Influence of thyroid hormone disruption on the incidence of shingles.

The reactivation of dormant alpha-human herpesvirus (αHHV) has been attributed to various causes often referred to as stressors. However, no clinical study investigating the relationship between stressors and reactivation exists in humans at this time. Herpes simplex virus type-1 (HSV-1), an important αHHV, was shown to have its gene expression and replication regulated by thyroid hormone (TH) using molecular biology approaches. Varicella zoster virus (VZV) is categorized in αHHV superfamily and shares similar homology with HSV-1. We hypothesize that a history of TH imbalance may be associated with the incidence of shingles (VZV reactivation). This current pilot study, based on a hospital medical claims database, was conducted as a retrospective case-controlled investigation to determine if a putative link between TH imbalance and incidence of shingles is present. An odds ratio of 2·95 with a χ 2 value of 51·74 was calculated for the total population diagnosed with TH disruption and shingles. Further analyses indicated that African American males exhibited a much higher chance of simultaneous diagnoses. These results show that a TH imbalance history may affect VZV reactivation at different incidence rates in different races and age groups.

Phytochemical induction of cell cycle arrest by glutathione oxidation and reversal by N-acetylcysteine in human colon carcinoma cells.

Cancer prevention by dietary phytochemicals has been shown to involve decreased cell proliferation and cell cycle arrest. However, there is limited understanding of the mechanisms involved. Previously, we have shown that a common effect of phytochemicals investigated is to oxidize the intracellular glutathione (GSH) pool. Therefore, the objective of this study was to evaluate whether changes in the glutathione redox potential in response to dietary phytochemicals was related to their induction of cell cycle arrest. Human colon carcinoma (HT29) cells were treated with benzyl isothiocyanate (BIT) (BIT), diallyl disulfide (DADS), dimethyl fumarate (DMF), lycopene (LYC) (LYC), sodium butyrate (NaB) or buthione sulfoxamine (BSO, a GSH synthesis inhibitor) at concentrations shown to cause oxidation of the GSH: glutathione disulfide pool. A decrease in cell proliferation, as measured by [(3)H]-thymidine incorporation, was observed that could be reversed by pretreatment with the GSH precursor and antioxidant N-acetylcysteine (NAC). Cell cycle analysis on cells isolated 16 h after treatment indicated an increase in the percentage (ranging from 75-30% for benzyl isothiocyanate and lycopene, respectively) of cells at G2/M arrest compared to control treatments (dimethylsulfoxide) in response to phytochemical concentrations that oxidized the GSH pool. Pretreatment for 6 h with N-acetylcysteine (NAC) resulted in a partial reversal of the G2/M arrest. As expected, the GSH oxidation from these phytochemical treatments was reversible by NAC. That both cell proliferation and G2/M arrest were also reversed by NAC leads to the conclusion that these phytochemical effects are also mediated, in part, by intracellular oxidation. Thus, one potential mechanism for cancer prevention by dietary phytochemicals is inhibition of the growth of cancer cells through modulation of their intracellular redox environment.

Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons.

Distinct classes of neurons are generated from progenitor cells distributed in characteristic dorsoventral patterns in the developing spinal neural tube. We define restricted neural progenitor populations by the discrete, nonoverlapping expression of Ngn1, Math1, and Mash1. Crossinhibition between these bHLH factors is demonstrated and provides a mechanism for the generation of discrete bHLH expression domains. This precise control of bHLH factor expression is essential for proper neural development since as demonstrated in both loss- and gain-of-function experiments, expression of Math1 or Ngn1 in dorsal progenitor cells determines whether LH2A/B- or dorsal Lim1/2-expressing interneurons will develop. Together, the data suggest that although Math1 and Ngn1 appear to be redundant with respect to neurogenesis, they have distinct functions in specifying neuronal subtype in the dorsal neural tube.

Neurilemoma of the medial plantar nerve: a case report and literature review.

A neurilemoma is an uncommon, benign, encapsulated neoplasm whose origin is derived from the Schwann cells. Its incidence in the foot is uncommon. A review of the literature, etiology, incidence, clinical presentation, histology, differential diagnosis, and treatment are discussed. The authors present a case of a neurilemoma of the medial plantar nerve of the foot.

Mechanical treatment of plantar fasciitis. A prospective study.

A randomized, prospective study was conducted to compare the effectiveness of three individual mechanical modalities in the treatment of plantar fasciitis. Two hundred fifty-five subjects were randomly assigned to one of three treatment groups: custom-made orthoses, over-the-counter arch supports, or tension night splints. Subjects were treated for 3 months, with follow-up visits at 2, 6, and 12 weeks. No statistically significant difference was noted among treatment groups with respect to final outcomes based on first-step pain or pain felt during the day. However, there was a statistically significant difference among the three groups with respect to early patient withdrawal from the study due to continued severe pain, noncompliance, or inability to tolerate the device. Patient compliance was greatest with the use of custom-made orthoses.

A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns.

BACKGROUND: Onychomycosis, a fungal infection of the nail bed, is responsible for up to 50% of nail disorders. Although several surveys have been conducted in different parts of the world, there have been no multicenter epidemiologic surveys of onychomycosis in North America. OBJECTIVE: A 12-center study was undertaken to (1) determine the frequency of onychomycosis, (2) identify organisms recovered from the nails, and (3) determine the antifungal susceptibility of isolates. METHODS: A total of 1832 subjects participated in this study and completed a comprehensive questionnaire, and nail clippings were collected for potassium hydroxide examination and culturing. RESULTS: The frequency of onychomycosis, as defined by the presence of septate hyphae on direct microscopy and/or the recovery of a dermatophyte, was found to be 13.8%. In general, the dermatophyte isolates were susceptible to the antifungals tested. CONCLUSION: Because of the limited number of large-scale studies, the baseline incidence is not firmly established. However, the higher frequency of onychomycosis in this study may confirm the suspected increase in incidence of disease in North America.

Regulation of antioxidant enzyme gene expression in response to oxidative stress and during differentiation of mouse skeletal muscle.

Various properties of skeletal muscle, including high metabolic activity and high levels of heme-containing proteins, render it particularly susceptible to free radical injury. Indeed, cellular injury from reactive oxygen species (ROS) has been implicated in many muscle disorders. Thus muscle cell survival is critically dependent on the ability of the cell to respond to periods of oxidative stress. To investigate this important homeostatic response, we studied the effect of oxidative challenges on the expression of genes encoding the antioxidant enzymes Cu,Zn-superoxide dismutase (CuZnSOD), Mn-superoxide dismutase (MnSOD), glutathione peroxidase (GPx), and catalase (CAT) in myotube cultures. Using Northern blot analysis, we found that treatment with the pro-oxidant paraquat resulted in time- and dose-dependent increases of transcript levels that were greatest for GPx and CAT (approximately 4-5 fold). CuZnSOD and MnSOD transcripts were also increased, albeit more modestly (approximately 2-3 fold). Transcript levels were also induced by treatment of the cells with two other pro-oxidants, menadione and H2O2, and correlated with the level of oxidative injury to the cells, measured as protein carbonyl group formation. Activities of all of the enzymes increased in response to the oxidative challenges, although the magnitudes of the increases were less robust than the increases of the respective transcript levels. In studying the effect of cellular differentiation on antioxidant gene expression and susceptibility to oxidative stress, we found that pro-oxidant treatment resulted in greater oxidative injury to differentiated myotubes than to undifferentiated myoblasts. Furthermore, the increased susceptibility of myotubes correlated with decreased antioxidant defenses-as muscle cells differentiated, both transcript and activity levels of antioxidant enzymes decreased. These data suggest that muscle cells regulate antioxidant defenses in response to oxidative stress and cellular differentiation.

Safety of itraconazole pulse therapy for onychomycosis. An update.

After experience with more than 34 million patients over 10 years, the safety of itraconazole and its potential drug-drug interactions are well known. In clinical trials, the average incidence of adverse events with a 1-week pulse regimen was 18% in pooled safety data (n = 2,867); only 2.2% of patients dropped out. In direct comparative trials, the incidence of mild and reversible adverse effects was comparable for itraconazole and terbinafine (31% and 28%, respectively) during treatment. The rate of permanent withdrawal because of adverse events was 3.6% for itraconazole and 7.5% for terbinafine (P < .05). Itraconazole was significantly better tolerated as evaluated by the investigator and patients. The analysis of the elderly subpopulation showed that patients 65 and older tolerated itraconazole pulse well, with only 20% experiencing mild and reversible side effects (total group). In direct comparative trials, itraconazole also produced fewer adverse effects than terbinafine (13% vs 32%, respectively). As newer oral antifungal agents gain widespread use, clinicians need to be aware of their potential drug-drug interactions and their possibly serious adverse events. However, pooled data from the 1-week itraconazole pulse regimen indicated a favorable safety profile, and a dose increase to 400 mg had no impact on safety.

Conservative treatment of plantar fasciitis. A prospective study.

A randomized, prospective study was conducted to compare the individual effectiveness of three types of conservative therapy in the treatment of plantar fasciitis. One hundred three subjects were randomly assigned to one of three treatment categories: anti-inflammatory, accommodative, or mechanical. Subjects were treated for 3 months, with follow-up visits at 2, 4, 6, and 12 weeks. For the 85 patients who completed the study, a statistically significant difference was noted between groups, with mechanical treatment with taping and orthoses proving to be more effective than either anti-inflammatory or accommodative modalities.

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail.

BACKGROUND: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens of onychomycosis, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of superficial fungal infections. OBJECTIVE: The purpose of this study was to compare the efficacy and safety of three different doses of fluconazole (150, 300, and 450 mg) given orally once weekly to that of placebo in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. METHODS: In this multicenter, double-blind study, 362 patients with mycologically confirmed onychomycosis were randomized to treatment with fluconazole, 150, 300, or 450 mg once weekly, or placebo once weekly for a maximum of 12 months. To enter the study, patients were required to have at least 25% involvement of the target nail with at least 2 mm of healthy nail from the nail fold to the proximal onychomycotic border. Patients who were clinically cured or improved at the end of treatment were further evaluated over a 6 month follow-up period. At both the end of therapy and the end of follow-up, clinical success of the target nail was defined as reduction of the affected area to less than 25% or cure. RESULTS: At the end of therapy, 86% to 89% of patients in the fluconazole treatment groups were judged clinical successes as defined above compared with 8% of placebo-treated patients. Clinical cure (completely healthy nail) was achieved in 28% to 36% of fluconazole-treated patients compared with 3% of placebo-treated patients. Fluconazole demonstrated mycologic eradication rates of 47% to 62% at the end of therapy compared with 14% for placebo. The rates at the end of follow-up were very similar, indicating that eradication of the dermatophyte was maintained over the 6-month period. All efficacy measures for the fluconazole groups were significantly superior to placebo (p=0.0001); there were no significant differences between the fluconazole groups on these efficacy measures. The clinical relapse rate among cured patients over 6 months of follow-up was low at 4%. Fluconazole was well tolerated at all doses over the 12-month treatment period, with the incidence and severity of adverse events being similar between the fluconazole and placebo treatment groups. Mean time to clinical success in the fluconazole treatment groups was 6 to 7 months. This time frame may be used as a guideline for fluconazole treatment duration. CONCLUSION: The results of this study support the use of fluconazole in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. Doses between 150 to 450 mg weekly for 6 months were clinically and mycologically effective as well as safe and well tolerated.

Pharmacokinetics of three doses of once-weekly fluconazole (150, 300, and 450 mg) in distal subungual onychomycosis of the toenail.

BACKGROUND: Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazole's distribution into and elimination from nails is needed. OBJECTIVE: The purpose of this study was to determine plasma and toenail concentrations of fluconazole. METHODS: In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued. RESULTS: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. CONCLUSION: Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis.

Topical metronidazole maintains remissions of rosacea.

BACKGROUND: Rosacea is a chronic skin disease that requires long-term therapy. Oral antibiotics and topical metronidazole successfully treat rosacea. Because long-term use of systemic antibiotics carries risks for systemic complications and adverse reactions, topical treatments are preferred. OBJECTIVE: To determine if the use of topical metronidazole gel (Metrogel) could prevent relapse of moderate to severe rosacea. DESIGN: A combination of oral tetracycline and topical metronidazole gel was used to treat 113 subjects with rosacea (open portion of the study). Successfully treated subjects (n = 88) entered a randomized, double-blind, placebo-controlled study applying either 0.75% topical metronidazole gel (active agent) or topical metronidazole vehicle gel (placebo) twice daily (blinded portion of the study). SETTING: Subjects were enrolled at 6 separate sites in large cities at sites associated with major medical centers. SUBJECTS: One hundred thirteen subjects with at least 6 inflammatory papules and pustules, moderate to severe facial erythema and telangiectasia entered the open phase of the study. Eighty-eight subjects responded to treatment with systemic tetracycline and topical metronidazole gel as measured by at least a 70% reduction in the number of inflammatory lesions. These subjects were randomized to receive 1 of 2 treatments: either 0.75% metronidazole gel or placebo gel. INTERVENTIONS: Subjects were evaluated monthly for up to 6 months to determine relapse rates. MAIN OUTCOME MEASURES: Inflammatory papules and pustules were counted at each visit. Relapse was determined by the appearance of a clinically significant increase in the number of papules and pustules. Prominence of telangiectases and dryness (roughness and scaling) were also observed. RESULTS: In the open phase, treatment with tetracycline and metronidazole gel eliminated all papules and pustules in 67 subjects (59%). The faces of 104 subjects (92%) displayed fewer papules and pustules after treatment, and 82 subjects (73%) exhibited less erythema. In the randomized double-blind phase, the use of topical metronidazole significantly prolonged the disease-free interval and minimized recurrence compared with subjects treated with the vehicle. Eighteen (42%) of 43 subjects applying the vehicle experienced relapse, compared with 9 (23%) of 39 subjects applying metronidazole gel (P<.05). The metronidazole group had fewer papules and/or pustules after 6 months of treatment (P<.01). Relapse of erythema also occurred less often in subjects treated with metronidazole (74% vs 55%). CONCLUSION: In a majority of subjects studied, continued treatment with metronidazole gel alone maintains remission of moderate to severe rosacea induced by treatment with oral tetracycline and topical metronidazole gel.

Double-blind, randomized comparison of itraconazole capsules vs. placebo in the treatment of toenail onychomycosis.

Three multicenter, randomized, double-blind, placebo-controlled studies were conducted to determine whether twelve weeks of therapy with itraconazole, 200 mg, was effective in the treatment of dermatophyte infection of the toenail. Significantly more patients treated with itraconazole (110 patients) than with placebo (104 patients) achieved clinical (65 percent vs. 3 percent) and mycologic (54 percent vs. 6 percent) success. The mean percentage of affected reference nail before the initiation of therapy was 76 percent. Adverse events were comparable in the two treatment groups. These findings demonstrate that twelve weeks of continuous itraconazole, 200 mg once daily, is a highly effective, well-tolerated therapy for the management of toenail onychomycosis.

Mycosis fungoides with onset before 20 years of age.

BACKGROUND: Recent identification of mycosis fungoides (MF) in a man in whom the diagnosis was established at age 22 months prompted us to evaluate our experience with early onset MF. OBJECTIVE: Our purpose was to summarize the clinical characteristics and course of 24 patients in whom MF began by history before age 20 years and was confirmed by biopsy in 13 by that time. METHODS: A retrospective study was conducted. RESULTS: All 24 patients had patch/plaque disease and represented 4.3% of the 557 patients with cutaneous T-cell lymphoma seen by us since 1971. None progressed to a more advanced stage in up to 24 years (median, 12 years) after histologic diagnosis. Five patients (21%) presented with hypopigmentation. CONCLUSION: Early onset MF is not more aggressive than that appearing in adult life. MF should be considered in the differential diagnosis of chronic dermatoses in young persons, particularly in those presenting with hypopigmentation.

A multicenter, placebo-controlled, double-blind study of intermittent therapy with itraconazole for the treatment of onychomycosis of the fingernail.

BACKGROUND: Onychomycosis is the most frequent cause of nail disease and represents 30% of all mycotic infections of the skin. OBJECTIVE: Our purpose was to compare the effectiveness and tolerability of intermittent dosing of itraconazole ("pulse therapy") with placebo in fingernail onychomycosis. METHODS: Seventy-three patients with clinically and mycologically diagnosed fingernail onychomycosis were randomly selected to receive itraconazole, 200 mg twice daily, or placebo for the first week of each month for 2 consecutive months; patients were observed for 19 weeks. Seventy-one patients received the study medication and were included in the safety analysis. Efficacy of treatment was evaluated in 46 patients. RESULTS: A significantly greater proportion of itraconazole-treated patients than placebo-treated patients achieved clinical success (77% vs 0%), mycologic success (73% vs 13%), and overall success (68% vs 0%). No itraconazole-treated patient had a clinical or mycologic relapse during the follow-up period. Ten itraconazole-treated patients (28%) and nine placebo-treated patients (26%) had adverse events. Three patients discontinued treatment for safety reasons. CONCLUSION: Pulse therapy with itraconazole for 2 consecutive months produces significantly greater clinical, mycologic, and overall success than placebo. Short-term itraconazole pulse therapy for fingernail onychomycosis is effective and well tolerated.

Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders.

Marfan syndrome (MFS), a common connective tissue disorder, is caused by fibrillin-1 (FBN1) mutations that are scattered throughout the gene and are largely unique to individual families. Mutation detection in this large gene of 65 exons is a considerable technical challenge. To develop an efficient method capable of identifying all possible mutations in this gene, we have explored the use of a novel denaturing high-performance liquid chromatography (DHPLC) system. This technique compares two or more chromosomes as a mixture of denatured and reannealed PCR amplicons. Under partially denaturing conditions, heteroduplexes can be separated from homoduplexes. A panel of 94 DNA samples from individuals with MFS or related connective tissue disorders was screened exon-by-exon by this method. A total of 66 unique heteroduplex profiles was identified. Sequencing of the amplicons detected 37 novel and two previously reported mutations, as well as 15 novel and 10 known polymorphisms or unique sequence variants that are probably of no clinical significance. Of the 34 mutations found in definitive MFS cases, 16 were identified in the 21 samples that had not been screened before (76% detection rate) and 17/40 (43%) were in samples previously screened by other mutation detection methods. In 32 individuals with MFS-related phenotypes, five FBN1 mutations were identified (16%). Our results demonstrate the power of the DHPLC method to detect FBN1 mutations. It should be applicable for mutation screening in any gene in a large population.

New therapies for onychomycosis.

Until recently, the treatment of onychomycosis was discouraging because of the relatively low success rate, the need for prolonged therapy, and the laboratory monitoring necessary with the traditional oral antifungal agents, griseofulvin and ketoconazole. The advent of a new generation of oral antifungal drugs, including two triazoles (itraconazole and fluconazole) and an allylamine (terbinafine), has greatly improved the outlook for patients with fungal nail infections, particularly those with toenail involvement. Recently, the broad-spectrum triazole, itraconazole, has been approved for the treatment of onychomycosis in the U.S. Numerous studies have demonstrated its efficacy when administered either continuously for 3 months or in "pulse" dosing. Preliminary findings suggest that fluconazole and terbinafine are also promising, although their spectrum of activity is not as broad as that of itraconazole.