Statin-associated immune-mediated necrotizing myositis in Native Americans.

OBJECTIVES: Statin-associated immune-mediated necrotizing myopathy (IMNM) and idiopathic inflammatory myositis (IIM) are myopathies with overlapping features. This study compared the manifestations of IMNM to IIM in Native Americans. METHOD: Twenty-one Native American patients with inflammatory myopathy (IM) were characterized as to diabetes mellitus, hyperlipidaemia, statin exposure, myopathy diagnosis, muscle histology, autoimmune and myositis-specific autoantibodies, therapy and outcome. RESULTS: IM consisted of 52.4% IMNM, 42.9% IIM and 4.8% metabolic myopathy. IMNM vs IIM patients were older [61.6 years (s.d. 9.8) vs 39.8 (14.3)], diabetes mellitus (100% vs 55.6%), hyperlipidaemia (100% vs 33.3%), statin-exposure (100% vs 22.2%), creatine kinase [CK; 11 780 IU (s.d. 7064) vs 1707 (1658)], anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibodies (85.7% vs 11.1%) and necrotizing IM (81.8% vs 11.1%), but shorter disease duration [26.2 months (s.d. 395) vs 78.4 (47.9)], RP (9.1% vs 55.6%), cutaneous manifestations (0% vs 55.6%), ANA (18.2% vs 66.7%) or any autoantibody (18.2% vs 88.9%) (all P < 0.05). MRI abnormalities, histologic IM, myositis-specific autoantibodies, pulmonary hypertension, oesophageal dysfunction, interstitial lung disease, disability and persistently elevated CK were similar. IMNM vs IIM was treated more with IVIG (72.7% vs 11.1%; P = 0.009) and less with antimetabolites (45.5% vs 88.9%; P = 0.05) and rituximab (18.2% vs 55.6%; P = 0.09). CONCLUSIONS: IMNM may occur in Native Americans and is associated with diabetes mellitus, hyperlipidaemia, statin use and older age and is characterized by marked CK elevation, necrotizing myopathy and anti-HMGCR antibodies with few cutaneous or vascular manifestations.

Intraarticular injection of the interphalangeal joint for therapy of digital mucoid cysts.

Mucoid cysts are associated with osteoarthritis (OA) of the digital joints and frequently recur after needle drainage, injection, or surgical ablation. This study determined whether intraarticular injection of the adjacent interphalangeal joint rather than the cyst itself might be effective in resolving digital mucoid cysts. Using paired case series design and sterile technique, 25 consecutive OA digital joints with an adjacent mucoid cyst underwent dorsal non-transtendinous intraarticular injection with a 25-gauge needle and 20-mg triamcinolone acetonide, followed by puncture and manual expression of cyst fluid. Patient pain was measured with the 10-cm Visual Analogue Pain Scale prior to the procedure and at 6 months. Cyst resolution was determined at 6 months and 3 years. The subjects were 61.0 ± 7.7 years old and 60% (15/25) female. Mucoid cysts were adjacent to 19 distal interphalangeal, 3 metacarpophalangeal, and 3 interphalangeal joints. Pre-procedural pain was 4.7 ± 1.0; procedural pain was 6.2 ± 0.6 cm, and post-procedural pain at 6 months was 1.2 ± 0.8 cm (74.5% reduction, 95% CI of difference: 3.0 < 3.5 < 4.0 (p < 0.0001)). 84% (21/25) of the cysts resolved at 6 months; however, 60% (15/25) of the mucoid cysts recurred within 3 years and required retreatment (14 adjacent joints re-injected and 1 ablative cyst surgery). No complications were noted. Intraarticular corticosteroid injection using a dorsal non-transtendinous approach of the joint adjacent to a mucoid cyst is effective resolving cysts and reducing pain at 6 months; however, 60% of mucoid cysts reoccur within 3 years and may require reinjection or surgery.Trial registration: This was not a clinical trial.

Hypertension and Acute Mountain Sickness in Himalayan Trekkers in Nepal: An Observational Cohort Study.

INTRODUCTION: A history of preexisting hypertension is common in people participating in mountain activities; however, the relationship between blood pressure (BP), preexisting hypertension, and acute mountain sickness (AMS) is not well studied. We sought to determine these relationships among trekkers in the Everest region of Nepal. METHODS: This was a prospective observational cohort study of a convenience sample of adult, nonpregnant volunteers trekking in the Everest Base Camp region in Nepal. We recorded Lake Louise Scores for AMS and measured BP at 2860 m, 3400 m, and 4300 m. The primary outcome was AMS. RESULTS: A total of 672 trekkers (including 60 with history of preexisting hypertension) were enrolled at 2860 m. We retained 529 at 3400 m and 363 at 4300 m. At 3400 m, 11% of participants had AMS, and 13% had AMS at 4300 m. We found no relationship between AMS and measured BP values (P>0.05), nor was there any relation of BP to AMS severity as measured by higher Lake Louise Scores (P>0.05). Preexisting hypertension (odds ratio [OR] 0.16; 95% CI 0.025-0.57), male sex (OR 0.59; 95% CI 0.37-0.96), and increased SpO2 (OR 0.93; 95% CI 0.87-0.98) were associated with reduced rates of AMS in multivariate analyses adjusting for known risk factors for AMS. CONCLUSIONS: AMS is common in trekkers in Nepal, even at 3400 m. There is no relationship between measured BP and AMS. However, a medical history of hypertension may be associated with a lower risk of AMS. More work is needed to confirm this novel finding.

Prion protein promotes kidney iron uptake via its ferrireductase activity.

Brain iron-dyshomeostasis is an important cause of neurotoxicity in prion disorders, a group of neurodegenerative conditions associated with the conversion of prion protein (PrP(C)) from its normal conformation to an aggregated, PrP-scrapie (PrP(Sc)) isoform. Alteration of iron homeostasis is believed to result from impaired function of PrP(C) in neuronal iron uptake via its ferrireductase activity. However, unequivocal evidence supporting the ferrireductase activity of PrP(C) is lacking. Kidney provides a relevant model for this evaluation because PrP(C) is expressed in the kidney, and ∼370 µg of iron are reabsorbed daily from the glomerular filtrate by kidney proximal tubule cells (PT), requiring ferrireductase activity. Here, we report that PrP(C) promotes the uptake of transferrin (Tf) and non-Tf-bound iron (NTBI) by the kidney in vivo and mainly NTBI by PT cells in vitro. Thus, uptake of (59)Fe administered by gastric gavage, intravenously, or intraperitoneally was significantly lower in PrP-knock-out (PrP(-/-)) mouse kidney relative to PrP(+/+) controls. Selective in vivo radiolabeling of plasma NTBI with (59)Fe revealed similar results. Expression of exogenous PrP(C) in immortalized PT cells showed localization on the plasma membrane and intracellular vesicles and increased transepithelial transport of (59)Fe-NTBI and to a smaller extent (59)Fe-Tf from the apical to the basolateral domain. Notably, the ferrireductase-deficient mutant of PrP (PrP(Δ51-89)) lacked this activity. Furthermore, excess NTBI and hemin caused aggregation of PrP(C) to a detergent-insoluble form, limiting iron uptake. Together, these observations suggest that PrP(C) promotes retrieval of iron from the glomerular filtrate via its ferrireductase activity and modulates kidney iron metabolism.

Comparative toxicogenomic responses of mercuric and methyl-mercury.

BACKGROUND: Mercury is a ubiquitous environmental toxicant that exists in multiple chemical forms. A paucity of information exists regarding the differences or similarities by which different mercurials act at the molecular level. RESULTS: Transcriptomes of mixed-stage C. elegans following equitoxic sub-, low- and high-toxicity exposures to inorganic mercuric chloride (HgCl2) and organic methylmercury chloride (MeHgCl) were analyzed. In C. elegans, the mercurials had highly different effects on transcription, with MeHgCl affecting the expression of significantly more genes than HgCl2. Bioinformatics analysis indicated that inorganic and organic mercurials affected different biological processes. RNAi identified 18 genes that were important in C. elegans response to mercurial exposure, although only two of these genes responded to both mercurials. To determine if the responses observed in C. elegans were evolutionarily conserved, the two mercurials were investigated in human neuroblastoma (SK-N-SH), hepatocellular carcinoma (HepG2) and embryonic kidney (HEK293) cells. The human homologs of the affected C. elegans genes were then used to test the effects on gene expression and cell viability after using siRNA during HgCl2 and MeHgCl exposure. As was observed with C. elegans, exposure to the HgCl2 and MeHgCl had different effects on gene expression, and different genes were important in the cellular response to the two mercurials. CONCLUSIONS: These results suggest that, contrary to previous reports, inorganic and organic mercurials have different mechanisms of toxicity. The two mercurials induced disparate effects on gene expression, and different genes were important in protecting the organism from mercurial toxicity.

The CD4+ T cell repertoire specific for citrullinated peptides shows evidence of immune tolerance.

Rheumatoid arthritis occurs most often in people who express HLA-DR molecules containing a five aa "shared epitope" in the ß chain. These MHCII molecules preferentially bind citrullinated peptides formed by posttranslational modification of arginine. Citrullinated peptide:HLA-DR complexes may act as arthritis-initiating neo-antigens for CD4+ T cells. Here, we used fluorophore-conjugated HLA-DR tetramers containing citrullinated peptides from human cartilage intermediate layer protein, fibrinogen, vimentin, or enolase 1 to track cognate CD4+ T cells. Immunization of HLA-DR transgenic mice with citrullinated peptides from vimentin or enolase 1 failed to cause any expansion of tetramer-binding cells, whereas immunization with citrullinated peptides from cartilage intermediate layer protein or fibrinogen elicited some expansion. The expanded tetramer-binding populations, however, had lower T helper 1 and higher regulatory T cell frequencies than populations elicited by viral peptides. These results indicate that HLA-DR-bound citrullinated peptides are not neo-antigens and induce varying degrees of immune tolerance that could pose a barrier to rheumatoid arthritis.

Outcomes and Complications of Corticosteroid Injection of Rheumatoid Nodules.

Objective: Rheumatoid nodules (RN), a classic cutaneous extra-articular manifestation of rheumatoid arthritis, can often cause discomfort or cosmetic embarrassment. This research determined the effectiveness and complications of corticosteroid injection of the RN. Methods: Using a repeated measure design, 66 consecutive symptomatic RN were measured, underwent corticosteroid injection with 1 to 2mL of a 50:50 mixture of 1% lidocaine and triamcinolone acetonide (20-40mg), and then reassessed at four months for softening, reduction in size, and complications, including infection. Results: The mean age of our patient group was 53.3±10.6 years; 45 percent were Hispanic, 55 percent were non-Hispanic White, 100 percent were seropositive (rheumatoid factor and/or anti-CCP antibody), and 87.5 percent were female. Baseline mean RN diameter was 0.50±0.51cm and four months after injection was reduced to 0.29±0.33cm (decreased 42% or 0.21±0.57cm reduction, 95% CI: 0.46 <0.21< 0.37, p=0.013), 100 percent (66/66) were less painful, and 77 percent (51/66) were palpably softened. However, 70 percent (46/66) demonstrated cutaneous atrophy and/or hypopigmentation at four months, 53 percent (35/66) nodules recurred within 12 months, and 47 percent (31/66) nodules were eventually surgically removed. Limitations: Two (3%) of the larger RN (2.5cm on the olecranon and 2cm on the 2nd toe) became infected and failed antibiotic therapy, necessitating surgical excision for complete resolution. Conclusion: For short-term symptomatic relief, smaller RN can be safely injected with triamcinolone. Large symptomatic RN (≥2cm) are at greater risk of infection; thus, in these cases, lower corticosteroid doses or surgical excision may be preferred. In the long-term, effective systemic antirheumatic therapy with treat-to-target is the best approach.

Enhanced arthrocentesis of the effusive knee with pneumatic compression.

AIM: Complete arthrocentesis of the effusive knee ameliorates patient pain, reduces intra-articular and intraosseous pressure, removes inflammatory cytokines, and has been shown to substantially improve the therapeutic outcomes of intra-articular injections. However, conventional arthrocentesis incompletely decompresses the knee, leaving considerable residual synovial fluid in the intra-articular space. The present study determined whether external pneumatic circumferential compression of the effusive knee permitted more successful arthrocentesis and complete joint decompression. METHODS: Using a paired sample design, 50 consecutive effusive knees underwent conventional arthrocentesis and then arthrocentesis with pneumatic compression. Pneumatic compression was applied to the superior knee using a conventional thigh blood pressure cuff inflated to 100 mm Hg which compressed the suprapatellar bursa and patellofemoral joint, forcing fluid from the superior knee to the anterolateral portal where the fluid could be accessed. Arthrocentesis success and fluid yield in mL before and after pneumatic compression were determined. RESULTS: Successful diagnostic arthrocentesis (≥3 mL) of the effusive knee was 82% (41/50) with conventional arthrocentesis and increased to 100% (50/50) with pneumatic compression (P = .001). Synovial fluid yields increased by 144% (19.8 ± 17.1 mL) with pneumatic compression (conventional arthrocentesis; 13.7 ± 16.4 mL, pneumatic compression: 33.4 ± 26.5 mL; 95% CI: 10.9 < 19.7 < 28.9 mL, P < .0001). CONCLUSIONS: Conventional arthrocentesis routinely does not fully decompress the effusive knee. External circumferential pneumatic compression markedly improves arthrocentesis success and fluid yield, and permits complete decompression of the effusive knee. Pneumatic compression of the effusive knee with a thigh blood pressure cuff is an inexpensive and widely available technique to improve arthrocentesis outcomes.

Systemic sclerosis in Native Americans of the American Southwest.

OBJECTIVE: Many indigenous non-Caucasian populations, including Native Americans, have been reported to have higher rates, distinct clinical phenotypes, increased complications, and greater severity of systemic sclerosis (SSc). However, little is known of SSc specifically in Native Americans of the American Southwest. This study compared the clinical and serologic manifestations and outcomes of SSc in Native Americans and non-Native Americans (non-Natives) of this region. METHODS: This cross-sectional retrospective study included 137 SSc patients (109 [80%] were non-Native and 28 [20%] were Native Americans) followed over a mean of 11.5 ± 7.6 years. Participants were repetitively evaluated with medical history, physical examination, echocardiography, chest imaging, and serologic testing. Disease characteristics and outcomes were statistically compared between Native Americans and non-Native patients. RESULTS: The estimated prevalence of SSc in Native Americans was 40.0 cases/100 000 vs 17.1 cases/100 000 for non-Natives (odds ratio 2.34, 95% confidence interval [CI] 1.55-3.55, P < .001). The cohorts were similar in terms age, age of onset, limited vs diffuse cutaneous SSc, telangiectasias, gastroesophageal reflux disease, Raynaud phenomenon, serologies, interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, cancer prevalence, and overall mortality (all P > .05). However, for Native Americans, mortality specifically from fatal infections was 3.94-fold that of non-Natives (hazard ratio 6.88, 95% CI 1.37-34.64; P < .001). CONCLUSION: In Native Americans of the American Southwest, SSc is increased in prevalence but is phenotypically similar to SSc in non-Natives. However, mortality due specifically to infection is increased in Native Americans with SSc.

The Caenorhabditis elegans germ line regulates distinct signaling pathways to control lifespan and innate immunity.

The relationship between the mechanisms that control an organism's lifespan and its ability to respond to environmental challenges are poorly understood. In Caenorhabditis elegans, an insulin-like signaling pathway modulates lifespan and the innate immune response to bacterial pathogens via a common mechanism involving transcriptional regulation by the DAF-16/FOXO transcription factor. The C. elegans germ line also modulates lifespan in a daf-16-dependent manner. Here, we show that the germ line controls the innate immune response of C. elegans somatic cells to two different Gram-negative bacteria. In contrast to the insulin-like signaling pathway, the germ line acts via distinct signaling pathways to control lifespan and innate immunity. Under standard nematode culture conditions, the germ line regulates innate immunity in parallel to a known p38 MAPK signaling pathway, via a daf-16-independent pathway. Our findings indicate that a complex regulatory network integrates inputs from insulin-like signaling, p38 MAPK signaling, and germ line stem cells to control innate immunity in C. elegans. We also confirm that innate immunity and lifespan in C. elegans are distinct processes, as nonoverlapping regulatory networks control survival in the presence of pathogenic and nonpathogenic bacteria. Finally, we demonstrate that the p38 MAPK pathway in C. elegans is activated to a similar extent by both pathogenic and nonpathogenic bacteria, suggesting that both can induce the nematode innate immune response.

Blood Pressure Trends in Patients With Seropositive Rheumatoid Arthritis Compared With Controls Without Rheumatoid Arthritis: A Retrospective Cohort Study.

OBJECTIVE: Rheumatoid arthritis (RA) conveys an increased risk of cardiovascular disease (CVD), making it imperative that traditional CVD risk factors are well controlled. This study compared blood pressure (BP) trends over 13 years among patients with seropositive RA and patients without RA who received care within a large health care system in Minnesota. METHODS: This retrospective cohort study compared 774 patients with seropositive RA and 3254 patients without RA who were matched on sex and year of birth (±5 years) and observed between 2005 and 2017. Generalized estimating equation models were used for longitudinal analyses, with adjustment for demographics, body mass index, smoking status, Charlson Comorbidity Index, number of BP measurements, and number of antihypertensive and oral glucocorticoid medications. RESULTS: Patients both with and without RA had a mean age of 55 and were predominately female (78% with RA; 79% without RA). The mean follow-up was 6.3 (SD 3.4) years for patients with RA and 7.2 (SD 3.3) years for patients without RA. Overall, systolic BP, diastolic BP, and the number of prescribed antihypertensive medications did not differ between groups. Patients with RA were more likely to be current smokers compared with patients without RA (23% vs 11%; P < 0.01) and were less likely to have serum lipid measurements (75% vs 85%; P < 0.01). CONCLUSION: BP was similarly controlled in patients with seropositive RA and patients without RA. However, diastolic BP in patients with RA was trending up in most recent years. Patients with RA were also more likely to smoke compared with controls and were less likely to have serum lipid measurements.

Ambulatory Blood Pressure at Sea Level and High Altitude in a Climber with a Kidney Transplant and Hypertension.

Background and Objectives: High altitude may increase blood pressure (BP) and the kidney plays an important role in acclimatization. Little is known about how transplanted kidneys respond to the hypoxic stress at high altitude. We compared 24 hour ambulatory BP in a climber with a kidney transplant and hypertension at sea level and at high altitude (2860-4300 m). Methods: Welch-Allyn ABPM 6100 monitor was used to collect heart rate, systolic BP (SBP), and diastolic BP every 30 minutes while awake, and hourly while asleep. BP was monitored for 49 hours at sea level and for 53 hours at 2860-4300 m. Results: Overall mean SBP did not differ between altitudes. At high altitude, the participant's mean nocturnal BP increased, but this "reverse dipping" pattern was not observed at sea level. The participant had no evidence of altitude illness or infectious complications at high altitude. Conclusions: This case builds on previous reports that kidney transplant recipients may safely travel to high altitude. Further study is required to determine the generalizability to other travelers with kidney transplant and/or underlying hypertension, and the clinical significance of short-term elevated nocturnal BP at high altitude.

mdm2 Is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation.

The function of the p53 tumor suppressor protein must be highly regulated because p53 can cause cell death and prevent tumorigenesis. In cultured cells, the p90MDM2 protein blocks the transcriptional activation domain of p53 and also stimulates the degradation of p53. Here we provide the first conclusive demonstration that p90MDM2 constitutively regulates p53 activity in homeostatic tissues. Mice with a hypomorphic allele of mdm2 revealed a heretofore unknown role for mdm2 in lymphopoiesis and epithelial cell survival. Phenotypic analyses revealed that both the transcriptional activation and apoptotic functions of p53 were increased in these mice. However, the level of p53 protein was not coordinately increased, suggesting that p90MDM2 can inhibit the transcriptional activation and apoptotic functions of p53 in a manner independent of degradation. Cre-mediated deletion of mdm2 caused a greater accumulation of p53, demonstrating that p90MDM2 constitutively regulates both the activity and the level of p53 in homeostatic tissues. The observation that only a subset of tissues with activated p53 underwent apoptosis indicates that factors other than p90(MDM2) determine the physiological consequences of p53 activation. Furthermore, reduction of mdm2 in vivo resulted in radiosensitivity, highlighting the importance of mdm2 as a potential target for adjuvant cancer therapies.

Identification of ATF-7 and the insulin signaling pathway in the regulation of metallothionein in C. elegans suggests roles in aging and reactive oxygen species.

It has been proposed that aging results from the lifelong accumulation of intracellular damage via reactions with reactive oxygen species (ROS). Metallothioneins are conserved cysteine-rich proteins that function as efficient ROS scavengers and may affect longevity. To better understand mechanisms controlling metallothionein expression, the regulatory factors and pathways that controlled cadmium-inducible transcription of the C. elegans metallothionein gene, mtl-1, were identified. The transcription factor ATF-7 was identified in both ethylmethanesulfonate mutagenesis and candidate gene screens. PMK-1 and members of the insulin signaling pathway, PDK-1 and AKT-1/2, were also identified as mtl-1 regulators. Genetic and previous results support a model for the regulation of cadmium-inducible mtl-1 transcription based on the derepression of the constitutively active transcription factor ELT-2. In addition, knockdown of the mammalian homologs of PDK1 and ATF7 in HEK293 cells resulted in changes in metallothionein expression, suggesting that this pathway was evolutionarily conserved. The insulin signaling pathway is known to influence the aging process; however, various factors responsible for affecting the aging phenotype are unknown. Identification of portions of the insulin signaling pathway as regulators of metallothionein expression supports the hypothesis that longevity is affected by the expression of this efficient ROS scavenger.

Blood Pressure and Altitude: An Observational Cohort Study of Hypertensive and Nonhypertensive Himalayan Trekkers in Nepal.

Keyes, Linda E., Thomas Douglas Sallade, Charles Duke, Jennifer Starling, Alison Sheets, Sushil Pant, David S. Young, David Twillman, Nirajan Regmi, Benoit Phelan, Purshotam Paudel, Matthew McElwee, Luke Mather, Devlin Cole, Theodore McConnell, and Buddha Basnyat. Blood pressure and altitude: an observational cohort study of hypertensive and nonhypertensive Himalayan trekkers in Nepal. High Alt Med Biol. 18:267-277, 2017. OBJECTIVES: To determine how blood pressure (BP) changes with altitude in normotensive versus hypertensive trekkers. Secondary aims were to evaluate the prevalence of severe hypertension (BP ≥180/100 mmHg) and efficacy of different antihypertensive agents at high altitude. METHODS: This was an observational cohort study of resting and 24-hour ambulatory BP in normotensive and hypertensive trekkers at 2860, 3400, and 4300 m in Nepal. RESULTS: We enrolled 672 trekkers age 18 years and older, 60 with a prior diagnosis of hypertension. Mean systolic and diastolic BP did not change between altitudes in normotensive or hypertensive trekkers, but was higher in those with hypertension. However, there was large interindividual variability. At 3400 m, the majority (60%, n = 284) of normotensive participants had a BP within 10 mmHg of their BP at 2860 m, while 21% (n = 102) increased and 19% (n = 91) decreased. The pattern was similar between 3400 and 4300 m (64% [n = 202] no change, 21% [n = 65] increased, 15% [n = 46] decreased). BP decreased in a greater proportion of hypertensive trekkers versus normotensives (36% [n = 15] vs. 21% at 3400 m, p = 0.01 and 30% [n = 7] vs. 15% at 4300 m, p = 0.05). Severe hypertension occurred in both groups, but was asymptomatic. In a small subset of participants, 24-hour ambulatory BP monitoring showed that nocturnal BP decreased in normotensive (n = 4) and increased in hypertensive trekkers (n = 4). CONCLUSIONS: Most travelers, including those with well-controlled hypertension, can be reassured that their BP will remain relatively stable at high altitude. Although extremely elevated BP may be observed at high altitude in normotensive and hypertensive people, it is unlikely to be symptomatic. The ideal antihypertensive regimen at high altitude remains unclear.

Older age, chronic medical conditions and polypharmacy in Himalayan trekkers in Nepal: an epidemiologic survey and case series.

BACKGROUND: The number of tourists in Nepal doubled between 2003 and 2013 is nearly 800 000. With the increased popularity of trekking, the number of those with pre-existing medical conditions requiring access to healthcare is likely to increase. We therefore sought to characterize the demographics and health status of trekkers on the Everest Base Camp route in the Solukhumbu Valley. In addition, we report cases that illustrate the potential complications of an ageing and medicated population of trekkers with underlying diseases. METHODS: Trekkers over 18 years were enrolled in a larger observational cohort study on blood pressure at high altitude at 2860 m. They answered a questionnaire regarding demographics, medical history and current medications. Acute medical problems relating to medication use that were brought to the attention of investigators were documented and are presented as case reports. RESULTS: We enrolled 670 trekkers, 394 (59%) male, with a mean age of 48 years (range 18-76). Pre-existing medical conditions were reported by 223 participants (33%). The most frequent conditions included hypertension, hypercholesterolemia, migraines and thyroid dysfunction. A total of 276 participants (41%) reported taking one or more medications. The most common medications were acetazolamide (79, 12%), antihypertensives (50, 8%) and NSAIDs (47, 7%), with 30 classes of drugs represented. Excluding acetazolamide, older trekkers (age >50 years) were more likely than younger ones to take medications (OR = 2.17; 95% CI 1.57-3.00; P <0.05). Acetazolamide use was not related to age. CONCLUSIONS: Our findings illustrate a wide variety of medical conditions present in trekkers in Nepal with wide-ranging potential complications that could pose difficulties in areas where medical care is scarce and evacuation difficult. Our cases illustrate the potential problems polypharmacy poses in trekkers, and the need for local and expedition healthcare workers to be aware of, and prepared for the common medical conditions present.

Iron in neurodegenerative disorders of protein misfolding: a case of prion disorders and Parkinson's disease.

SIGNIFICANCE: Intracellular and extracellular aggregation of a specific protein or protein fragments is the principal pathological event in several neurodegenerative conditions. We describe two such conditions: sporadic Creutzfeldt-Jakob disease (sCJD), a rare but potentially infectious and invariably fatal human prion disorder, and Parkinson's disease (PD), a common neurodegenerative condition second only to Alzheimer's disease in prevalence. In sCJD, a cell surface glycoprotein known as the prion protein (PrP(C)) undergoes a conformational change to PrP-scrapie, a pathogenic and infectious isoform that accumulates in the brain parenchyma as insoluble aggregates. In PD, α-synuclein, a cytosolic protein, forms insoluble aggregates that accumulate in neurons of the substantia nigra and cause neurotoxicity. RECENT ADVANCES: Although distinct processes are involved in the pathogenesis of sCJD and PD, both share brain iron dyshomeostasis as a common associated feature that is reflected in the cerebrospinal fluid in a disease-specific manner. CRITICAL ISSUES: Since PrP(C) and α-synuclein play a significant role in maintaining cellular iron homeostasis, it is important to understand whether the aggregation of these proteins and iron dyshomeostasis are causally related. Here, we discuss recent information on the normal function of PrP(C) and α-synuclein in cellular iron metabolism and the cellular and biochemical processes that contribute to iron imbalance in sCJD and PD. FUTURE DIRECTIONS: Improved understanding of the relationship between brain iron imbalance and protein aggregation is likely to help in the development of therapeutic strategies that can restore brain iron homeostasis and mitigate neurotoxicity.

Comparative toxicology of mercurials in Caenorhabditis elegans.

Mercury (Hg) is a toxic metal that can exist in multiple chemical species. Humans are commonly exposed to methylmercury and Hg vapor, which are converted to mercuric species in the body. Despite years of research, little information exists on the similarities and differences in the mechanisms of Hg toxicity. The relative toxicity of mercuric chloride (HgCl(2)) and methylmercury chloride (MeHgCl) in Caenorhabditis elegans was determined in assays that measured growth, feeding, reproduction, and locomotion. The effect of HgCl(2) and MeHgCl on the expression of several archetypal stress-response genes was also determined. There was no significant difference between the EC50s of the two mercurials in terms of C. elegans growth. However, MeHgCl was more toxic to C. elegans than HgCl(2) when assessing feeding, movement, and reproduction, all of which require proper neuromuscular activity. Methylmercury chloride exposure resulted in increased steady-state levels of the stress response genes at lower concentrations than HgCl(2). In general, MeHgCl was more toxic to C. elegans than HgCl(2), particularly when assaying behaviors that require neuromuscular function.

Copper activation of NF-kappaB signaling in HepG2 cells.

Copper is a persistent environmental contaminant, and exposure to elevated levels of this transition metal can result in a variety of pathologies. Copper affects the transcription of multiple defense and repair genes to protect against metal-induced pathologies. HepG2 cells were treated with copper under multiple conditions and microarray analyses were previously performed to better understand the mechanisms by which copper affects the transcription of stress-responsive genes. Analysis of the microarray data indicated that copper modulates multiple signal transduction pathways, including those mediated by NF-kappaB. Luciferase assays, quantitative reverse transcription real-time PCR, and chemical inhibition in HepG2 cells validated the microarray results and confirmed that NF-kappaB was activated by stress-inducible concentrations of copper. In addition, two novel NF-kappaB-regulated genes, SRXN1 (sulfiredoxin 1 homolog) and ZFAND2A (zinc-finger, AN1-type domain 2A), were identified. Our results indicate that the activation of NF-kappaB may be important for survival under elevated concentrations of copper.