Clinical Characteristics of Idiopathic Granulomatous Mastitis in a Hispanic Border Population: A Case Series and Literature Review.

Idiopathic granulomatous mastitis (IGM) is an autoimmune condition of the breast that is commonly encountered in women of non-white ethnicity such as Southeast Asians, Middle Easterners, and Hispanics. This condition often presents as a painful breast mass, and many patients undergo invasive diagnostic procedures or surgical excision, which can lead to disfiguring scars. Early recognition and prompt treatment with immunosuppressive medications can prevent invasive workups and management. Although previously thought to require an exclusively surgical approach, it now prompts interdisciplinary management. In this context, we present a case series of patients with IGM in a Hispanic population of South Texas.

Acute Hypersensitivity Reaction After Casirivimab/Imdevimab Infusion in a COVID-19-Positive Young Male: Myopericarditis or Kounis Syndrome?

Myocarditis has been a rare, but well-documented side effect of the mRNA-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as a complication of viral infections including SARS-CoV-2. However, myopericarditis as a complication of monoclonal antibody infusion or as a complication of allergic reaction to antibody infusions might be underreported. We report the case of a 30-year-old man with a previous diagnosis of coronavirus disease 2019 (COVID-19) infection one week prior to presentation, unvaccinated for SARS-CoV-2, who was referred from a monoclonal infusion center where he received casirivimab/imdevimab and 15 minutes after the infusion began to complain of chills, chest pain, shortness of breath, and was hypotensive. In the infusion center, the patient received epinephrine and diphenhydramine and was directed to the ER, where the patient was febrile, tachycardic, and hypotensive. Initial troponin was 1.91 which peaked at 11.73 and CK-MB which peaked at 21.2. EKG had no ischemic changes. A two-dimensional echocardiogram showed an ejection fraction (EF) of about 45%, with a left ventricular dysfunction and trivial posterior pericardial effusion, and it was diagnosed as myopericarditis. On admission, he was started on full-dose enoxaparin, aspirin, fluid resuscitation, steroids, remdesevir, and bilevel positive airway pressure (BiPap) due to his respiratory compromise. Three days later, with clinical improvement, a repeat echocardiogram showed EF of 65%, with normal ventricular contractility and no pericardial effusion. The patient was discharged home with close cardiology follow-up. Though this could be a simple case of viral myopericarditis with troponinemia secondary to demand-ischemia, the differential should be broadened to complication of monoclonal antibody, given the sudden symptom onset after infusion completion and/or a possible Kounis syndrome. Though there have not been any reported cases of casirivimab/imdevimab causing myopericarditis, adverse cardiac events after monoclonal therapy have been reported mainly in cancer patients receiving monoclonal infusions.

Bitten to the Bone: A Case of Anxiety-Induced Osteomyelitis.

Onychophagia is a habitual nail-biting disorder, usually associated with mental or emotional diseases. It affects 20-30% of the population in all age groups. Human bites have the potential to become serious injuries due to high virulence in the human oral flora and may often require hospital admission, antibiotics and even debridement in the operating room. Thus, repetitive nail biting has the potential to be limb-threatening if not treated early and appropriately. We present a 49-year-old Spanish-speaking gentleman, with a past medical history of repetitive nail biting secondary to severe anxiety, major depression disorder, bilateral hand neuropathy secondary to diabetes mellitus (DM) type 2 who was initially admitted to the hospital due to cellulitis of the fingers with suspected osteomyelitis in the right hand. Anxiety was being treated by psychiatrist with paroxetine however, given no improvement and prolonged follow-ups, the primary care physician (PCP) added hydroxyzine and scheduled alprazolam in an attempt to minimize symptoms. Despite these efforts, patient continued with nail biting. On initial physical exam, the patient had a lack of fingernails and multiple wounds at various stages of healing across all digits. The distal and middle phalanges of the third right digit showed increased erythema and swelling and band tightening. Patient was started on broad-spectrum antibiotics. Initial radiography of the right hand was concerning for osteomyelitis which was later confirmed with Magnetic Resonance Imaging (MRI). Infectious disease specialist agreed on a course of cefepime, vancomycin and metronidazole. On admission, hand surgeon did not see a need for amputation and patient was treated conservatively. Due to minimal improvement after six days on IV antibiotics, patient underwent fasciotomy of the flexor compartment of the right middle finger after patient rejected hand surgeon's recommendation for amputation. He was discharged to a skilled nursing facility where he was to continue intravenous antibiotics for an additional four weeks. The vulnerable patient population of South Texas is predominately Hispanic, Spanish-speaking and uninsured. It is imperative to treat psychiatric disorders early to prevent complications, however, given the low numbers of psychiatrists in the Rio Grande Valley and even fewer who speak Spanish it is not unusual to find an appointment in more than six months. In this case, we observe how a trivial everyday behavior can lead to limb-threatening complications if not treated early and appropriately.

Early insight into the potential contribution of aluminum to neurodegeneration - A tribute to the research work of Robert D. Terry, Igor Klatzo, Henryk M. Wisniewski and Donald R.C. Mclachlan.

The first successful attempt to obtain purified aluminum metal was accomplished by the Danish physicist and chemist Hans Christian Orsted in 1824, however it was not until about ~140 years later that aluminum's capacity for neurological disruption and neurotoxicity was convincingly established. The earliest evidence of the possible involvement of this biosphere-rich metallotoxin in Alzheimer's disease (AD) originated in the early-to-mid-1960's from animal and human research investigations that arose almost simultaneously from independent laboratories in the United States and Canada. This short communication pays tribute to the pioneering research work on aluminum in susceptible species, in AD animal models and in AD patients by the early investigators Drs. Robert D. Terry, Igor Klatzo and Henryk M. Wisniewski with special acknowledgement to the late Dr. Donald RC McLachlan, and their contemporary physician-scientist colleagues and collaborators. Together these researchers established the groundwork and foundation towards our understanding of the potential contribution of aluminum to progressive, age-related and lethal neurodegenerative diseases of the human central nervous system.

Aluminum-induced generation of lipopolysaccharide (LPS) from the human gastrointestinal (GI)-tract microbiome-resident Bacteroides fragilis.

Gram-negative bacteria of the human gastrointestinal (GI) tract microbiome: (i) are capable of generating a broad-spectrum of highly neurotoxic, pro-inflammatory and potentially pathogenic molecules; and (ii) these include a highly immunogenic class of amphipathic surface glycolipids known as lipopolysaccharide (LPS). Bacteroides fragilis (B. fragilis), a commensal, Gram negative, non-motile, non-spore forming obligatory anaerobic bacillus, and one of the most abundant bacteria found in the human GI tract, produces a particularly pro-inflammatory and neurotoxic LPS (BF-LPS). BF-LPS: (i) is known to be secreted from the B. fragilis outer membrane into the external-medium; (ii) can damage biophysiological barriers via cleavage of zonula adherens cell-cell adhesion proteins, thereby disrupting both the GI-tract barrier and the blood-brain barrier (BBB); (iii) is able to transit GI-tract barriers into the systemic circulation and cross the BBB into the human CNS; and (iv) accumulates within CNS neurons in neurodegenerative disorders such as Alzheimer's disease (AD). This short communication provides evidence that the incubation of B. fragilis with aluminum sulfate [Al2(SO4)3] is a potent inducer of BF-LPS. The results suggest for the first time that the pro-inflammatory properties of aluminum may not only be propagated by aluminum itself, but by a stimulation in the production of microbiome-derived BF-LPS and other pro-inflammatory pathogenic microbial products normally secreted from human GI-tract-resident microorganisms.

Chromosome 21-Encoded microRNAs (mRNAs): Impact on Down's Syndrome and Trisomy-21 Linked Disease.

Down's syndrome (DS; also known as trisomy 21; T21) is caused by a triplication of all or part of human chromosome 21 (chr21). DS is the most common genetic cause of intellectual disability attributable to a naturally-occurring imbalance in gene dosage. DS incurs huge medical, healthcare, and socioeconomic costs, and there are as yet no effective treatments for this incapacitating human neurogenetic disorder. There is a remarkably wide variability in the 'phenotypic spectrum' associated with DS; the progression of symptoms and the age of DS onset fluctuate, and there is further variability in the biophysical nature of the chr21 duplication. Besides the cognitive disruptions and dementia in DS patients other serious health problems such as atherosclerosis, altered lipogenesis, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), autoimmune disease, various cancers including lymphoma, leukemia, glioma and glioblastoma, status epilepticus, congenital heart disease, hypotonia, manic depression, prostate cancer, Usher syndrome, motor disorders, Hirschsprung disease, and various physical anomalies such as early aging occur at elevated frequencies, and all are part of the DS 'phenotypic spectrum.' This communication will review the genetic link between these fore-mentioned diseases and a small group of just five stress-associated microRNAs (miRNAs)-that include let-7c, miRNA-99a, miRNA-125b, miRNA-155, and miRNA-802-encoded and clustered on the long arm of human chr21 and spanning the chr21q21.1-chr21q21.3 region.

Prevalence, Age Profile, and Associated Risk Factors for Hymenolepis nana Infection in a Large Population-Based Study in Northern Peru.

Hymenolepis nana, the dwarf tapeworm, is a common intestinal infection of children worldwide. We evaluated infection and risk factor data that were previously collected from 14,761 children aged 2-15 years during a large-scale program in northern Peru. We found that 1,124 of 14,761 children (7.61%) had H. nana infection, a likely underestimate given that only a single stool sample was examined by microscopy for diagnosis. The strongest association with infection was lack of adequate water (adjusted prevalence ratio [aPR] 2.22, 95% confidence interval [CI] 1.82-2.48) and sanitation infrastructure in the house (aPR 1.94, 95% CI 1.64-2.29). One quarter of those tested did not have a bathroom or latrine at home, which doubled their likelihood of infection. Similarly, one quarter did not have piped public water to the house, which also increased the likelihood of infection. Continued efforts to improve access to basic water and sanitation services will likely reduce the burden of infection in children for this and other intestinal infections.

The prevalence of CALR mutations in a cohort of patients with myeloproliferative neoplasms.

INTRODUCTION: To investigate the prevalence of calreticulin (CALR) mutations in JAK2- and MPL-non-mutated patients with suspected myeloproliferative neoplasm (MPN) from a large MPN clinic and confirm a diagnosis of MPN. METHODS: JAK2/MPL-non-mutated patients from the Belfast City Hospital (BCH) with either of the MPNs - ET or MF - and diagnosed between 1988 and 2014 were selected for CALR screen. All cases were validated according to the WHO 2008 classification for MPNs. Statistical analysis was performed with Minitab 16 Statistical Software package. Exon 9 of CALR was amplified by PCR using genomic DNA, and mutations were detected by fragment analysis. RESULTS: Of the 62 JAK2/MPL-non-mutated MPN patients screened, 57 had ET and 5 had MF; 34 patients (53.1%) carried CALR mutations. Three of 5 MF patients were CALR positive. Thirty-one ET patients (54.3%) harboured CALR mutation, whereas 26 (45.7%) were classified as 'triple negatives'. CONCLUSION: Detection of CALR mutations in a cohort of JAK2/MPL-non-mutated patients with suspected MPN confirmed the diagnosis of MPN in around 53% of cases. This is lower than initially reported, but similar to subsequent studies. However, a sizable cohort of patients remains lacking a specific molecular marker.

Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.

Prevalence and antimicrobial resistance pattern of Salmonella in animal feed produced in Namibia.

The occurrence of Salmonella is a global challenge in the public health and food production sectors. Our study investigated the prevalence, serovar and antimicrobial susceptibility of strains of Salmonella serovars isolated from animal feed (meat-and-bone and blood meal) samples from two commercial abattoirs in Namibia. A total of 650 samples (n=650) were examined for the presence of Salmonella. Results showed that 10.9% (n=71) were positive for Salmonella. Of the Salmonella serovars isolated, S. Chester was the most commonly isolated serovar (19.7%), followed by S. Schwarzengrund at 12.7%. From the Salmonella isolates, 19.7% (n=14) were resistant to one or more of the antimicrobials (nalidixic acid, trimethoprim-sulfamethoxazole, sulfisoxazole, streptomycin and/or tetracycline), whereas 80.3% (n=57) were susceptible to all 16 antimicrobials tested. Resistance to sulfisoxazole and the trimethroprimsuflamethoxazole combination were the most common. The resistant isolates belonged to ten different Salmonella serovars. The susceptibility of most of the Salmonella isolated to the antimicrobials tested indicates that anti-microbial resistance is not as common and extensive in Namibia as has been reported in many other countries. It also appears that there is a range of antimicrobials available that are effective in managing Salmonella infections in Namibia. However, there is some evidence that resistance is developing and this will need further monitoring to ensure it does not become a problem.

NADH-cytochrome b5 reductase in a Turkish family with recessive congenital methaemoglobinaemia type I.

The development of cyanosis at birth, the so-called blue baby syndrome, alerts paediatricians to the presence of congenital heart disease. In rare cases where the arterial blood gas analysis is normal the cyanosis is a consequence of methaemoglobinaemia. There are three distinct origins of methaemoglobinaemia; the presence of a haemoglobin variant, environmental toxicity and deficiency of cytochrome b5 reductase (cb(5)r). Two children born to two sets of first-degree related parents were cyanotic from birth. Differential diagnosis eliminated cardiac and pulmonary abnormalities. Measurement of methaemoglobin levels confirmed recessive congenital methaemoglobinaemia (RCM) and treatment with ascorbic acid was commenced. In the absence of neurological defects, type I disease was diagnosed. Sequence analysis of CYB5R3 revealed two different missense mutations (one which is novel, Ile85Ser) in the two families. Neither of the mutations was located in the FAD or the NADH binding sites of cb(5)r, thus supporting a diagnosis of type I disease.

Mutation of the von Hippel-Lindau gene alters human cardiopulmonary physiology.

Intracellular responses to hypoxia are coordinated by the von Hippel-Lindau--hypoxia-inducible factor (VHL-HIF) transcriptional system. This study investigated the potential role of the VHL-HIF pathway in human systems-level physiology. Patients diagnosed with Chuvash polycythaemia, a rare disorder in which VHL signalling is specifically impaired, were studied during acute hypoxia and hypercapnia. Subjects breathed through a mouthpiece and ventilation was measured while pulmonary vascular tone was assessed echocardiographically. The patients were found to have elevated basal ventilation and pulmonary vascular tone, and ventilatory, pulmonary vasoconstrictive and heart rate responses to acute hypoxia were greatly increased, as were heart rate responses to hypercapnia. The patients also had abnormal pulmonary function on spirometry. This study's findings demonstrate that the VHL-HIF signalling pathway, which is so central to intracellular oxygen sensing, also regulates the organ systems upon which cellular oxygen delivery ultimately depends.

Pyruvate kinase deficient hemolytic anemia in the Northern Irish population.

A common cause of hereditary nonspherocytic hemolytic anemia is pyruvate kinase deficiency, which is associated with lifelong chronic hemolysis. Pyruvate kinase deficiency has a worldwide distribution with a higher prevalence in the Caucasian population, and especially in Europe and North America. It is inherited in an autosomal fashion and over 180 different mutations have been described. Investigation of hemolytic anemia in Northern Ireland has uncovered 4 new cases of pyruvate kinase deficiency. Molecular investigation revealed a total of six different mutations. One mutation (p.Arg495Val) is reported here for the first time in a homozygous patient. Another mutant PKLR allele harbored a nonsense and frameshift mutation in cis: c.[721G>T; 826delG]. Considering the three previously described Irish cases of pyruvate kinase deficiency, this study raises the total number of pyruvate kinase-deficient Irish patients to seven in which a total of nine mutant PKLR alleles were identified. This indicates the absence of a founder pyruvate kinase mutation in the Northern Ireland population. Although pyruvate kinase deficiency is prevalent in the Caucasian population it is not reflected in the number of individuals diagnosed in Northern Ireland. Hence, many cases of pyruvate kinase deficiency may remain undetected possibly due to the resultant anemia being mild.

Genetically heterogeneous origins of idiopathic erythrocytosis.

The idiopathic erythrocytosis (IE) group of disorders is defined by an absolute increase in red cell mass and hematocrit without elevation of the megakaryocytic or granulocytic lineages. It is associated with a wide range of serum erythropoietin (Epo) levels and broadly falls into groups of raised/inappropriately normal or low/undetectable Epo levels. A spectrum of molecular defects has been described in association with IE, which reflects the heterogeneity of this disorder. To date the most common identified cause of IE has been mutations in the von Hippel Landau (VHL) protein, which results in aberrant oxygen sensing and dysregulated Epo production. Studying the molecular basis of IE will provide insights into the control of Epo synthesis and Epo-induced signaling pathways.

Induction of signalling in non-erythroid cells by pharmacological levels of erythropoietin.

Erythropoiesis is maintained by the hormone erythropoietin (Epo) binding to its cognate receptor (EpoR) on erythroid progenitor cells. The Epo-EpoR interaction initiates a signal transduction process that regulates the survival, growth and differentiation of these cells. Originally perceived as highly lineage-restricted, Epo is now recognised to have pleiotropic effects extending beyond the maintenance of red cell mass. Functional interactions between Epo and EpoR have been demonstrated in numerous cells and tissues. EpoR expression on neoplastic cells leads to concern that recombinant human erythropoietin, used to treat anaemia in cancer patients, may augment tumour growth. Here we demonstrate that EPO, at pharmacological concentrations, can activate three major signalling cascades, viz. the Jak2/STAT5, Ras/ERK and PI3K/Akt pathways in non-small cell lung carcinoma (NSCLC) cell lines. EpoR synthesis is normally under the control of GATA-1, but NSCLC cells exhibit decreased GATA-1 levels compared to GATA-2, -3 and -6, suggesting that GATA-1 is not essential for EpoR production. The increased Epo-induced signalling was not associated with a growth advantage for the NSCLC cells.

Novel and Mediterranean beta thalassemia mutations in the indigenous Northern Ireland population.

beta thalassemia is one of the most common genetic diseases worldwide resulting from aberrant beta-globin chain production. It is highly prevalent in regions with endemic malaria, but it is also present at low frequency in the indigenous populations of non-tropical areas such as Britain. Screening beta thalassemia trait individuals from Northern Ireland has detected 2 Mediterranean mutations, 39 (C --> T) and IVS-I-110 (G --> A); the previously reported IVS-II-850 (G --> A) mutation originally described in individuals of Scottish/English ancestry; and 2 novel mutations, initiation codon A --> C and 109 delG. Haplotype analysis indicates that the Mediterranean mutations are present on previously described haplotypes, suggesting that they have arisen due to migration. It remains to be established whether the novel mutations have arisen de novo in Northern Ireland.