Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP).

Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11,840 cases, 10,931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on γ-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P≤0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk.

Urban legends: recurrent aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) is the most common idiopathic intraoral ulcerative disease in the USA. Aphthae typically occur in apparently healthy individuals, although an association with certain systemic diseases has been reported. Despite the unclear etiopathogenesis, new drug trials are continuously conducted in an attempt to reduce pain and dysfunction. We investigated four controversial topics: (1) Is complex aphthosis a mild form of Behçet's disease (BD)? (2) Is periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome a distinct medical entity? (3) Is RAS associated with other systemic diseases [e.g., celiac disease (CD) and B12 deficiency]? (4) Are there any new RAS treatments? Results from extensive literature searches, including a systematic review of RAS trials, suggested the following: (1) Complex aphthosis is not a mild form of BD in North America or Western Europe; (2) Diagnostic criteria for PFAPA have low specificity and the characteristics of the oral ulcers warrant further studies; (3) Oral ulcers may be associated with CD; however, these ulcers may not be RAS; RAS is rarely associated with B12 deficiency; nevertheless, B12 treatment may be beneficial, via mechanisms that warrant further study; (4) Thirty-three controlled trials published in the past 6 years reported some effectiveness, although potential for bias was high.

Lichen planus and cicatricial conjunctivitis: disease course and response to therapy of 11 patients.

BACKGROUND: Lichen planus is an autoimmune, inflammatory dermatosis of unknown cause that affects the skin and mucous membranes. OBJECTIVE: The aim of this study was to report the clinical features and response to therapy in a series of patients with ocular lichen planus. METHODS: A retrospective chart review was performed to identify patients with ocular lichen planus. Information about clinical presentation, treatment, and therapeutic response was extracted from the medical records. RESULTS: Eleven patients with ocular lichen planus were identified. The diagnosis was confirmed histologically for 10 patients. Nine patients were women. The average time from onset of ocular symptoms to diagnosis was 4.1 years. Eight patients had mucous membrane involvement at other sites. Disease was well controlled in eight patients. CONCLUSION: Lichen planus should be considered in the differential diagnosis of cicatricial conjunctivitis, especially when severe lichen planus is noted at other sites.

Alpha-lipoic acid treatment of 31 patients with sore, burning mouth.

OBJECTIVE: To review a series of patients with sore, burning mouth treated with alpha-lipoic acid between 2000 and May 2006 and subjectively evaluate improvement in symptoms. DESIGN: Retrospective review of medical records of 195 consecutive patients who sought treatment for sore, burning mouth. Treatment of 47 patients was a prescription/recommendation for alpha-lipoic acid. Of these patients, 35 were available for follow-up. SETTING: Tertiary care academic medical center. SUBJECTS: Ambulatory patients given prescription /recommendation for alpha-lipoic acid 600 mg per day, in divided doses. MAIN OUTCOME MEASURE: Reported improvement in symptoms documented in medical records and at follow-up (visits or telephone interviews). RESULTS: Thirty-one of the 35 patients (66% of all 47) actually took alpha-lipoic acid as recommended. No patient reported a complete alleviation of symptoms. Six (19%) of these 31 patients felt mostly better, five (16%) felt somewhat better, and 14 (45%) reported no difference. Two patients (7%) reported a worsening of symptoms and four (13%) did not know whether there had been improvement. CONCLUSION: Eleven of 31 patients (35%) reported benefit from taking alpha-lipoic acid. Because we examined only a small number of patients and relied on a subjective outcome assessment, further larger studies using a prospective, randomized, controlled, and double-blind structure are warranted.

Cutaneous Crohn's disease mimicking Melkersson-Rosenthal syndrome: treatment with methotrexate.

A woman with a 5-year history of unilateral orofacial granulomatosis required repeated evaluations (including sequential colonoscopies) to establish the diagnosis of cutaneous Crohn's disease, a condition that proved responsive to low doses of oral methotrexate administered weekly. To our knowledge this is the first report describing the use of methotrexate for treatment of orofacial granulomatosis caused by underlying Crohn's disease.

Oral ulcerations are associated with the loss of response to infliximab in Crohn's disease.

We describe a 25-year-old Caucasian man with a 13-year history of inflammatory Crohn's disease (CD) who was suffering recurrent severe oral and esophageal ulcerations for the past 3 years. His CD had been treated with infliximab infusions among other medications. The loss of efficacy was confirmed by antibodies to infliximab (ATI) and serum infliximab tests that showed high levels of ATIs and undetectable levels of infliximab respectively. These findings were consistent with significant immunogenic response to infliximab leading to loss of effect. Infliximab infusions and prednisone were discontinued and treatment of the CD was instituted with adalimumab, a human anti-tumor necrosis factor (TNF)-alpha biologic agent, to control the inflammatory small intestinal disease and dapsone for the oral and esophageal CD ulcerations. The patient's oral and esophageal lesions as well as the enteric CD are under control after 5 months of therapy.

Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats.

Penile veno-occlusive dysfunction (venogenic erectile dysfunction) is a common cause of erectile dysfunction (ED). We investigated whether vascular endothelial growth factor (VEGF) can be used to prevent and reverse venogenic ED in a rat model. Pharmacological cavernosometry was developed and validated using adult male rats with either arteriogenic or venogenic ED. Castrated animals were treated with intracavernous VEGF as either a recombinant protein (C+VEGF) or adeno-associated virus (AAV)-mediated VEGF gene therapy (C+VEGF gene) in an attempt to prevent the development of venogenic ED. Other animal groups received testosterone replacement (C+testosterone) or intracavernous AAV-LacZ gene (C+LacZ). Animals with documented venogenic ED were treated with intracavernous VEGF in an attempt to reverse their ED. Functional analysis (pharmacological infusion cavernosometry) was performed following treatment. Penile specimens were harvested for immunohistochemistry and electron microscopic evaluation. Castrated rats showed a decrease in papaverine-induced intracavernous pressure and an increase in maintenance and drop rates during pharmacological cavernosometry. These changes were prevented by systemic testosterone and intracavernous VEGF or AAV-VEGF therapy. Moreover, intracavernous VEGF was able to reverse the venogenic ED produced by castration. The quantity of penile smooth muscle detected by alpha actin staining decreased after castration but not in the C+T, C+VEGF, or C+VEGF gene groups. Transmission electron microscopy revealed atrophy of penile smooth muscle cells and nerves in the castrated rats. In VEGF-treated rats, regeneration of smooth muscle and nerves as well as endothelial cell hypertrophy and hyperplasia were the prominent features. In our animal model, systemic testosterone replacement or intracavernous VEGF (protein and VEGF gene) prevented the veno-occlusive dysfunction in castrated animals. In rats with established venous leakage, VEGF treatment reversed the cavernosometric findings of leakage. Intracavernous injection of either VEGF protein or VEGF gene may be a preferred therapy to preserve erectile function in patients in whom testosterone therapy is contraindicated.

Erythema multiforme secondary to herpes simplex infection: a case report.

BACKGROUND: Erythema multiforme (EM) is a complex disease that may have cutaneous and/or mucosal involvement. The severity may range from mild to severe and potentially life threatening. The literature cites many factors including viruses, infections, and medications as causes. This report documents a patient who developed EM secondary to a herpes simplex viral (HSV) infection. METHODS: Two weeks following an eruption of herpes labialis, a 20-year-old white female patient developed acutely painful oral and labial ulcers accompanied by target skin lesions. A diagnosis of erythema multiforme (EM) was made. The patient was treated with antivirals, analgesics, and symptomatic therapy. RESULTS: Nine days after the onset of symptoms, the oral and cutaneous lesions had started to heal and the patient no longer required pain medication. CONCLUSIONS: Although the etiology of EM is still often unknown, infections with herpes simplex virus have been implicated as a possible precipitating factor. This case illustrates the association of the occurrence of EM with an HSV infection.

Metal transporters that contribute copper to metallochaperones in Saccharomyces cerevisiae.

Copper metallochaperones represent a new family of soluble, low-molecular-weight proteins that function to deliver copper to specific sites within a cell. How the metallochaperones acquire their copper, however, is not known. In this study, we have conducted a survey of known metal ion transporters in bakers' yeast, Saccharomyces cerevisiae, to identify those that contribute copper to pathways involving the metallochaperones Atxlp and Lys7p. The results indicatethat, in addition to the well known Ctr1p and Ctr3p high-affinity copper transporters, the metallochaperones can acquire their copper through pathways involving the relatively non-specific divalent metal ion transporter Fet4p and the putative low-affinitycopper transporter Ctr2p. We have examined the localization of Ctr2p using an epitope tagged version of the protein and find that Ctr2p does not localize to the cell surface but may operate at the level of the vacuole to mobilize intracellular copper. Inaddition to Ctrlp, Ctr2p, Ctr3p and Fet4p, other metal transport systems can act as upstream donors of copper for the metallochaperones when copper availability in the medium is increased. Although the nature of these auxiliary systems is unknown, they do not appear to involve the yeast members of the Nramp family of divalent transporters, or uptake mechanisms that involve endocytosis. Since vastly different metal transporters located at either the cell surface or intracellular sites can all contribute copper to metallochaperones, it is unlikely that the metallochaperones directly interact with the metal transporters to obtain the metal.

Natural history of erythromelalgia: presentation and outcome in 168 patients.

OBJECTIVE: To describe the demographics, presentation, and outcome in patients with erythromelalgia--a rare and poorly understood clinical syndrome defined by the triad of red, hot, painful extremities. DESIGN: Retrospective medical record review with follow-up by survey questionnaire. SETTING: Large tertiary care medical center. SUBJECTS: Patients with erythromelalgia examined at the Mayo Clinic, Rochester, Minn, between 1970 and 1994. INTERVENTION: The medical records of 168 patients were analyzed. Follow-up data, which consisted of answers to 2 survey questionnaires or the most recent information in the medical record from patients still alive and death certificates or reports of death for those deceased patients, were obtained for all but 13 patients. MAIN OUTCOME MEASURES: Survival, morbidity, and quality of life. RESULTS: All patients were white; 122 (72.6%) were female, and 46 (27.4%) were male. At presentation, the patients' mean age was 55.8 years (age range, 5-91 years). Symptoms had been present since childhood in 7 patients (4.2%). Six patients (3.6%) had a first-degree relative with erythromelalgia. Symptoms were intermittent in 163 patients (97.0%) and constant in 5 (3.0%). Symptoms predominantly involved feet (148 patients [88.1%]) and hands (43 patients [25.6%]). Kaplan-Meier survival curves revealed a significant decrease in survival compared with that expected in persons of similar age and of the same sex (P<.001). After a mean follow-up of 8.7 years (range, 1.3-20 years), 30 patients (31.9%) reported worsening of, 25 (26.6%) no change in, 29 (30.9%) improvement in, and 10 (10.6%) complete resolution of the symptoms. On a standard health status questionnaire, scores for all but one of the health domains were significantly diminished in comparison with those in the US general population. CONCLUSION: Erythromelalgia is a syndrome with significantly increased mortality and morbidity compared with the US general population.

Relevant contact sensitivities in patients with the diagnosis of oral lichen planus.

BACKGROUND: The concept of contact allergy aggravating or inducing oral lichenoid mucositis diagnosed as oral lichen planus (OLP) is well recognized but somewhat controversial. OBJECTIVE: We sought to identify clinically relevant contact allergens that may be important in the management of patients with OLP. METHODS: We retrospectively reviewed patients with OLP who had patch tests performed at Mayo Clinic Rochester and Mayo Clinic Scottsdale from 1994 to 1997 and 1988 to 1997, respectively. RESULTS: Patch tests were performed on 46 patients with a clinical and histopathologic diagnosis of OLP. Of these, 25 (54%) had positive patch test results. Eighteen (72%) of the patients with positive results had clinically relevant reactions. Of the patients with positive metal reactions, 5 had improvement after removal of the metal prosthesis or restoration. Six others noted that their most troublesome areas were adjacent to metal dental restorations. Six patients with reactions to flavorings and one patient with an acrylate dental retainer sensitivity had improvement after avoiding these allergens. CONCLUSION: Our findings support the concept that contact allergy to metals, flavorings, and plastics can be important in the pathogenesis and management of patients with oral lichenoid mucositis diagnosed as OLP.

Clinical assessment and outcome in 70 patients with complaints of burning or sore mouth symptoms.

OBJECTIVE: To review a series of patients with a burning or sore mouth for elucidation of associated conditions and treatment outcome. MATERIAL AND METHODS: We retrospectively studied 70 consecutive patients with a burning or sore mouth who were encountered at a tertiary-care center between 1979 and 1992. Clinical and laboratory findings were summarized, and follow-up data were analyzed. RESULTS: The study cohort of 56 women and 14 men had a mean age of 59 years. They had had a burning or sore mouth for a mean duration of 2.5 years. Multiple etiologic factors for the burning or sore mouth were present in 37% of the study subjects. The most frequently associated conditions were psychiatric disease (30%), xerostomia (24%), geographic tongue (24%), nutritional deficiencies (21%), and allergic contact stomatitis (13%). With a treatment course tailored to the suspected causal factor, 72% of the patients who had follow-up reported improvement. CONCLUSION: With a directed investigation, one or more causes could be identified in most patients who had a burning or sore mouth. Successful management of these symptoms was possible in a majority of the patients.

Neurophysiologic and vascular studies in erythromelalgia: a retrospective analysis.

Erythromelaigia is a poorly understood clinical syndrome characterized by painful, hot, red extremities. We assessed the frequency and types of abnormalities observed during tests of vascular, peripheral neurophysiologic, and autonomic function in patients with erythromelalgia.Methods Of" 163 charts of patients fulfilling the clinical diagnosis of erythromelalgia. 93 patients underwent vascular studies Five of them had detailed vascular studies in 10 affected lower extremities performed before and during symptoms, fifty-four patients underwent neurophysiologic testing, 27 had autonomic reflex screening (ARS). and two had recordings of peripheral autonomic surface potentials (PASP).Results. Measurements in the toes during symptoms revealed a mean temperature increase of 11.6 C (P = 0,00011 along with a laser flow increase from a mean of 6.8 mL/min per 100 g tissue to 76.5 mL/min per 100 g tissue (P<.0.0001). Baseline TcPO; in the feet decreased by 6.7 mmHg (P = 0.032) during symptoms. Twenty-one of 54 electromyographic recordings were abnormal: all fulfilled the criteria for axonal neuropathy. Seventeen of 27 ARSs and one PASP showed severe postganglionic sudomotor impairment; five of 17 additionally had peripheral adrenergic dysfunction.Conclusions During symptoms, an increase in flow and temperature is accompanied paradoxically by a decrease in oxygenation of the affected area; a high proportion of patients have a distal small fiber neuropathy with selective involvement of cutaneous sympathetic fibers; in addition, large fiber neuropathy is often present.

Bullous pemphigoid presenting as generalized pruritus: observations in six patients.

BACKGROUND: Bullous pemphigoid is a chronic immunobullous disease of the elderly. Classically, tense, pruritic blisters develop on normal or erythematous skin. These may be preceded by a prodromal pruritic, urticarial, or eczematous eruption. Occasionally, patients may develop generalized pruritus without blisters as a prodrome of bullous pemphigoid. METHODS: The records of the patients were reviewed. Biopsy specimens were studied by light and immunofluorescence microscopy. Serum specimens were studied by indirect immunofluorescence techniques including the salt-split skin technique. RESULTS: We studied six elderly patients presenting with generalized pruritus as the dominant or single presenting feature of early bullous pemphigoid. Two of the six had rare vesicles at presentation. All had excoriations and one each presented with minimal urticarial or eczematous papules. Routine skin biopsies were largely nonspecific. All patients had confirmation of their diagnosis by either indirect or direct immunofluorescence testing or both. All six patients had their disease completely controlled by their treatment. CONCLUSIONS: The clinical presentation of the six patients in our series and the eight previously reported patients should be regarded as an unusual prodromal manifestation of bullous pemphigoid characterized by generalized pruritus without primary skin lesions. This presentation could be described as "pruritic pemphigoid," because it joins the remarkable clinical finding of generalized pruritus with the underlying diagnosis of bullous pemphigoid. Elderly patients with severe or persistent unexplained generalized pruritus merit immunofluorescence testing to exclude bullous pemphigoid as the cause of the generalized pruritus. Establishing an early diagnosis permits the prompt institution of effective therapy with dapsone or systemic corticosteroids with an excellent prognosis for complete control of the disease.