Skeletal Fluorosis: An Unusual Manifestation of Computer Cleaner Inhalant Abuse.

Skeletal fluorosis is a metabolic bone disease caused by accumulation of fluoride and is generally associated with chronic exposure to fluoride-contaminated groundwater, a phenomenon endemic to developing countries. Whereas elevated water fluoride concentrations do not constitute a public health issue in the United States, emergence of skeletal fluorosis as a sequela of chronic recreational exposures has been described. In this case report, our 33-year-old male patient with a history of major depressive disorder and substance abuse was hospitalized for hyperkalemia and acute kidney injury discovered on routine bloodwork due to concomitant nonsteroidal anti-inflammatory drugs (NSAID) and antihypertensive use. Upon hospital admission, he was found to be anemic with a significantly elevated alkaline phosphatase. Given a history of low back pain in the setting of these laboratory abnormalities, lower spine and pelvic imaging revealed diffusely increased bone density and sclerosis. Hematologic evaluation ensued to include a peripheral smear and bone marrow biopsy. Given the patient's history of computer cleaner inhalant abuse, serum and urinary fluoride levels were obtained. Serum fluoride returned within normal limits though urinary fluoride was increased. Bone marrow histopathology revealed prominent diffuse sclerosis which in conjunction with urinary fluoride levels and computer cleaner inhalant abuse history supported the diagnosis of skeletal fluorosis. Skeletal fluorosis in the United States is rare and presents with non-specific findings requiring a high index of suspicion based on a detailed patient history for expedient diagnosis.

Survival of Casualties Undergoing Prehospital Supraglottic Airway Placement Versus Cricothyrotomy.

BACKGROUND: Airway compromise is the second leading cause of preventable death on the battlefield. Unlike a cricothyrotomy, supraglottic airway (SGA) placement does not require an incision and is less technically challenging. We compare survival of causalities undergoing cricothyrotomy versus SGA placement. METHODS: We used a series of emergency department (ED) procedure codes to search within the Department of Defense Trauma Registry (DoDTR) from January 2007 to August 2016. This is a subanalysis of that dataset. RESULTS: During the study period, 194 casualties had a documented cricothyrotomy and 22 had a documented SGA as the sole airway intervention. The two groups had similar proportions of explosive injuries (57.7% versus 63.6%, p = .328), similar composite injury severity scores (25 versus 27.5, p = .168), and similar AIS for the head, face, extremities, and external body regions. The cricothyrotomy group had lower AIS for the thorax (0 versus 3, p = .019) a trend toward lower AIS for the abdomen (0 versus 0, p = .077), more serious injuries to the head (67.5% versus 45.5%, p = .039), and similar rates of serious injuries to the face (4.6% versus 4.6%, p = .984). Glasgow Coma Scale (GCS) scores were similar upon arrival to the ED (3 versus 3, p = .467) as were the proportion of patients surviving to discharge (45.4% versus 40.9%, p = .691). On repeated multivariable analyses, the odds ratios (ORs) for survival were not significantly different between the two groups. CONCLUSION: We found no difference in short-term outcomes between combat casualties who received an SGA vs cricothyrotomy. Military prehospital personnel rarely used either advanced airway intervention during the recent conflicts in Afghanistan and Iraq.

Survival of Casualties Undergoing Prehospital Supraglottic Airway Placement Versus Cricothyrotomy.

BACKGROUND: Airway compromise is the second leading cause of preventable death on the battlefield. Unlike a cricothyrotomy, supraglottic airway (SGA) placement does not require an incision and is less technically challenging. We compare the survival of causalities undergoing cricothyrotomy versus SGA placement. METHODS: We used a series of emergency department (ED) procedure codes to search within the Department of Defense Trauma Registry (DODTR) from January 2007 to August 2016. This is a subanalysis of that data set. RESULTS: During the study period, 194 casualties had a documented cricothyrotomy and 22 had a documented SGA as the sole airway intervention. The two groups had similar proportions of explosive injuries (57.7% versus 63.6%, p = .328), similar composite injury severity scores (25 versus 27.5, p = .168), and similar AIS for the head, face, extremities, and external body regions. The cricothyrotomy group had lower AIS for the thorax (0 versus 3, p = .019), a trend toward lower AIS for the abdomen (0 versus 0, p = .077), more serious injuries to the head (67.5% versus 45.5%, p = .039), and similar rates of serious injuries to the face (4.6% versus 4.6%, p = .984). Glasgow Coma Scale (GCS) scores were similar on arrival to the ED (3 versus 3, p = .467) as were the proportion of patients surviving to discharge (45.4% versus 40.9%, p = .691). On repeated multivariable analyses, the odds ratios for survival were not significantly different between the two groups. CONCLUSIONS: We found no difference in short-term outcomes between combat casualties who received an SGA vs those who received a cricothyrotomy. Military prehospital personnel rarely used either advanced airway intervention during the recent conflicts in Afghanistan and Iraq.

Therapeutic targeting of N-cadherin is an effective treatment for multiple myeloma.

Elevated expression of the cell adhesion molecule N-cadherin (cadherin 2, type 1, N-cadherin (neuronal); CDH2) is associated with poor prognosis in newly-diagnosed multiple myeloma (MM) patients. In this study, we investigated whether targeting of N-cadherin represents a potential treatment for the ~50% of MM patients with elevated N-cadherin. Initially, we stably knocked-down N-cadherin in the mouse MM plasma cell (PC) line 5TGM1 to assess the functional role of N-cadherin in MM pathogenesis. When compared with 5TGM1-scramble-shRNA cells, 5TGM1-Cdh2-shRNA cells had significantly reduced adhesion to bone marrow endothelial cells. However, N-cadherin knock-down did not affect 5TGM1 cell proliferation or adhesion to bone marrow stromal cells. In the C57BL/KaLwRij murine MM model, mice intravenously inoculated with 5TGM1-Cdh2-shRNA cells showed significantly decreased tumour burden after 4 weeks, compared with animals bearing 5TGM1-scramble-shRNA cells. Finally, the N-cadherin antagonist ADH-1 had no effect on tumour burden in the established disease setting, whereas up-front ADH-1 treatment resulted in significantly reduced tumour burden after 4 weeks. Our findings demonstrate that N-cadherin may play a key role in the extravasation of circulating MM PCs promoting bone marrow homing. Moreover, these studies suggest that N-cadherin may represent a viable therapeutic target to prevent the dissemination of MM PCs and delay MM disease progression.

Tetraspanin 7 (TSPAN7) expression is upregulated in multiple myeloma patients and inhibits myeloma tumour development in vivo.

BACKGROUND: Increased expression of the tetraspanin TSPAN7 has been observed in a number of cancers; however, it is unclear how TSPAN7 plays a role in cancer progression. METHODS: We investigated the expression of TSPAN7 in the haematological malignancy multiple myleoma (MM) and assessed the consequences of TSPAN7 expression in the adhesion, migration and growth of MM plasma cells (PC) in vitro and in bone marrow (BM) homing and tumour growth in vivo. Finally, we characterised the association of TSPAN7 with cell surface partner molecules in vitro. RESULTS: TSPAN7 was found to be highly expressed at the RNA and protein level in CD138(+) MM PC from approximately 50% of MM patients. TSPAN7 overexpression in the murine myeloma cell line 5TGM1 significantly reduced tumour burden in 5TGM1/KaLwRij mice 4 weeks after intravenous adminstration of 5TGM1 cells. While TSPAN7 overexpression did not affect cell proliferation in vitro, TSPAN7 increased 5TGM1 cell adhesion to BM stromal cells and transendothelial migration. In addition, TSPAN7 was found to associate with the molecular chaperone calnexin on the cell surface. CONCLUSION: These results suggest that elevated TSPAN7 may be associated with better outcomes for up to 50% of MM patients.

Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma.

Histone deacetylases (HDAC) control gene expression through their ability to acetylate proteins, thereby influencing a diverse range of cellular functions. Class I HDAC (HDAC1-3 and 8) and HDAC6 are predominantly upregulated in malignancies and their altered expression in some cancers has a significant prognostic implication. The expression and prognostic consequence of dysregulated Class I HDAC and HDAC6, key players in multiple myeloma (MM), are unknown. This study hypothesized that HDAC are dysregulated in MM and patients with high expression have significantly poorer prognostic outcomes. Quantitative PCR for 11 HDAC (Class I, II, and IV) was performed in genetically heterogeneous human myeloma cell lines (HMCL) and primary MM and compared to normal plasma cells (PC). In HMCL, HDAC1-3 and 8 (Class I), and HDAC5 and HDAC10 (Class II) were significantly upregulated compared to normal PC. In primary MM, the median expression level of all of the HDAC, except HDAC1 and HDAC11, were elevated when compared to normal PC. Patients with higher levels of HDAC1-3, HDAC4, HDAC6, and HDAC11 transcripts demonstrated a significantly shorter progression-free survival (PFS). Immunohistochemical staining for HDAC1 and HDAC6 on bone marrow trephines from a uniformly treated cohort of transplant eligible MM patients revealed that HDAC1 protein was detectable in most patients and that higher levels of MM cell HDAC1 protein expression (≥90 % versus ≤20 % MM cell positivity) correlated with both shorter PFS (P = 0 .07) and shorter overall survival (P = 0 .003). Conversely, while the majority of patients expressed HDAC6, there was no correlation between HDAC6 levels and patient outcome. Together, these results indicate that overexpression of Class I HDAC, particularly HDAC1, is associated with poor prognosis in MM.

Alpha thalassaemia due to non-deletional mutations on the -3.7 alpha globin fusion gene: laboratory diagnosis and clinical importance.

AIMS: Alpha (α) thalassaemia may be caused by large deletions of the α globin gene(s), or rarely, non-deletional mutations. Both types of mutations may co-exist, and if located on the same allele (α), produce a reproductive risk of hydrops fetalis. We illustrate how clinical-laboratory correlation and accurate α gene sequencing are essential in identifying such patients. METHOD: Nine asymptomatic patients with -α thalassaemia trait were noted to have significant microcytosis that was insufficiently explained by a single α deletion. Hence α1 and α2 globin gene sequencing were performed, which detected a non-deletional mutation in all patients. A new set of α1 specific primers were designed for separate sequencing of the α1 gene and the -α fusion gene, respectively, so that the non-deletional mutation could be localised to the correct allele. RESULTS: In six of nine patients tested, the non-deletional mutation was on the α1 globin gene. In three patients the mutation was located on the -α fusion gene. The latter group functionally has an α allele (αα/-) with a reproductive risk for Hb Barts hydrops fetalis. CONCLUSION: Non-deletional mutations can occur on the α globin gene or a fusion gene such as the -α allele. Identification and accurate localisation of these mutations is important as this can have significant reproductive implications.

Emergency provider analgesic practices and attitudes toward patients with sickle cell disease.

STUDY OBJECTIVE: We determine whether emergency provider attitudes and demographics are associated with adherence to national guidelines for the management of acute sickle cell disease pain. METHODS: We conducted a cross-sectional survey of emergency providers at the 2011 annual American College of Emergency Physicians Scientific Assembly, using a validated instrument to assess provider attitudes and self-reported analgesic practices toward patients with sickle cell disease. Multivariable, relative risk regressions were used to identify factors associated with adherence to guidelines. RESULTS: There were 722 eligible participants, with a 93% complete response rate. Most providers self-reported adherence to the cornerstones of sickle cell disease pain management, including parenteral opioids (90%) and redosing opioids within 30 minutes if analgesia is inadequate (85%). Self-reported adherence was lower for other recommendations, including use of patient-controlled analgesia, acetaminophen, non-steroidal anti-inflammatory drugs and hypotonic fluids for euvolemic patients. Emergency providers in the highest quartile of negative attitudes were 20% less likely to redose opioids within 30 minutes for inadequate analgesia (risk ratio 0.8; 95% confidence interval [CI] 0.7 to 0.9). High-volume providers (those who treat more than 1 sickle cell disease patient per week), were less likely to redose opioids within 30 minutes for inadequate analgesia (risk ratio 0.9; 95% CI 0.8 to 0.9). Pediatric providers were 6.6 times more likely to use patient-controlled analgesia for analgesia (95% CI 2.6 to 16.6). CONCLUSION: The majority of emergency providers report that they adhere to national guidelines about use of opioids for sickle cell disease-related acute pain episodes. Other recommendations have less penetration. Negative attitudes toward individuals with sickle cell disease are associated with lower adherence to guidelines.

Circulating N-cadherin levels are a negative prognostic indicator in patients with multiple myeloma.

N-cadherin (cadherin 2, type 1, N-cadherin (neuronal); CDN2) is a homotypic adhesion molecule that is upregulated in breast, prostate and bladder cancer. Here we investigated the prognostic significance of upregulated N-cadherin expression in multiple myeloma (MM). Our results indicate that N-cadherin protein and gene expression is abnormally increased in trephine biopsies and CD38(++) /CD138(+) plasma cells from MM patients, when compared with those of normal donors. In addition, levels of circulating N-cadherin were elevated in a subset of patients with MM (n = 81; mean: 14·50 ng/ml, range: 0-146·78 ng/ml), relative to age-matched controls (n = 27; mean: 2·66 ng/ml, range: 0-5·96 ng/ml), although this did not reach statistical significance. Notably, patients with abnormally high levels of N-cadherin (>6 ng/ml) had decreased progression-free survival (P = 0·036; hazard ratio: 1·94) and overall survival (P = 0·002; hazard ratio: 3·15), when compared with patients with normal N-cadherin levels (≤6 ng/ml). Furthermore, multivariate analyses revealed that the combination of N-cadherin levels and International Staging System (ISS) was a more powerful prognostic indicator than using ISS alone. Collectively, our studies demonstrate that circulating N-cadherin levels are a viable prognostic marker for high-risk MM patients.

Wheezing and asthma are independent risk factors for increased sickle cell disease morbidity.

To assess the associations between a doctor diagnosis of asthma and wheezing (independent of a diagnosis of asthma) with sickle cell disease (SCD) morbidity, we conducted a retrospective review of Emergency Department (ED) visits to the Mount Sinai Medical Center for SCD between 1 January 2007 and 1 January 2011. Outcomes were ED visits for pain and acute chest syndrome. The cohort included 262 individuals, median age 23·8 years, (range: 6 months to 67·5 years). At least one episode of wheezing recorded on a physical examination was present in 18·7% (49 of 262). Asthma and wheezing did not overlap completely, 53·1% of patients with wheezing did not carry a diagnosis of asthma. Wheezing was associated with a 118% increase in ED visits for pain (95% confidence interval [CI]: 56-205%) and a 158% increase in ED visits for acute chest syndrome (95% CI: 11-498%). A diagnosis of asthma was associated with a 44% increase in ED utilization for pain (95% CI: 2-104%) and no increase in ED utilization for acute chest syndrome (rate ratio 1·00, 95%CI 0·41-2·47). In conclusion, asthma and wheezing are independent risk factors for increased painful episodes in individuals with SCD. Only wheezing was associated with more acute chest syndrome.