product. Since sodium thiosulfate is known to prevent precipitation of Ca-P complexes, its empiric use during initial HD treatments may be effective in preventing CUA, a potentially fatal disease.

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We report the case of a 63-year-old man who presented with acute kidney injury, active urine sediment, nephrotic syndrome, and hypocomplementemia after a recent report of a sore throat. Kidney biopsy showed diffuse proliferative and exudative glomerulonephritis with C3-dominant staining by immunofluorescence. Taken together, clinical and pathologic findings were most suggestive of acute postinfectious glomerulonephritis, although the history of full nephrotic syndrome, presence of segmental membranoproliferative features, and absence of classic subepithelial hump-shaped deposits were unusual for this condition. Three months after the initial biopsy, the patient continued to have hypocomplementemia and nephrotic syndrome, prompting a repeated kidney biopsy that showed findings most consistent with C3 glomerulopathy. C3 glomerulopathy is a proliferative pattern of glomerulonephritis characterized by complement deposits that stain solely or dominantly for C3. A subset of cases of C3 glomerulopathy have features that overlap extensively with acute postinfectious glomerulonephritis. Clinicians and pathologists should be aware of the similar findings seen in these 2 conditions.

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The term "Pseudocellulitis" can be used to describe an uncomplicated nonnecrotizing inflammation of the dermis and hypodermis from a noninfectious etiology. Chemotherapeutic agents have been associated with a variety of cutaneous reactions, including radiation recall dermatitis, hypersensitivity reactions, and erysipeloid reactions. Gemcitabine (2,2-difluorodeoxycytidine) is currently being used for treatment of a variety of solid malignancies, including carcinoma of the lung. The dermatitis involved with gemcitabine is typically a radiation recall reaction whereby an inflammatory reaction occurs in the area previously treated with radiotherapy. We describe here a case of Gemcitabine-induced pseudocellulitis that was unrelated to radiation exposure and manifested in an area of lymphedema. The pseudocellulitis in such cases could be related to the drug's pharmacokinetics and may last until the drug is displaced from the subcutaneous tissue of the affected area. Antibiotics have no role in the treatment, and diphenhydramine with nonsteroidal anti-inflammatories may be used for symptomatic management.

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Calciphylaxis or calcific uremic arteriolopathy is a life-threatening condition that predominantly affects patients with end-stage renal disease on hemodialysis. A prevalence of up to 4% and a 6-month mortality rate of up to 80% have been reported in those with proximal disease (thighs, abdomen wall, and buttocks). Penile calciphylaxis is very rare but has a mortality rate of 69% within 6 months. Its treatment is controversial. For small lesions, conservative treatment with local wound care and debridement may suffice. Partial or complete penectomy may be needed for more extensive lesions, and especially those associated with signs of local infection. In addition to surgical intervention, as with any other case of calcific uremic arteriolopathy, the cornerstones of therapy should be to keep serum phosphorus <6 mg/dL, and a Ca × P product <55 mg²/dL². We report here the first case of penile calciphylaxis whereby intravenous sodium thiosulfate was used in addition to the standard medical and surgical therapy. Two months after surgery, the patient's wound completely healed and he has experienced no new lesions over the past 11 months.

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Acute kidney injury in HIV patients is primarily related to HIV-mediated viral or immunological disease or to treatment-related toxicity (tenofovir). Neoplasms are a rare cause of non-obstructive acute kidney injury, primarily because when they occur, they manifest as discrete masses and not as diffuse infiltration of the renal parenchyma. Diffusely infiltrating tumors include carcinoma of the renal pelvis invading the renal parenchyma, renal lymphoma, squamous cell carcinoma (from lung) metastasizing to the kidney and infiltrating sarcomatous type of renal cell carcinoma. To be classified as a true case of renal lymphoma, the tumor should have escaped detection on routine imaging preceding biopsy, and lymphoma-associated renal failure/nephrotic proteinuria should have given rise to the indication for kidney biopsy. We present here a case of an acute kidney injury due to renal lymphoma in a patient with acquired immune deficiency syndrome that manifested clinically as bland urine sediment, minimal proteinuria and normal-sized kidneys. Chemotherapy resulted in complete reversal of acute kidney injury.

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BACKGROUND: According to the Centers for Disease Control and Prevention, the risk of fatal malaria in non-endemic countries can be reduced greatly if physicians are alert to the atypical presenting features of malaria. CASE REPORT: A patient arrived in the United States from Nigeria 2 days before presenting to an emergency department (ED) with sore throat, dry cough, fever (without chills), headache, and severe lethargy. A presumptive diagnosis of influenza-like illness was made. The patient improved after symptomatic treatment and was therefore discharged from the ED; she continued with her travel. After 24 h, the patient presented to our ED with symptoms suggestive of meningitis. The analysis of the cerebrospinal fluid was normal. A peripheral blood smear was diagnostic of falciparum malaria (parasitic index of 1). Because the disease was acquired from a chloroquine-resistant endemic area, the patient was treated with quinine and doxycycline, and she responded well. CONCLUSION: In this era of heightened influenza alert, differentiating between influenza-like illness and malaria can be challenging. Patients with a history of travel to a malaria-endemic area in the preceding year should undergo a complete blood count (CBC), hepatic panel, and blood smear. Due to logistic reasons, the result of a blood smear may not be available immediately. Thrombocytopenia and hyperbilirubinemia each has a positive predictive value of 95% in the presumptive diagnosis of malaria. Patients who do not appear sick, and those who have a normal CBC and hepatic panel, may be treated symptomatically and discharged (with follow-up advised). Those with a presumptive diagnosis of malaria or unclear speciation should be admitted for anti-malarial therapy.

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BACKGROUND: Pure mucinous breast carcinoma (PMBC) is uncommon and associated with better prognosis than mixed mucinous breast carcinoma (MMBC). A micropapillary pattern in PMBC has been identified although its prognostic significance is questionable. METHODS: A retrospective review of 100 cases of mucinous carcinoma diagnosed between 2000 and 2009 was conducted. Two broad categories were studied: PMBC (more than 90% mucinous component; n=45) and MMBC (less than 90% mucinous component; n=55). PMBC was further subclassified as hypocellular/type A (n=37) and cellular/type B (n=8). Receptor status, clinicomorphological and prognostic features were compared without patient follow-up. RESULTS: Mean age at diagnosis in PMBC and MMBC was 60 and 63 years, while mean tumour size was 1.65 and 2.5 cm, respectively. Mean age in type A and type B PMBC patients was 75 and 55 years, respectively. The majority of PMBCs were well differentiated, with two poorly differentiated cases as well. The majority of MMBCs were moderately differentiated. A micropapillary pattern was seen in 20% of PMBCs. Sentinel lymph nodes were positive in 18.5% of PMBCs and 16% of MMBCs. Non-sentinel lymph nodes were positive in 14% of PMBCs and 39% of MMBCs. A micropapillary pattern was seen in 60% of LN positive PMBCs and 14% of LN negative PMBCs. Furthermore, 95% of PMBCs were ER(+), 84% were PR(+) and 9% were Her-2(+); 91% of MMBCs were ER(+), 87% were PR(+) and 33% were Her-2(+). CONCLUSIONS: PMBCs with a micropapillary pattern were more frequently associated with nodal disease. PMBCs with axillary disease had one or more of the following: micropapillary pattern, high nuclear grade, Her-2 positivity, smaller tumour size or younger age. Hence, axillary staging by sentinel lymph node biopsy is recommended in PMBCs.

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Pulmonary renal syndrome (PRS) is a combination of diffuse pulmonary haemorrhage and glomerulonephritis (GN). Though an established form of presentation in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated GN and vasculitis, diffuse pulmonary haemorrhage is extremely unusual in those with ANCA-negative GN. We present here a case of a 76-year-old Hispanic female with stage IV chronic kidney disease (serum creatinine of 2 mg/dL), who presented with diffuse alveolar haemorrhage and nephritic syndrome. Less than 1 week prior to the full-blown PRS, she was treated for an apparent pneumonia as was evidenced by a right lower lobe infiltrate on her chest X-ray. Retrospectively, this was likely a focal pulmonary haemorrhage. ANCA were persistently negative, and the remainder of her immunologic workup was normal. Renal biopsy was diagnostic of crescentic pauci-immune GN. The patient required a ventilator and haemodialysis support (serum creatinine 6 mg/dL), and was successfully treated with methylprednisolone, cyclophosphamide and a total of six cycles of plasmapheresis. Once her oliguria resolved, the creatinine plateaued at 2.7 mg/dL. Our case illustrates that diffuse alveolar haemorrhage can be a distinct clinical feature even in patients with ANCA-negative pauci-immune crescentic glomerulonephritis.