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Objectives: Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting primarily oral mucosa and skin. Among the drugs used for the therapy of pemphigus, both methylprednisolone (MP) and pyridostigmine bromide (PBr) can prevent acantholysis in vitro. However, their putative therapeutic properties in regenerating PV-like lesions and promoting the healing process still remain to be demonstrated. To address this issue, here we have developed a model for studying the process of epithelial cleft regeneration in PV by artificially wounding keratinocyte monolayers. Materials and methods: The experimental model was established by scratching confluent monolayers to simulate the epithelial cleft; then, wound regeneration in the presence of submaximal concentrations of PV sera was studied by time-lapse microscopy, with or without the addition of MP and PBr in the culture medium. Results: Pemphigus vulgaris serum inhibited epithelial cleft repair of wounded monolayers. Indeed, in the presence of 10% (v/v) PV serum, keratinocytes reached only 2% confluence within 72 h vs an almost complete healing of controls. When administered together with PV sera, MP significantly (P

We have previously demonstrated that serum autoantibodies of patients with pemphigus vulgaris (PV) may affect desmoglein 3 (Dsg3)-mediated adhesion by decreasing its half-life and inducing Dsg3 cleavage. Here we sought to gain more insights into the role of Dsg3-targetting IgG in acantholysis. To do so, alterations of keratinocyte morphology and cell–cell adhesion strength were investigated in the presence of PV serum, PV IgG, and IgG purified from PV patients’ sera against linear epitopes of Dsg3 (anti-Dsg3-L IgG). Changes in Dsg3 protein levels were assessed by Western blotting. Results showed that both PV serum and PV IgG were able to induce acantholysis and decrease the total amount of Dsg3 in cell lysates. Polyclonal anti-Dsg3-L IgG displayed Dsg3-depleting activity solely when used at 1 μg/ml, i.e. under non-physiologic conditions. Furthermore, cell–cell detachment induced by PV IgG and anti-Dsg3-L IgG seemed to precede the loss of Dsg3 from keratinocytes, suggesting that depletion/degradation of Dsg3 represents a late event in acantholysis. Collectively, the data presented here demonstrate that PV IgG recognizing non-conformational epitopes of Dsg3 are pathogenic when administered on doses largely exceeding those found in PV sera.

BACKGROUND: Alpha-lipoic acid (ALA), is a potent antioxidant mitochondrial coenzyme, the trometamol salt of thioctic acid that has been shown in clinical studies to be neuroprotective. This study examined the effect of ALA on the symptomatology of Burning mouth syndrome (BMS),SUBJECTS AND METHODS: Forty-two patients with EMS and no clinical or laboratory evidence of organic oral disease were divided into two groups (Test and Control) each of 21 subjects, matched for age and sex, The Test group were given ALA (thioctic acid; Tiobec) for 30 days, as 600 mg per day orally for 20 days followed by 200 mg per day for 10 days. The Control group were given cellulose starch 100 mg per day as placebo for 30 days. All EMS patients were reviewed at 10- day intervals and scored for changes in symptomatology.RESULTS: Significant improvements were shown in the symptomatology of EMS in up to two-thirds of patients with EMS receiving alpha-lipoic acid, in about 15% of those using placebo and also in up to two-thirds of those who, having tried placebo, were switched to ALA.

Aphthous ulcers are the most common oral mucosal lesions in the general population. Several precipitating factors for aphthous ulcers are suggested to operate on subjects with genetic predisposition. Sometimes aphthous ulcers can be the sign of systemic diseases. Therefore, it is essential to establish a correct diagnosis to determine suitable therapy. There are several diseases potentially responsible for oral ulcers. Sometimes appearance of periodic oral ulcers coincides with periodic fever and other symptoms leading to the diagnosis of a rare childhood disease: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenopathy) syndrome. PFAPA or Marshall's syndrome is characterized by abrupt onset of periodic episodes of high fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis, often associated with headache and / or abdominal or joint pain. Owing to the periodic onset of oral symptoms, often an oral physician or pediatric dentist may be the first healthcare worker to evaluate a child with clinical signs compatible with PFAPA syndrome. Children diagnosed with this condition require systematic oral follow-up to monitor for signs of ulceration.

Primary oral melanoma (POM) is an uncommon malignant tumor that originates from the proliferation of melanocytes. Such tumors can be present at any location in the oral cavity; however, it affects more frequently the hard palate and the maxillary alveolar mucosa. POM is usually asymptomatic in the early stages and it presents normally as a pigmented patch or as a mass with a rapid growth rate. In the advanced stages, it can show ulceration, swelling, bleeding, rapid enlargement and loosening of teeth. Melanoma of the mouth is rare, most commonly occurring in the upper jaw of patients more than 65 years. Because of a frequent delay in diagnosis, the tumors are often diagnosed when they are deeper than the average cutaneous melanoma. The prognosis is extremely poor, especially in advanced stages. Therefore, pigmented lesions of undetermined origin should be routinely subjected to a biopsy examination. In this study, we aimed to present a review on primary malignancy.

Background Burning mouth syndrome (BMS) is a common disorder frequently affecting women past the 5th decade of age. It is characterized by oral burning, mainly involving the tongue, lip, and anterior palate, but without oral lesions or alteration showing in blood tests and/or instrumental findings. Objective We proposed to exclude alterations due to thyroid function and echographic abnormality in formulating BMS diagnosis. The aim of this study was to propose a blood and instrumental protocol including thyroid function and echography to obtain a correct BMS diagnosis. In the absence of such an assessment, a number of patients with oral burning and hypothyroidism may erroneously be considered BMS patients. Study design For this study, a group of 123 patients initially diagnosed with BMS was selected, following use of the current preliminary diagnostic protocol for BMS (study group). A further 123 patients with dental problems and without oral burning were selected as a control group. All patients were submitted to further protocol based on a study of their thyroid function and echography. Results Thirteen control patients showed some thyroid alteration compared with 85 patients of the study group. In relation to these further examinations, a therapeutic protocol based on use of thyroxine, lipoic acid, or clonazepam was applied for patients belonging to the study group. Fifty-eight patients (47%) showed hypothyroidism and were treated with thyroxine, and 37 (64%) of these showed a positive response (VAS 1 and 0). Twenty-seven patients (22%) evinced euthyroidism with an inhomogeneous parenchyma thyroid echographic pattern. These were treated with lipoic acid, and 23 (85%) of them responded positively (VAS 1 and 0). Thirty-eight patients (31%) showed euthyroidism and no echographic alteration. Only these were considered to be true BMS patients and were treated with lipoic acid. Only 10 (26%) of these patients responded positively (VAS 1 and 0). Conclusions This study reveals that subjects with thyroid alterations are often considered to be BMS patients and that hypothyroidism could be responsible for oral burning and/or dysgeusia in some supertaster subjects. For these reasons, we propose that the study of thyroid function be inserted in the diagnostic process for BMS patients.

Intercellular adhesion among keratinocytes is guaranteed by desmosomes. Disruption of desmosomal integrity leads to cell-cell detachment or acantholysis, as it classically occurs in pemphigus vulgaris (PV), an autoimmune blistering disease of skin and mucous membranes. While purified PV IgG seems to trigger intracellular signaling that crucially involves p38 MAPK, keratinocyte acantholysis induced by whole PV serum may recruit a number of additional signals. In this study, the Pro-Q® Diamond Phosphoprotein Assay was used to investigate the overall changes in protein phosphorylation levels in an in vitro model of PV. We showed that keratinocytes exposed to whole PV sera underwent at least three early and transient phosphorylation events. Two bands with apparent molecular masses of ∼35 and ∼45 kDa were found to be phosphorylated within 1 min after incubation with PV sera. A third band of about 80 kDa reached the peak of phosphorylation level after 3 hours. Morphologic evidence of cell shrinkage and acantholysis were late events and did not correlate temporally with kinase activation, suggesting that cytoskeleton reorganization is a downstream phenomenon. Interestingly, pharmacological abrogation of PV-specific protein phosphorylation was able to inhibit the cell-cell detachment, rounding up, and redistribution of Dsg3 in keratinocytes. Thus, at least three phosphorylation events are pathogenically involved in pemphigus acantholysis.

Aphthous ulcers are the most common oral mucosal lesions in the general population. These often are recurrent and periodic lesions that cause clinically significant morbidity. Many suggestions have been proposed but the etiology of recurrent aphthous stomatitis (RAS) is unknown. Several precipitating factors for aphthous ulcers appear to operate in subjects with genetic predisposition. An autoimmune or hypersensitivity mechanism is widely considered possible. Sometimes aphthous ulcers can be the sign of systemic diseases, so it is essential to establish a correct diagnosis to determine suitable therapy. Before initiating medications for aphthous lesions, clinicians should determine whether well-recognized causes are contributing to the disease and these factors should be corrected. Various treatment modalities are used, but no therapy is definitive. Topical medications, such as antimicrobial mouth-washes and topical corticosteroids (dexamethasone, triamcinolone, fluocinonide, or clobetasol), can achieve the primary goal to reduce pain and to improve healing time but do not improve recurrence or remission rates. Systemic medications can be tried if topical therapy is ineffective.

Pemphigus vulgaris (PV) blistering occurs as a result of the disruption of intercellular contacts among keratinocytes, or acantholysis. The hallmark of PV acantholysis in vitro is considered to be the retraction of keratin intermediate filaments (KIF) onto the nucleus, which parallels with loss of cell-cell adhesion and rounding up of keratinocytes. However, the fine morphological changes of keratinocytes as well as the fate of cell adhesion structures cannot be appreciated on immunofluorescence by the simple cytokeratin staining. In this paper, we show that acantholytic dysmorphisms are sharply investigated by using PV IgG as a primary antibody on metabolically quiescent living cells. Indeed, PV IgG recognise a wide spectrum of molecules and enabled us to monitor the main changes occurring in acantholytic keratinocytes, including cell shrinkage with the appearance of prickle-like processes, detachment of keratinocytes from one another and collapse of cytoskeleton-bound proteins along nuclear periphery. This method has wider applications as it could be useful for staining cell periphery of keratinocytes and changes in cell shape. Furthermore, images displayed clear and sharp contours because living cell microscopy allows to avoid antigen distortion due to cell manipulation, which usually precedes the immunolabelling. © 2007 Springer-Verlag.

Serum antibodies against desmoglein 1 (Dsg1) are known to induce the clinical and histological manifestations of pemphigus foliaceus (PF), autoimmune bullous disease targeting skin. The basic pathophysiological phenomenon of PF blistering is the disruption of epithelial integrity in the granular layer of the epidermis due to separation of keratinocytes from one another, or acantholysis. In this report we investigate the changes in subcellular distribution of Dsg1 in response to serum of patients with PF by using an in vitro model of PF. Immunofluorescence analysis on HaCaT cells indicates that non-clustered Dsg1 is markedly internalized after exposure to serum. However, binding of PF IgG to Dsg1-rich adhesion complexes (desmosomes) does not cause disruption of such structures nor depletion of clustered Dsg1, as revealed by colocalization of PF IgG and Dsg1 in a punctate staining on cell membrane 24 hours after treatment. Furthermore, morphological studies demonstrate that the dramatic alterations induced by PF sera are not the result of apoptotic programs. Taken together, our data strongly suggest that anti-Dsg1 antibodies from PF serum could cause the internalization of non-clustered Dsg1 and perturb the formation of new desmosomes but not directly disrupt Dsg1-containing junctions when stable contacts are already formed.

Pemphigus vulgaris (PV) is considered to be an autoimmune disease affecting skin and mucous membranes. Traditionally, PV autoantibodies are thought to recognize antigens located in the intercellular substance (ICS) of keratinocytes; antigens represented mainly by the desmosomal cadherin desmoglein 3 (Dsg3). Accordingly, titres of anti-ICS and anti-Dsg3 immunoglobulin G (IgG) are considered to be major laboratory criteria when making a diagnosis of PV. In this paper, we demonstrated for the first time that PV IgG bind antigen(s) expressed on the surface of peripheral blood mononuclear cells (PBMC), as revealed by immunofluorescence studies. This novel autoantigen is immunoprecipitated by PV IgG as a 130 000 molecular weight protein. However, Western blot analysis of the immunocomplexes failed to show reactivity with anti-Dsg3 monoclonal and polyclonal antibodies. Taken together, our data provide strong evidence that PV autoimmunity targets a 130 000 antigen other than Dsg3 on PBMC. This shifting from epidermis to blood cells may open new perspectives for a better understanding of pemphigus autoimmunity and more rational approaches to its treatment.

Pemphigus vulgaris (PV) is a disease of epidermal adhesion. Its pathogenesis is currently traced back to the action of autoantibodies against antigens located within the intercellular substance of keratinocytes, such as desmogleins and acetylcholine receptors. In the present paper, we sought to elucidate the non-IgG-mediated effects of PV sera on keratinocytes. Results showed that PV sera depleted of IgG were able to induce well-defined changes on keratinocyte morphology and metabolic activity. Indeed, PV IgG-free sera determined marked alterations on cell shape, accompanied by partial loss of keratinocyte–keratinocyte interactions within 48 h after treatment. Furthermore, PV IgG-depleted sera caused a sharp reduction of cell viability along with a less sustained weakening of intercellular adhesion strength. In light of the above findings, loss of cell–cell adhesion in PV occurs as a result of the cooperating action of both IgG and non-IgG-mediated mechanisms. These data have remarkable consequences on experimental models of PV and might open new “biological” approaches to its therapy. Thus, researchers are well advised that PV pathophysiology cannot be faithfully reproduced by leaving non-IgG serum factors out of consideration. J. Cell. Physiol. 212:563–567, 2007. © 2007 Wiley-Liss, Inc.

Background: Pemphigus vulgaris is a life-threatening autoimmune blistering disease targeting skin and mucous membranes, characterized by disruption of keratinocytes’ adhesion termed acantholysis. Today multiple classes of targets are considered to play a role in the genesis of the acantholysis; of these, the classical pemphigus antigens, desmosomal cadherins (desmoglein 1 and 3) are the best characterized and considered as the most important. Additional antigens include the novel epithelial acetylcholine receptors (a9 and pemphaxin). Thus, acantholysis in pemphigus seems to result from a cooperative action of antibodies to different keratinocyte self-antigens, but the mechanisms by which epithelial cleft occurs are not yet clearly understood. In fact, the binding of the autoantibodies to these targets generates a plethora of biological effects due, on one hand, to their direct interference with adhesive function and, on the other, to more complex events involving intracellular pathways that modify proteases activity or calcium metabolism, leading to loss of cell–cell adhesion.

Summary Objective The aim of our study is to evaluate, in accordance with EUROCLEFT guidelines, the aesthetics of nasolabial area in a sample of complete unilateral cleft of lip and palate patients (UCLP), after surgical correction with Delaire’ technique. Methods Twenty-two UCLP patients (16 males and 6 females, 9 right and 13 left side clefts) were enrolled in this retrospective study. Patients were operated at 7 (mean value) months of age by a single surgeon. Frontal and sub-mental photos for each baby were recorded at 8.5 (mean value) years of age, and evaluated twice, by three independent maxillofacial surgeons. A five-point scale (EUROCLEFT guidelines) was used. Nonparametric analysis (Kruskal–Wallis test) was applied to detect differences in medians obtained in studied groups. Results Kruskal–Wallis test showed no statistical significant differences among evaluations of three surgeons and between the first and the second evaluation of the same surgeon. The global appearance of the upper lip and nose was scored with a mean value of 2 (i.e. good). The sample was then divided into two subgroups, according with patient’ age; the aesthetics and the symmetry of the nose resulted better in elder patients (i.e. subgroup A, mean period of observation = 10.2 years), whereas upper lip achieved better results in younger patients (i.e. subgroup B, mean period of observation = 4.9 years). Conclusions EUROCLEFT guidelines are a useful method to evaluate – aesthetically and over time – cleft lip and palate patients, treated with a single surgical procedure. We hypothesize that Delaire technique could progressively improve aesthetics and symmetry of the nose, throughout the growth of the patient.

A 68-year-old female patient treated with benazepril for arterial hypertension developed oral and cutaneous blistering. Biopsy of the oral and cutaneous lesions showed neutrophilic microabscesses in the mesenchymal papillae, with epitheliomesenchymal separation. Direct immunofluorescence revealed linear immunoglobulin deposits at the epithelial basement membrane zone, consisting predominantly of IgA. The histologic results supported the clinical diagnosis of drug-induced linear IgA disease. The substitution of benazepril with a beta blocker resulted in complete resolution of all mucocutaneous lesions.

We selected two homogenous groups, each of 22 patients with idiopathic dysgeusia, an altered perception of taste, matched for age and sex, for an open trial of alpha lipoic acid compared with placebo. The 22 patients in the study group were treated with alpha lipoic acid for 2 months. The 22 patients in the control group were treated for 2 months with carboxymethylcellulose. The latter group was then treated with alpha lipoic acid for 2 months. The results showed significant symptomatic improvements compared with placebo, in both groups of patients with dysgeusia treated with alpha lipoic acid, suggesting that idiopathic dysgeusia may be a neuropathy comparable to the burning mouth syndrome.

Proliferative verrucous leukoplakia (PVL) is a unique oral white lesion in which human papillomavirus (HPV) may play a role. PVL behaves far more aggressively than other forms of leukoplakia with a high rate of recurrence after surgical excision, and relentless progression to verrucous hyperplasia and to verrucous or squamous cell carcinomas. The treatment of PVL is usually by surgery, but there is often early recurrence. This study was an open trial of surgery in 25 patients with oral HPV-positive PVL, compared with combined therapy using surgery and methisoprinol in another group of 25 patients with oral PVL. Six months postoperatively there was a significant difference, with 18 recurrences in the patients treated by surgery alone compared to only two recurrences in the patients treated also with methisoprinol (isoprinosine or inosine pranobex), a synthetic agent with immunomodulatory properties and some antiviral activity against HPV. Eighteen months postoperatively there were no further recurrences in the patients treated by surgery alone but another two recurrences in the patients treated with methisoprinol. Overall, by 18 months follow-up, there were 18 recurrences in the group treated by surgery alone, compared with four in those also receiving methisoprinol. The use of this antiviral agent appeared to offer a significant enhancement to the surgical management of PVL.

Maternal folic acid supplementation in early pregnancy has been suggested to play a role in the prevention of nonsyndromic orofacial cleft, i.e., cleft lip with or without cleft palate (CL/P). Moreover, some authors demonstrated association of the C→T mutation (C677T), converting an alanine to a valine residue in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, with other congenital anomalies such as neural tube defects (NTDs). Because of MTHFR’s involvement in the metabolism of folate, we investigated 64 CL/P patients and their parents for C677T MTHFR mutation. No linkage disequilibrium was found using the transmission disequilibrium test (TDT). However, a significantly higher mutation frequency was detected in mothers of CL/P patients compared to controls. The odds ratios calculated for mothers having CT or TT genotype, compared to the normal CC genotype, were 2.75 (95% confidence interval 1.30–5.57) and 2.51 (1.00–6.14), respectively. These results support the involvement of the folate pathway in the etiology of CL/P, and indicate an effect of the maternal genotype, rather than influence of the embryo’s genotype. © 2001 Wiley-Liss, Inc.

There is good evidence from linkage analysis and mouse model knockouts that the endothelin-1 gene (EDN1) is a good candidate for non-syndromic orofacial cleft (OFC) disease. EDN1 maps to the chromosomal region of the OFC1 locus in 6p23. Therefore we have examined three other candidate genes in the endothelin pathway (ECE1, EDNRA and EDNRB, which map to chromosomes 1, 4 and 13 respectively) in a linkage study of 9 families with OFC, where the disorder is not linked to chromosome 6p23. The total lod score for these 9 multiplex families never exceeded -2.00 and thus our data suggest that EDN1 and related genes are not involved in non-syndromic familial OFC.

BACKGROUND: The aim of this report is to highlight the case that pemphigus vulgaris (PV) may mimic aphthous stomatitis. Pemphigus classically causes persistent oral ulceration. METHODS AND RESULTS: We report five patients from southern Europe, who presented with recurrent oral ulceration mimicking aphthous stomatitis, but who proved by histology, immunostaining and antibodies against epithelial intercellular substance to have PV. CONCLUSION: It is advisable to assay antibodies against desmoglein 3 in patients who appear to suffer recurrent aphthous stomatitis (RAS) with atypical ulceration for location and in adulthood.

Folate receptor family members (FOLRs) mediate the delivery of 5-methyltetrahydrofolate to the interior of, out of within, or between cells in a process known as potocytosis. Three FOLRs and a pseudogene map to 11q13.4. The aim of this study was to verify whether FOLRs could be responsible for the onset of nonsyndromic cleft lip with or without cleft palate (CL/P). Linkage and linkage disequilibrium between genetic markers and disorder were analyzed. Patients and their mothers from 71 familial CL/P pedigrees and 75 sporadic cases from Italian population were investigated by PCR-SSCP analysis. Data from mutation scanning allowed us to find only a silent mutation in FOLR1 present in a mother and her child. Our findings do not support FOLR1 and FOLR2 genes in the onset of CL/P.

A novel explanation of pemphigus vulgaris (PV) pathogenesis suggests that serum autoantibodies may affect desmoglein 3 (Dsg3)-mediated adhesion by triggering depletion of Dsg3 from desmosomes. Furthermore, abrogation of Dsg3 from the cell seems to depend on anti-Dsg3 pemphigus IgG. In this study we sought to gain more insights into the role of PV IgG recognizing non-conformational epitopes of Dsg3 (anti-Dsg3-L IgG) by semi-quantitative living cell immunofluorescence (LCIF) microscopy, in-cell ELISA and morphometric analysis of acantholysis. Our data demonstrate that PV serum and PV IgG can induce acantholysis and reduce the total amount of Dsg3 in cultured keratinocytes, whereas anti-Dsg3-L IgG fail to do so when administered at concentrations comparable to those present in pathogenic PV sera. However, the Dsg3-depleting activity of such polyclonal anti-Dsg3 IgG was acquired when used at 1μg/ml. Interestingly, both PV sera and IgG, including anti-Dsg3-L IgG, caused early depletion of surface Dsg3 while slightly affecting the total cell content of Dsg3 until late acantholysis. This raises a possibility that depletion of Dsg3 from cell membrane and reduction of the total cellular levels of Dsg3 represent distinct phenomena in PV acantholysis. Taken together, our data demonstrate that anti-Dsg3 PV IgG against linear epitopes of Dsg3 can induce acantholytic changes of keratinocytes in a dose- and time-dependent manner. Specifically, both morphological and biochemical changes suggestive of acantholysis are seen only at high IgG concentrations. We conclude that anti-Dsg3L IgG play a minor role in experimental PV under physiologic conditions.

This study compares the effects of topical acyclovir and penciclovir in the treatment of recurrent herpes labialis. The study patients were a population of 40 patients with in excess of five recurrences annually, and were separated into four homogeneous groups each of 10 subjects. The antiviral creams were used to achieve total lesional cover, every 2 h during waking hours. The effects on the time to lesion crusting and to resolution of pain, were assessed. The results not only confirmed that aciclovir is ineffective, but confirmed that penciclovir is effective, and that penciclovir is superior to aciclovir.

SUMMARY The aim of this research was to evaluate the effect of the Delaire surgical technique on the midfacial morphology in a group of subjects with a congenital unilateral cleft of lip and palate (UCLP), prior to orthodontic treatment. Thirty-fi ve UCLP (15 left and 20 right) patients (16 males and 19 females, mean age 7.03 ± 0.9 years; age range 8.7 – 5.0 years), treated for the correction of congenital malformation, were retrospectively selected. Analysis of midfacial growth was undertaken on lateral cephalograms, and the data were compared with reference values (Ricketts analysis). A Mann – Whitney ranked sum test was used to detect signifi cant differences between the fi ndings and reference values. P ≤ 0.05 was considered as signifi cant. The results demonstrated a retropositioning of both the maxilla and mandible (SNA and SNB P < 0.01) and increased mandibular development (Go – Me distance). Vertically, there was a trend to a posterior rotation of the mandible ( P < 0.01), resulting in a hyperdivergent profi le. This trend was confi rmed by the increase in SpA – SpP/Go – Me ( P < 0.05). In agreement with previous studies, the effects of surgical closure of a cleft lip might be responsible for excessive maxillary retropositioning with a downward rotation.

Burning mouth disorder (BMD) is a burning or stinging sensation affecting the oral mucosa, lips, and/or tongue, in the absence of clinically visible mucosal lesions. There is a strong female predilection, with the age of onset being approximately 50 years. The causes of BMD are multifactorial and remain poorly understood. Often BMD patients report, in association, change in taste. In this regards, it is relevant that in central nervous system connections exist between taste and oral pain and that taste normally inhibits oral pain.The working hypothesis of this study considers a possible relationship between burning mouth disorders and alterations of taste. Several conditions or pathologies can be responsible of taste disturbances that might be the cause of oral pain in BMD patients.We have analyzed, retrospectively, 142 cases of BMD with associated taste disturbance. Possible causes that could be responsible for alterations of taste were investigated.Sixty-one subjects revealed the habitual use of drugs having a documented interference with taste perception. Thirty-five subjects, among the 81 patients who had no associated pathology or habitual use of drugs, noticed in their clinical history conditions, pathologies or use of drugs that are known to affect the gustatory system. Therefore, we propose that BMD may represent an oral phantom pain induced in susceptible individuals by alteration of taste.

We have previously demonstrated that serum of patients with pemphigus vulgaris induces reduction of desmoglein 3 (Dsg3) half-life in keratinocytes (FEBS Lett 2006: 580: 3276). This phenomenon seems to occur as a consequence of the progressive depletion of Dsg3 from desmosomes. Here we reported that reduction of full-length Dsg3 may be due to its progressive cleavage, leading to the formation of two fragmentation products with apparent molecular masses of about 60 kDa (fragment 1) and 70 kDa (fragment 2), as revealed by Western blotting. Unexpectedly, analysis of fragmentation pattern suggested cleavage to occur intracellularly. Consistently, fragment 1 was shed and localized within the cytosol, as shown by living cell immunofluorescence microscopy. Total amounts of full-length plakoglobin and Dsg1 were apparently unchanged. Taken together, our findings provide evidence that proteolytic processing of Dsg3 can lead to depletion of Dsg3 from the cell.

Recurrent aphthous stomatitis (RAS) is characterized by recurrent painful oral ulcers whose etiology remains largely unknown. Numerous therapeutic protocols have been tried so far, but effectiveness remains an issue.To test a new drug for patients with recurrent oral aphthae nonresponsive to local corticosteroid therapy, we compared the therapeutic effectiveness and adverse effects of systemic prednisone and systemic montelukast in a placebo-controlled trial.Sixty patients suffering from minor RAS foror =6 months were studied and randomly assigned to 3 groups of 20 each in a double-blind study. Patients of group A took 25 mg prednisone orally daily for 15 days, 12.5 mg daily for 15 days, 6.25 mg daily for 15 days, then 6.25 mg on alternate days for 15 days. Patients of group B took 10 mg montelukast orally every evening and then on alternate days for the second month. Patients of group C took 100 mg cellulose (placebo) by mouth daily for the first month and on alternate days for the second month. Outcomes assessed were days til pain cessation, days to ulcer healing, and number of aphthae occurring during the follow-up period.Both prednisone and montelukast were effective in reducing the number of lesions and improving pain relief and ulcer healing when compared with placebo. Prednisone was more effective than montelukast in pain cessation (P.0001) and in accelerating ulcer healing (P.0001). However, adverse drug reactions recorded during the entire trial were more common in the prednisone group compared with montelukast (10%) and placebo (10%).These data suggest that the effectiveness of systemic montelukast is similar to that of systemic prednisone in patients with RAS. The lack of serious side effects makes montelukast a candidate drug to use in cases of RAS where pharmacologic therapy for long periods is needed.

Background Adverse drug reactions are noxious and unintended responses to a medicinal product. Many drugs have the potential to induce adverse reactions in the mouth. The extent of such reactions is unknown; however, because a lot of them are asymptomatic, many are believed to go unnoticed. Adverse oral drug reactions are responsible for oral lesions and manifestations that can mime local or systemic disease. Their pathogenesis, especially of the mucosal reactions, is largely unknown and appears to involve complex interactions between the drug in question, other medications, the patient’s underlying disease, genetics and lifestyle factors. Aim In this study, we have listed the principal signs and symptoms of oral and perioral adverse drug reactions and the responsible drugs. Diagnosis for adverse drug reaction is not easy given also the limited utility of laboratory tests. The association between a drug and an adverse drug reaction is mostly based on the disappearance of the reactions following discontinuance of the offending drug. Sometimes, it is useful to perform rechallenge tests reintroducing the drug to establish cause and effect. Conclusions Knowledge of adverse drug-induced oral effects helps health professionals to better diagnose oral disease, administer drugs and improve patient compliance during drug therapy and may foster a more rational use of drugs.

Aphthous ulcers are the most common oral mucosal lesions in the general population. Several precipitating factors for aphthous ulcers are suggested to operate on subjects with genetic predisposition. Sometimes aphthous ulcers can be the sign of systemic diseases. Therefore, it is essential to establish a correct diagnosis to determine suitable therapy. There are several diseases potentially responsible for oral ulcers. Sometimes appearance of periodic oral ulcers coincides with periodic fever and other symptoms leading to the diagnosis of a rare childhood disease: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenopathy) syndrome. PFAPA or Marshall's syndrome is characterized by abrupt onset of periodic episodes of high fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis, often associated with headache and / or abdominal or joint pain. Owing to the periodic onset of oral symptoms, often an oral physician or pediatric dentist may be the first healthcare worker to evaluate a child with clinical signs compatible with PFAPA syndrome. Children diagnosed with this condition require systematic oral follow-up to monitor for signs of ulceration.

The pathogenesis of pemphigus vulgaris (PV) is still poorly understood. Autoantibodies present in PV patients can promote detrimental effects by triggering altered transduction of signals, which results in a final acantholysis. To investigate mechanisms involved in PV, cultured keratinocytes were treated with PV serum. PV sera were able to promote the cell cycle progression, inducing the accumulation of cyclin-dependent kinase 2 (Cdk2). Microarray analysis on keratinocytes detected that PV serum induced important changes in genes coding for one and the same proteins with known biological functions involved in PV disease (560 differentially expressed genes were identified). Then, we used two different approaches to investigate the role of Cdk2. First, small interfering RNA depletion of Cdk2 prevented cell-cell detachment induced by PV sera. Second, pharmacological inhibition of Cdk2 activity through roscovitine prevented blister formation and acantholysis in the mouse model of the disease. In vivo PV serum was found to alter multiple different pathways by microarray analysis (1463 differentially expressed genes were identified). Major changes in gene expression induced by roscovitine were studied through comparison of effects of PV serum alone and in association with roscovitine. The most significantly enriched pathways were cell communication, gap junction, focal adhesion, adherens junction, and tight junction. Our data indicate that major Cdk2-dependent multiple gene regulatory events are present in PV. This alteration may influence the evolution of PV and its therapy. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

Apoptotic cells are known to regulate the ordered dismantling of intercellular contacts through caspase activity. Despite the important role of desmoglein (Dsg) 2 in epithelial cell–cell adhesion, the fate of this widespread desmosomal cadherin during apoptosis is yet poorly understood. Here, by means of pharmacological approaches, we investigated whether Dsg2 was targeted by caspases in HaCaT and HT-29 cell lines undergoing staurosporine (STS)- induced apoptosis. Results showed that STS induced a caspase-dependent form of cell-death in both keratinocytes (HaCaT) and enterocytes (HT-29), that associated with progressive depletion of Dsg2 from cell lysates. The proteolytic processing of full-length Dsg2 resulted in the appearance of a 70-kDa fragment which was released into the cytosol. Consistently, immunofluorescence studies revealed that Dsg2 staining was abolished from cell surface whereas the cytoplasmic region of Dsg2 did localize intracellularly. Plakoglobin (Pg) also underwent cleavage and detached from Dsg2. Apoptotic changes paralleled with progressive loss of intercellular adhesion strength. All these biochemical, morphological, and functional changes were regulated by caspase 3. Indeed, in the presence of the caspase 3-inhibitor z- DEVD-fmk, full-length Dsg2 protein levels were preserved, whereas the amount of the 70-kDa fragment was maintained on control levels. Furthermore, cells pretreated with z-DEVD-fmk retained the membrane labeling of Dsg2. Taken together, our data demonstrate that the apoptotic processing of Dsg2 is mediated by caspase 3 in epithelial cells. J. Cell. Biochem. 103: 598–606, 2008. 2007 Wiley-Liss, Inc Apoptotic cells are known to regulate the ordered dismantling of intercellular contacts through caspase activity. Despite the important role of desmoglein (Dsg) 2 in epithelial cell-cell adhesion, the fate of this widespread desmosomal cadherin during apoptosis is yet poorly understood. Here, by means of pharmacological approaches, we investigated whether Dsg2 was targeted by caspases in HaCaT and HT-29 cell lines undergoing staurosporine (STS)-induced apoptosis. Results showed that STS induced a caspase-dependent form of cell-death in both keratinocytes (HaCaT) and enterocytes (HT-29), that associated with progressive depletion of Dsg2 from cell lysates. The proteolytic processing of full-length Dsg2 resulted in the appearance of a 70-kDa fragment which was released into the cytosol. Consistently, immunofluorescence studies revealed that Dsg2 staining was abolished from cell surface whereas the cytoplasmic region of Dsg2 did localize intracellularly. Plakoglobin (Pg) also underwent cleavage and detached from Dsg2. Apoptotic changes paralleled with progressive loss of intercellular adhesion strength. All these biochemical, morphological, and functional changes were regulated by caspase 3. Indeed, in the presence of the caspase 3-inhibitor z-DEVD-fmk, full-length Dsg2 protein levels were preserved, whereas the amount of the 70-kDa fragment was maintained on control levels. Furthermore, cells pretreated with z-DEVD-fmk retained the membrane labeling of Dsg2. Taken together, our data demonstrate that the apoptotic processing of Dsg2 is mediated by caspase 3 in epithelial cells. © 2007 Wiley-Liss, Inc.

Pemphigus vulgaris (PV) is considered to be an autoimmune disease affecting skin and mucous membranes. Traditionally, PV autoantibodies are thought to recognize antigens located in the intercellular substance (ICS) of keratinocytes; antigens represented mainly by the desmosomal cadherin desmoglein 3 (Dsg3). Accordingly, titres of anti-ICS and anti-Dsg3 immunoglobulin G (IgG) are considered to be major laboratory criteria when making a diagnosis of PV. In this paper, we demonstrated for the first time that PV IgG bind antigen(s) expressed on the surface of peripheral blood mononuclear cells (PBMC), as revealed by immunofluorescence studies. This novel autoantigen is immunoprecipitated by PV IgG as a 130 000 molecular weight protein. However, Western blot analysis of the immunocomplexes failed to show reactivity with anti-Dsg3 monoclonal and polyclonal antibodies. Taken together, our data provide strong evidence that PV autoimmunity targets a 130 000 antigen other than Dsg3 on PBMC. This shifting from epidermis to blood cells may open new perspectives for a better understanding of pemphigus autoimmunity and more rational approaches to its treatment.

Genetic studies have demonstrated that nonsyndromic cleft is composed of two separate entities: the cleft palate only and cleft of the lip, alveolus with or without cleft palate; both have a heterogeneous genetic background and environmental factors contribute to the onset of these malformations. The role of transforming growth factor alpha (TGF-A) was considered possible, but conflicting results have been reported. To detect if TGF-A is involved in the onset of cleft diseases, a series of patients with nonsyndromic clefts and control subjects were analyzed with regard to protein expression. Forty-three patients with nonsyndromic clefts and 21 unaffected subjects were enrolled in this study. Paraffin-embedded specimens were matched with TGF-A antibody and then scanned with a computerized image analyzer. TGF-A was scored as absent, moderately (from 10% to 30%), and highly expressed in epithelium, gland, and muscle. Data were statistically analyzed with a Kruskal-Wallis test. Comparison between control subjects and patients with clefts showed that only gland and epithelium reached a significant P value. A subsequent comparison between cleft of the lip, alveolus with or without cleft palate and cleft palate only groups demonstrated a statistically significant difference only for gland. TGF-A was decreasingly expressed in unaffected, cleft of the lip, alveolus with or without cleft palate, and patient with cleft palate only and thus further strength has been given to its role in the onset of the disease. © 2007 Muntaz B. Habal, MD.

Pemphigus vulgaris (PV) acantholysis represents a complex phenomenon wherein a number of factors cooperates. PV serum is known to modulate important cellular events, including kinase activity, transcriptional regulation, and proteinase expression. Indeed, transduction of signals to the cell triggered by PV serum may induce proteinase up-regulation potentially responsible for disruption of epidermal adhesion and, ultimately, blister formation. Here, we sought to investigate this hypothesis by using both in vivo and in vitro models of PV. Microarray analysis on mouse skin tissues suggested that the equilibrium between extracellular proteinases and their inhibitors moved towards enhanced proteolytic activity in PV neonatal mouse model, at least on the transcriptional level. Conversely, genes codifying cell adhesion proteins were dramatically down-regulated. The effects of PV serum on the protein level were then studied in vitro both in keratinocyte monolayers and skin organ cultures focusing on matrix metalloproteinase (MMP) 9 expression and activity. By means of Western blotting, zymography, and living cell immunofluorescence studies, we showed that MMP-9 was early overexpressed in keratinocytes exposed to PV serum, and subsequently secreted in the culture medium. However, we failed to demonstrate extracellular activation of MMP-9, since it was found in its 92 kDa inactive form in serum-free culture supernatants. Taken together, our data demonstrated that proteinase expression, particularly of MMP-9, is modulated by PV serum and associated with PV acantholysis.

The current knowledge on Pemphigus vulgaris (PV) pathophysiology suggests that blister formation relies on both PV IgG and non-IgG serum factors activity. PV autoimmunity seems to develop against both desmoglein 1/3 and acetylcholine receptors leading to transduction of signals to the cell mediated by phosphorilation events. Serum factors other than IgG also participate to PV acantholysis through apoptotic or cytokine-mediated mechanisms. Apart from the role played by each actor within the acantholysis, however, the current scenario arises important methodological issues. For example, the use of PV IgG or monoclonal anti-Dsg3 antibodies to experimentally reproduce the disease appears inadequate, as it does not take into account the role of non-IgG factors. On the basis of the above observations and those from our laboratories, here we propose that using whole sera from PV patients with active disease represents the most faithful manner to mimic the disease.

Within the last decade, a number of theories on the pathogenesis of pemphigus vulgaris (PV) have followed one another. Of these, plesminogen activation and desmoglein compensation hypotheses have been substantiated by a conspicuous body of evidence. A significant change of this scenario occurred with the discovery that autoimmunity in PV can target acetylcholine receptors and that PV serum elicits a pletora of intracellular signals. Since then, a myriad of explanations accounting for PV acantholysis have appeared in the literature. However, as revolutionary as they can be, the majority of organic theories seemed to be highly speculative. We have recently obtained evidence for a proteolytic cleavage of desmoglein 3 in an in vitro model of PV; furthermore, our previous findings suggested the possible involvement of proteases such as matrix metalloproteinase (MMP) 9 in PV acantholysis both in vitro and in vivo. Hence, in formulating the "specific proteolysis theory" we have kept the rationale and the well-established evidence of both plasminogen activation and desmoglein compensation hypotheses. However, the specific proteolysis theory proposed by us is not just a return to the past. On the basis of the current knowledge on MMP substrate specificity we propose that Dsg1 and Dsg3, along with other important cadherins which are likely to be proteolytically targeted in PV, could be cleaved by either ADAM or typical MMPs, respectively. Whether this view was confirmed by further investigations, these enzymes could be specifically targeted by selective drugs which would permit more rational approaches to the treatment of pemphigus. © 2007 Elsevier Ltd. All rights reserved.

The complexity of pemphigus acantholysis together with the weak expression of desmoglein 1 (Dsg1) in cultured keratinocytes have made the study on the pathogenic action of anti-Dsg1 antibodies quite difficult. The pathophysiology of the acantholytic phenomenon could depend on the reduction of Dsg1 adhesion function occurring after its massive internalization or decrease of its synthesis. Here, we have investigated this hypothesis by using sera of patients having antibodies against Dsg1 or monoclonal anti-Dsg1 antibodies to simulate pemphigus autoimmunity in Dsg1-rich keratinocytes. Similar to pemphigus foliaceus (PF) and vulgaris (PV) sera, monoclonal anti-Dsg1 antibodies induced transient internalization of Dsg1 and reduced the adhesion strength among keratinocytes. However, binding of IgG to Dsg1 did not determine its early depletion from the adhesion complexes but reduced the amount of Dsg1 found in the Triton X-100 soluble pool of proteins. Taken together, our results represent the first demonstration that anti-Dsg1 antibodies induce similar alterations on the subcellular distribution of Dsg1 irrespective of the disease where they come from. Furthermore, the present study provides insight into the mechanisms underlying epithelial blistering observed in the skin type of pemphigus.

Defects of cell–cell adhesion underlie disruption of epithelial integrity observed in patients with pemphigus vulgaris (PV), an autoimmune disease characterized by severe mucosal erosions and skin blisters. Pathogenic PV autoantibodies found in patients’ sera target desmoglein 3 (Dsg3), a major component of the desmosome, but how does this phenomenon affect Dsg-dependent adhesion and lead to acantholysis still remains controversial. Here, we show that PV serum determines a reduction of Dsg3 half-life in HaCaT keratinocytes, although the total amount of Dsg3 remains unchanged. Immunofluorescence studies suggest that PV IgG exert their effect prevalently by binding non-desmosomal Dsg3 without causing its massive internalization. Furthermore, PV IgG targeting desmosome-assembled Dsg3 do not induce depletion of Dsg3 from the adhesion sites. Conversely, incorporation of PV IgG-Dsg3 complexes into new forming desmosomes appears perturbed. With our study, the basic biochemical changes of Dsg3 in an in vitro model of PV have been defined.

Moderate physical exercise (PE) combined with metabolic treatment (MT) (antioxidants and l -arginine) are well known to reduce atherosclerotic lesion formation in hypercholesterolemic mice. However, the long-term beneficial effects on unstable atheroma remain poorly understood. We started early PE training in large groups of 6-week-old hypercholesterolemic mice (by graduated swimming) alone or in combination with nutritional supplementation (1.0% vitamin E added to the chow and 0.05% vitamin C and 6% l -arginine added to the drinking water). Inactive controls did not receive PE. The spontaneous development of atherosclerotic plaque rupture (associated with advanced atherosclerosis) and survival rates were evaluated. Moderate PE elicited an increase in plasma levels of nitric oxide. Early combined treatment with PE and MT in the hypercholesterolemic mice significantly reduced lesions (also detected noninvasively at 10 months) and spontaneous atherosclerotic plaque rupture and prolonged survival more effectively than each intervention alone. Thus, early concerted actions of MT and PE improve the natural history of atherosclerotic lesions and reduce the plaque instability in hypercholesterolemic mice.

Background: Genetic studies have demonstrated that non-syndromic cleft is composed of two separate entities - cleft palate only (CPO) and cleft of lip, alveolus with or without cleft palate (CL ± P) -, both have a heterogeneous genetic background and environmental factors contribute to the onset of these malformations. Previous studies have shown that TGFβ3 could be involved in these diseases, but no conclusive results have been reached. Purpose: In order to detect if TGFβ3 has a role in cleft diseases, a series of non-syndromic cleft patients and controls are analyzed for TGFβ3 protein expression. Material and methods: Forty-three non-syndromic cleft patients and 21 unaffected subjects were involved in this study. Paraffin-embedded specimens were matched with the TGFβ3 antibody and then scanned with a computerized image analyzer. TGFβ3 was found to be absent (less than 10%), moderate (from 10% to 30%) and highly expressed (higher than 30%) in epithelium (EP), minor palatal salivary gland (GL) and fibres of elevator palati muscle (MU). Data was statistically analyzed with a Kruskal-Wallis test. Results: Only GL and EP have a statistically significant lower expression in non-syndromic cleft compared to unaffected subjects. A subsequent comparison between CL ± P and CPO groups demonstrates a statistically significant difference only for GL, with a lower expression in GL of CPO patients. Conclusions: TGFβ3 is decreasingly expressed in GL of unaffected CL ± P and CPO patients and thus further strength is given to a pathogenetic role of TGFβ3 in the onset of clefts. © 2006 Elsevier Ireland Ltd. All rights reserved.

Folate receptor family members (FOLRs) mediate the delivery of 5-methyltetrahydrofolate to the interior of, out of within, or between cells in a process known as potocytosis. Three FOLRs and a pseudogene map to 11q13.4. The aim of this study was to verify whether FOLRs could be responsible for the onset of nonsyndromic cleft lip with or without cleft palate (CL/P). Linkage and linkage disequilibrium between genetic markers and disorder were analyzed. Patients and their mothers from 71 familial CL/P pedigrees and 75 sporadic cases from Italian population were investigated by PCR-SSCP analysis. Data from mutation scanning allowed us to find only a silent mutation in FOLR1 present in a mother and her child. Our findings do not support FOLR1 and FOLR2 genes in the onset of CL/P.

BACKGROUND: The objective of this study was to investigate the effect of zinc on recurrent herpes labialis.MATERIALS AND METHODS: Twenty patients (12 females; median age 26.6 years) with a history of recurrent herpes labialis > 6 episodes each year were treated with systemic zinc sulphate 22.5 mg twice daily for the months of February, March, September and October. All patients were followed for 12 months.RESULTS: Herpetic lesions reduced to < 4 episodes (average 3) for the 12 months and the duration was < 7 days for each episode (average 5.7).CONCLUSIONS: Systemic zinc sulphate appeared to reduce both the number of episodes and the time to recovery of herpes labialis.

Summary Background Genetic studies have demonstrated that non-syndromic clefts of the lip, alveolus and palate have an heterogeneous genetic background, and that environmental factors contribute to the onset of this malformation. Therefore studies on different and homogeneous populations can be useful in detecting potentially related environmental and genetic factors. Purpose The aim of the present study was to evaluate whether gender, folic acid intake, family history of diabetes and/or smoking during pregnancy were associated with a specific type of cleft in a group of patients affected by non-syndromic clefts, collected from Southern Italy. Material and methods Data from one hundred and twenty-six patients were evaluated retrospectively. Each cleft was described as composed by separate antomical entities such as lip, alveolus, primary and secondary palate. None had an isolated alveolar cleft and this was used as internal control. Pattern analysis was used to detect differences in the frequencies of any possible combination of 7 types of clefting stratified according to the studied variables. Data were analysed by comparing observed proportions. Results Isolated cleft palate as well as right-sided clefts of lip, alveolus and palate were more frequent in females ( p = 0.0014 and 0.0281, respectively), while left sided clefts were more frequent in males ( p = 0.0359 ) . A lack of consumption of folic acid was associated with an higher incidence of clefts of the left lip ( p = 0.018 ) , while familial diabetes was associated more often with isolated cleft palate ( p = 0.0014 ) . Conclusions Gender-related results were comparable with those found in Northern Italy and other countries. Environmentally related results disclosed specific subclasses of clefting associated with lack of folic acid consumption and familial diabetes.

Objective We have examined the effect of alpha-lipoic acid (ALA, tioctic acid; Tiobec), a free radical scavenger, on the discomfort of burning mouth syndrome (BMS) in patients who had used tranquillizers previously, compared with those who had not.Methods In this study we gave lipoic acid for 2 months to two groups of 20 BMS patients, one of which had previously been treated with tranquillizers.Results The results showed greater effectiveness of lipoic acid in BMS patients who had not previously used tranquillizers.Conclusions The patients with BMS who had previously been treated with tranquillizers responded poorly to therapy with lipoic acid compared with those who had not received previous psychotropic therapy.

This open study of 192 otherwise healthy persons with burning mouth syndrome, examined the efficacy on control of symptoms of psychotherapy alone with two hour sessions weekly for two months; alpha lipoic acid (ALA, tioctic acid; Tiobec) 600 mg/day alone for two months; or combination therapy of psychoanalysis and 600 mg/day ALA for two months. Controls received placebo alone.Most benefit was obtained with combination therapy. Combination therapy of psychoanalysis and alpha lipoic acid (ALA, tioctic acid; Tiobec. 600 mg/day) for two months gave most benefit and significantly more than psychoanalysis alone for two 1 hour sessions weekly for two months (p0.0005), or ALA 600 mg/day alone for two months (p0.0005).The present results suggest that alpha lipoic acid may complement psychotherapy and can be an acceptable alternative to psychoactive agents, but trials to compare the two approaches are now warranted.

Nonsyndromic cleft of the lip with or without palate (CLP) derives from an embryopathy with failure of the nasal processes and/or fusion of the palatal shelves. This severe birth defect is one of the most common malformations among live births. Human cleft is composed of two separate entities: cleft lip and/or palate (CLP) and cleft palate only (CPO). Both have a genetic origin, whereas environmental factors contribute to these congenital malformations. In this review we analyse the role of drugs, environmental factors, genes and loci related to the onset of cleft. The data were obtained from (i) epidemiologic studies, (ii) animal models and (iii) human genetic investigations. Epidemiologic studies have demonstrated a relation between certain environmental factors (alcohol, cigarette smoking, steroids and anticonvulsants) during pregnancy and a higher risk of generating offspring with CLP. On the contrary, folic acid intake seems to have a protective effect. No clear relation has been demonstrated between aspirin and CLP. Murine models were developed to investigate drug-induced embryopathy and, more recently, to obtain information regarding genes and biochemical pathways. Steroids and anticonvulsants are the most widely studied clefting drugs, whereas TGFs and retinoic acids are the most thoroughly investigated among biochemical pathways. Human genetic studies on CLP have identified several loci and, in one case, also a specific gene. In CPO, one gene has been identified, though many more are probably involved. Among the identified chromosomal regions, there are some carrying genes with functions related to environmental factors with a clefting or protective effect.

Background Recurrent aphthous stomatitis (RAS) is a common oral condition, the etiology of which remains largely unclear. Numerous therapeutic protocols have been tried. Apart from immunomodulators, no therapy is unequivocally effective, and many systemic therapies have potential adverse effects. Objective To compare, in patients with frequent RAS unresponsive to conventional therapies, the therapeutic effectiveness of systemic prednisone with that of systemic sulodexide, a low-molecular-weight heparin with immunosuppressive activity but few adverse effects. Methods The study involved a group of 30 patients suffering from frequent minor RAS over ≥ 4 months unresponsive to topical corticosteroids. Patients were randomly assigned to one of three study groups: blind therapy with systemic sulodexide or systemic prednisone and control (no treatment). The outcomes were assessed blind on the basis of the days to recovery from pain and days to recovery from ulceration (epithelialization) during the first month of therapy; the number of aphthae appearing during the second month of therapy; and the number of aphthae appearing in the 2 months after the end of the 2-month treatment cycle. Results and conclusions The effectiveness of systemic sulodexide was almost comparable with that of systemic prednisone in patients with frequent RAS, without significant adverse effects.

We report a case of Sweet's syndrome with recurrent oral ulceration, pyrexia, skin lesions, and migratory thrombophlebitis, with no detectable systemic cause, during a 2-year follow-up. Biopsy examination both of oral lesions and the skin eruption showed a characteristic dense, perivascular, neutrophilic infiltrate in the lamina propria. Laboratory investigations confirmed an inflammatory syndrome with an increased erythrocyte sedimentation rate, but no underlying cause was found. Sweet's syndrome is a rare immunologically mediated condition that belongs to the group of neutrophilic dermatoses that must be differentiated particularly from Behcet's disease. It is characterized by red-brown plaques and nodules that are frequently painful and occur primarily on the head, neck, and upper extremities. Often the patients also have neutrophilia and fever and may have oral ulceration. In approximately 10% of patients with Sweet's syndrome, there is an associated malignancy - most commonly acute myelogenous leukemia - but some cases, as here, are unassociated with detectable malignant or other disease, although the syndrome may precede the onset of definable systemic disease.

Objective To study the effect of the heparinoid sulodexide systemically, compared with topical cyclosporine (ciclosporin), on chronic oral erosive/ulcerative lichen planus. Study design An open nonrandomized trial was conducted in two groups of 10 Italian patients with lichen planus, with subjective assessment of pain and assessment of ulceration amelioration by nonblinded clinicians. Results Comparable pain relief and amelioration of erosions/ulcers were seen in patients on sulodexide and in those on ciclosporin, but with faster healing in those on sulodexide. Conclusions Sulodexide appears to be as effective, and perhaps more effective, than topical ciclosporin in the therapy of oral lichen planus, and is less expensive, but full double-blind placebo-controlled studies are required.