Disease propagation in amyotrophic lateral sclerosis (ALS): an interplay between genetics and environment.

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease affecting the neuromuscular system. While there have been a number of important genetic discoveries, there are no therapeutics capable of stopping its insidious progression. Lessons from clinical histories reveal that ALS can start focally at a single limb, but then segmentally spread up and down the spinal cord as well as in the motor cortex and cortex of frontal and temporal lobes until respiratory muscles fail. With or without a clear genetic etiology, often there is no explanation as to why it starts in one region of the body versus another. Similarly, once the disease starts the mechanisms by which the neurodegenerative process spreads are not known. Here, we summarize recent work in animal models that support the hypothesis that critical environmental contributions, such as a nerve injury, can initiate the disease process. We also propose that pathological axoglial signaling by the glial growth factor neuregulin-1 leads to the slow propagation of neuroinflammation resulting in neurodegeneration up and down the spinal cord and that locally applied drugs that block neuregulin-1 signaling could slow or halt the spread of disease.

Mutant SOD1 prevents normal functional recovery through enhanced glial activation and loss of motor neuron innervation after peripheral nerve injury.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is poorly understood with no effective therapeutics. One long entertained observation is that ALS may be precipitated focally by nerve injury. Many patients with ALS are athletes or veterans, and some have suffered nerve injuries at the site where ALS first presents. Here we explore how a genetic SOD1 mutation alters the inflammatory response and affects functional recovery after an environmental insult in a rat model. METHODS: Unilateral sciatic nerve crush injuries were performed in SOD1 G93A rats prior to disease symptom onset. Functional recovery was compared between injured wild-type littermates and uninjured SOD1 rats. Spinal cord tissues were analyzed quantitatively for SOD1 expression, glial reactivity, and motor neuron synaptic integrity. RESULTS: Injured SOD1 rats failed to recover and showed hastened functional decline with decreased survival. Injury induced extracellular SOD1 expression was associated with heightened, prolonged microglial and astrogial activation in the ventral horn. This inflammatory response spread to uninjured motor neuron pools and was associated with increased motor neuron synaptic loss. DISCUSSION: This study identified a relationship between genetic and environmental contributions to disease onset and progression in ALS. The findings suggest that injury induced SOD1 mutant protein induces a heightened and prolonged inflammatory response resulting in motor neuron degeneration through synaptic loss. Once initiated, this process spreads to adjacent motor neurons leading to contiguous spread of the disease. Treatments that suppress this heightened glial response could slow disease progression in ALS patients with focal sites of disease onset. SIGNIFICANCE STATEMENT: The contribution of environmental factors such as peripheral nerve insults in ALS is not well understood. Here we examined the effect of a single sciatic nerve injury in SOD1 (G93A) rats to explore the contribution of this environmental insult on disease onset and progression. After the injury, SOD1 animals failed to recover and had a more rapid functional decline. Histopathologically, SOD1 animals had heightened SOD1 expression, microglial and astroglial responses, and a reduction of motor neuron innervation. Taken together, these results provide a plausible mechanism of how the SOD1 mutated protein promotes an abnormal response to injury that leads to neurodegenerative changes in an ALS model that is amenable to therapeutic testing.

A Review of the Association Between Parkinson Disease and Malignant Melanoma.

BACKGROUND: An association between melanoma and Parkinson disease (PD) has been hinted at in the neurology and oncology literature since the 1970s after the initiation of levodopa (L-DOPA) therapy for PD. Given that L-DOPA is a substrate in melanin synthesis, there existed a concern that this therapy might cause melanoma. OBJECTIVE: The objective was to research possible etiological links to explain the connection between PD and melanoma. METHODS: A PubMed and Google Scholar literature search was performed using access provided by the University of Minnesota biomedical library. RESULTS: Patients with PD have an overall decreased risk of cancer diagnoses. However, breast cancer and melanoma have an uncharacteristically high rate of co-occurrence with PD. Family history of melanoma and lighter hair and skin color confer a higher risk of developing PD, and having a first-degree relative with either disease conveys a significantly increased risk of developing the other. Other possible connections that have been explored include pigmentation genes in neural-derived cells, pesticides, MC1R polymorphisms, and abnormal cellular autophagy. CONCLUSION: Although a link between PD and melanoma exists, the etiology of this link continues to be elusive. Both PD and melanoma are likely multifactorial diseases involving genetic and environmental risk factors.

Canonical Wnt signaling is necessary for object recognition memory consolidation.

Wnt signaling has emerged as a potent regulator of hippocampal synaptic function, although no evidence yet supports a critical role for Wnt signaling in hippocampal memory. Here, we sought to determine whether canonical ß-catenin-dependent Wnt signaling is necessary for hippocampal memory consolidation. Immediately after training in a hippocampal-dependent object recognition task, mice received a dorsal hippocampal (DH) infusion of vehicle or the canonical Wnt antagonist Dickkopf-1 (Dkk-1; 50, 100, or 200 ng/hemisphere). Twenty-four hours later, mice receiving vehicle remembered the familiar object explored during training. However, mice receiving Dkk-1 exhibited no memory for the training object, indicating that object recognition memory consolidation is dependent on canonical Wnt signaling. To determine how Dkk-1 affects canonical Wnt signaling, mice were infused with vehicle or 50 ng/hemisphere Dkk-1 and protein levels of Wnt-related proteins (Dkk-1, GSK3ß, ß-catenin, TCF1, LEF1, Cyclin D1, c-myc, Wnt7a, Wnt1, and PSD95) were measured in the dorsal hippocampus 5 min or 4 h later. Dkk-1 produced a rapid increase in Dkk-1 protein levels and a decrease in phosphorylated GSK3ß levels, followed by a decrease in ß-catenin, TCF1, LEF1, Cyclin D1, c-myc, Wnt7a, and PSD95 protein levels 4 h later. These data suggest that alterations in Wnt/GSK3ß/ß-catenin signaling may underlie the memory impairments induced by Dkk-1. In a subsequent experiment, object training alone rapidly increased DH GSK3ß phosphorylation and levels of ß-catenin and Cyclin D1. These data suggest that canonical Wnt signaling is regulated by object learning and is necessary for hippocampal memory consolidation.

Partners for a healthy city: implementing policies and environmental changes within organizations to promote health.

Current research has suggested that obesity prevention efforts should promote policy and environmental changes. The Partners for a Healthy City project, implemented in Douglas County, Nebraska, focused on collaborating with local organizations to help them select and implement 1 or more policies that promoted healthy eating and physical activity. Of the 346 organizations participating in the project and completing the follow-up assessment, 92% implemented at least 1 new policy or expanded an existing policy related to healthy food and drink options and physical activity, totaling 952 individual policy changes. Common policies included providing water as the primary beverage and installing bike racks to support active commuting to and from work. These findings suggest widespread support for policy changes that promote community health.

Complications in cosmetic laser surgery: a review of 494 Food and Drug Administration Manufacturer and User Facility Device Experience Reports.

BACKGROUND: Complications in cosmetic laser and energy based surgery affect a number of patients every year and may cause scars, burns, blisters, and pigmentation damage. OBJECTIVE: To evaluate documented complications in cosmetic laser- and energy-based surgeries, determine the most common errors, and recommend a simple procedural sequence to reduce patient complications. MATERIALS AND METHODS: U.S. Food and Drug Administration Manufacturer and User Facility Device Experience Adverse Event Reports after cosmetic laser- and energy-based procedures with varied devices were reviewed (N = 494). The laser manufacturer, device used, event type, injury type, cause, operator, and indication for treatment for each case were identified. RESULTS: In the 494 cases reviewed between 2006 and 2011, the most common complications were burns, scarring, blistering, pigmentation damage, and infection. The most common cause of these complications was user error by a healthcare provider (30%), followed by laser device malfunction (20%) and patient error (4%). Indications for treatment were unknown for 69% of cases, and 38% of the cases were an unknown cause of complication. CONCLUSIONS: User error was a major factor in laser surgery complications. To improve safety and reduce errors, we propose the implementation of a procedural sequence for cosmetic laser surgery.

Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma using Mel-5 immunostaining: an update from the University of Minnesota.

BACKGROUND: Mohs micrographic surgery (MMS) is gaining acceptance as a treatment for lentigo maligna (LM) and lentigo maligna melanoma (LMM), especially with the use of melanocyte-staining immunohistochemical (IHC) stains. In 2006, we reported our 4-year experience with Mel-5 immunostaining, with only one recurrence noted in 200 patients after a mean follow-up of 38.4 months.(1) OBJECTIVES: We present an update regarding our 13-year experience with the use of Mel-5. METHODS AND MATERIALS: Patients with primary or recurrent LM or LMM (n = 260) underwent MMS with Mel-5; 174 were followed up to evaluate for recurrence, with a mean follow-up of 34 months. The 200 patients described in the initial case series from 1999 to 2003 were also followed. RESULTS: Of the 460 patients treated from January 1999 to December 2011, five recurrences were noted in four patients; one in the initial case series and four in this new, updated series, including one re-recurrence from the initial series. One melanoma-related death occurred in a patient intermittently lost to follow-up. CONCLUSION: MMS with Mel-5 immunostaining continues to yield excellent results in the treatment of LM and LMM.

Prevention of Alzheimer Pathology by Blocking Neuregulin Signaling on Microglia.

Plaque formation, microglial activation, and synaptic loss are pathologic hallmarks of Alzheimer's disease; however, removing plaques has had little clinical benefit. Here, we show that neuregulin-1, a glial growth factor, induces inflammatory cytokines and promotes phagocytic activity in vitro and augments microglial activation and plaque formation in 5XFAD Alzheimer's mice. Brain-specific targeting of neuregulin-1 by intraventricular delivery of a novel neuregulin-1 fusion protein antagonist, GlyB4, significantly alters microglial morphology and function to a nonpathogenic morphology in early-stage 5XFAD mice and prevents plaques from forming. Once plaques have already formed, GlyB4 reduces new plaque formation and prevents synaptic loss. Selective, targeted disruption of neuregulin-1 signaling on brain microglia with GlyB4 could be a novel "upstream" approach to slow or stop disease progression in Alzheimer's disease.

Healthy weight in young perinatal women: exploring beliefs.

The purpose of this brief is to explore beliefs about health and body weight in young perinatal women. Thirty-two women were interviewed. Findings point to the importance of young women receiving education related to physical activity, nutrition, and the link between these components and a healthy weight during reproductive years.

Type I allergy to insulin: case report and review of localized and systemic reactions to insulin.

Allergic reactions to insulin preparations are not uncommon. Although patients often present with skin symptoms, most articles on insulin allergy are published in endocrinology and allergy journals. The purpose of this report is to describe a case of localized type I allergy to insulin as well as provide a review of the classification of insulin allergy, methods of evaluation, and management options.

Black-spot poison ivy.

In black-spot poison ivy dermatitis, a black lacquerlike substance forms on the skin when poison ivy resin is exposed to air. Although the Toxicodendron group of plants is estimated to be the most common cause of allergic contact dermatitis in the United States, black-spot poison ivy dermatitis is relatively rare.

Neuregulin1 modulation of experimental autoimmune encephalomyelitis (EAE).

Neuregulin1 (NRG1) is a differentiation factor that regulates glial development, survival, synaptogenesis, axoglial interactions, and microglial activation. We previously reported that a targeted NRG1 antagonist (HBD-S-H4) given intrathecally, reduces inflammatory microglial activation in a spinal cord pain model and a neurodegenerative disease mouse model in vivo, suggesting that it may have effects in neuroninflammatory and neuronal disorders. We hypothesized that expression of HBD-S-H4 in the central nervous system (CNS) could reduce disease severity in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). In the present study, we generated tetO-HBD-S-H4, a single transgenic (Tg) mouse line in, which the fusion protein in expressed in the brain, resulting in reduction of disease severity in both male and female mice when compared to sex- and age-matched wild type littermates. We also generated GFAP-tTA:tetO-HBD-S-H4 double Tg mice, which express this fusion protein in the brain and the spinal cord, they displayed sex differences in the reduction of disease severity. In healthy mice, expression of HBD-S-H4 in the CNS does not result in any significant neurological or other overt phenotypes. In myelin oligodendrocyte glycoprotein (MOG)-induced EAE, female double Tg mice show delayed disease onset and reduced disease severity compared to male double Tg as well as wild type littermates. In male double Tg mice, the levels of HBD-S-H4 gene expression negatively correlates with disease severity and increased microglia associated genes' expression. In conclusion, expression of neuregulin antagonist in the brain and spinal cord protects females but not males, suggesting a complex interplay between NRG1 and sex difference in EAE that may be associated with microglia-mediated inflammation. This study provides important information for understanding the heterogeneity of disease pathology and the therapeutic potential of targeting microglial activation in male and female MS patients.

Evaluation of prospectively collected presenting signs/symptoms of biopsy-proven melanoma, basal cell carcinoma, squamous cell carcinoma, and seborrheic keratosis in an elderly male population.

BACKGROUND: Presenting signs/symptoms of skin cancer may aid in earlier detection and diagnosis. OBJECTIVE: We sought to compare prospectively collected, presenting signs/symptoms of malignant melanoma (MM), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and seborrheic keratosis (SK). METHODS: This analysis was part of a larger study on teledermatology involving 3039 skin neoplasms in 2152 patients at a Department of Veterans Affairs medical center. At presentation, participants were asked about signs/symptoms of specific skin lesions. In all, 912 biopsy-proven MM (39), BCC (411), SCC (238), and SK (224) were included in this analysis. Pearson chi(2) analyses were used to test associations of lesion type and specific signs/symptoms in pairwise comparisons. RESULTS: "No symptoms" was reported more often with MM (82%) as compared with BCC (relative risk [RR] 2.26, confidence interval [CI] 1.86, 2.75), SCC (RR 3.31, CI 2.54, 4.32), or SK (RR 2.0, CI 1.61, 2.48; all P < .0001). Tenderness was more commonly reported with SCC (40%) as compared with MM (RR 15.9, CI 2.28, 110.69), SK (RR 3.0, CI 2.11, 4.39), or BCC (RR 2.6, CI 1.97, 3.38; all P < .0001). Bleeding was more commonly reported with BCC (37%) as compared with SK (RR 2.3, CI 1.67, 3.20), SCC (RR 1.6, CI 1.22, 2.05), or MM (RR 29.8, CI 1.89, 469.65; all P

Genetics of nickel allergic contact dermatitis.

Nickel sulfate is the most frequently detected cause of allergic contact dermatitis in the world; the prevalence of nickel allergic contact dermatitis is between 8 and 11% in the general female population. Although it is well recognized that environmental factors are important in the pathogenesis of this dermatitis, some investigators have hypothesized that genetic factors are important as well. This review summarizes animal and human studies evaluating genetic factors in the development of allergic contact dermatitis from nickel.

Allergic contact cheilitis from benzophenone-3 in lip balm and fragrance/flavorings.

Benzophenones are the most frequent cause of sunscreen allergy. Photoallergic and nonphotoallergic reactions may occur. We present a patient with allergic contact dermatitis of the lips from benzophenone-3 in a lip balm and fragrance/flavorings.

Shoe allergens: retrospective analysis of cross-sectional data from the north american contact dermatitis group, 2001-2004.

BACKGROUND: Chemicals used in leather tanning, rubber processing, and/or adhesives are the most often-cited culprits in footwear dermatitis. Patch testing patients with suspected shoe dermatitis is essential for diagnosis and management. OBJECTIVES: The four goals for this study were to (1) determine the frequency of allergens associated with a shoe source in North American Contact Dermatitis Group (NACDG) patients with footwear allergic contact dermatitis; (2) compare these results to allergen frequencies from other published studies; (3) quantify the number of shoe-related reactions that were not identified with the NACDG standard series; and (4) identify relevant allergens not included on the NACDG standard series, based on data from other published studies. METHODS: The NACDG patch-tested 10,061 patients between 2001 and 2004. Data were retrospectively analyzed by (1) allergen source coded as "shoe," (2) site of dermatitis as "feet," and (3) diagnosis of "allergic contact dermatitis." RESULTS: Among the 109 NACDG patients with allergic contact dermatitis (ACD) of the foot and a shoe source of allergens, p-tertiary butylphenol formaldehyde resin, an adhesive, was the most common allergen, accounting for 24.7% of positive patch-test results, followed by potassium dichromate (17.5%) and carba mix (11.7%). When the data were examined according to groups of allergens, rubber chemicals (40.4%) were the most frequent allergens, followed by adhesives (32.5%), and leather components (20.1%). When data from published studies were pooled, potassium dichromate (31.5%) was the most frequent allergen, followed by p-tertiary butylphenol formaldehyde resin (17.1%) and cobalt chloride (12.9%). NACDG patients were statistically more likely to have positive patch-test reactions to p-tertiary butylphenol formaldehyde resin and statistically less likely to have a positive patch-test reaction to potassium dichromate than patients represented in pooled data from past studies. Nineteen (17.4%) of the 109 NACDG patients with ACD of the foot and a shoe source of allergens were identified as having a shoe source of a relevant allergen not included in the NACDG standard series. CONCLUSIONS: In NACDG patients, the most common individual shoe allergen was p-tertiary butylphenol formaldehyde resin. As a group, rubber chemicals were most common, a finding consistent with those of other studies.

Physician skin examinations for melanoma screening.

A variety of estimates of the value and impact of physician skin examinations (PSEs) in screening for melanoma have been published. Although current melanoma screening guidelines vary, new evidence supports improved melanoma outcomes associated with PSEs. In this systematic review, we evaluated 5 observational studies of the impact of PSEs on melanoma thickness at diagnosis and melanoma mortality rates. Although definitive evidence from randomized controlled trials supporting improved health outcomes associated with PSEs is lacking, these well-designed observational studies have found PSEs to be correlated with thinner melanomas at diagnosis and reduced melanoma mortality rates.

A randomized comparison of the efficacy of low volume deep placement cheek injection vs. mid- to deep dermal nasolabial fold injection technique for the correction of nasolabial folds.

BACKGROUND: Hyaluronic acid (HA) fillers are FDA approved for improving the appearance of the nasolabial folds. Previous reports on the use of HA for this treatment have focused on injections directly into the location of the desired correction. To our knowledge, a study has not been done evaluating the efficacy of injecting a low volume of HA into the adjacent area of volume loss to correct both volume loss and adjacent lines. OBJECTIVE: The objective of this study was to compare the effectiveness and safety of three HA injection protocols including deep dermal cheek injection, mid- to deep dermal local nasolabial fold injection, and both injections for the correction of nasolabial folds. METHODS: This was a split-face, randomized study evaluating the use of three injection techniques - (i) deep bolus injection into the mid- to lateral cheek, (ii) local mid- to deep dermal injection into the nasolabial fold, and (iii) both deep injection into the mid- to lateral cheek and local mid- to deep dermal injection into the nasolabial fold - for the treatment of moderate to severe nasolabial folds. Wrinkle severity and Global Aesthetic Improvement Scales were measured before and 4-6 weeks after treatment as assessed by a blinded investigator. RESULTS: Patient and physician observations showed improvement both globally and in wrinkle severity score with each technique used with no statistical difference between techniques. Patients showed a slight preference for injection to both the mid- to lateral cheek and nasolabial fold, which was associated with the greatest amount of filler product administered. No serious adverse events were reported. CONCLUSION: Injection of a dermal filler, at low volumes, into either the nasolabial fold or mid- to lateral cheek results in similar improvement to the correction of the nasolabial folds.