Capacity to improve fine motor skills in Williams syndrome.

BACKGROUND: Individuals with Williams syndrome (WS) are known to have difficulties in carrying out fine motor movements; however, a detailed behavioural profile of WS in this domain is still missing. It is also unknown how great the capacity to improve these skills with focused and extensive practice is. METHOD: We studied initial performance and learning capacity in a sequential finger tapping (FT) task in WS and in typical development. Improvement in the FT task has been shown to be sleep dependent. WS subjects participating in the current study have also participated in earlier polysomnography studies, although not directly related to learning. RESULTS: WS participants presented with great individual variability. In addition to generally poor initial performance, learning capacity was also greatly limited in WS. We found indications that reduced sleep efficiency might contribute to this limitation. CONCLUSIONS: Estimating motor learning capacity and the depth of sleep disorder in a larger sample of WS individuals might reveal important relationships between sleep and learning, and contribute to efficient intervention methods improving skill acquisition in WS.

Atypical sleep architecture and altered EEG spectra in Williams syndrome.

BACKGROUND: Williams syndrome (WS) is a neurodevelopmental genetic disorder characterised by physical abnormalities and a distinctive cognitive profile with intellectual disabilities (IDs) and learning difficulties. METHODS: In our study, nine adolescents and young adults with WS and 9 age- and sex-matched typically developing (TD) participants underwent polysomnography. We examined sleep architecture, leg movements and the electroencephalogram (EEG) spectra of specific frequency bands at different scalp locations. RESULTS: We found an atypical, WS characteristic sleep pattern with decreased sleep time, decreased sleep efficiency, increased wake time after sleep onset, increased non-rapid eye movement percentage, increased slow wave sleep, decreased rapid eye movement sleep percentage, increased number of leg movements and irregular sleep cycles. Patients with WS showed an increased delta and slow wave activity and decreased alpha and sigma activity in the spectral analysis of the EEG. CONCLUSIONS: Sleep maintenance and organisation are significantly affected in WS, while EEG spectra suggest increases in sleep pressure.

Controversial role of antibodies against linear epitopes of desmoglein 3 in pemphigus vulgaris, as revealed by semiquantitative living cell immunofluorescence microscopy and in-cell ELISA.

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 1 microg/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.

Pilot study on recurrent aphthous stomatitis (RAS): a randomized placebo-controlled trial for the comparative therapeutic effects of systemic prednisone and systemic montelukast in subjects unresponsive to topical therapy.

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: Sixty patients suffering from minor RAS for > or =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. RESULTS: 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%). CONCLUSIONS: 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.

Serum of patients with oral pemphigus vulgaris impairs keratinocyte wound repair in vitro: a time-lapse study on the efficacy of methylprednisolone and pyridostigmine bromide.

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 < 0.01) enhanced wound fill by 30% after 72 h. PV-associated wound repair was significantly (P < 0.05) ameliorated by PBr by 24 h and keratinocytes reached 20% confluence after 72 h. Interestingly, neither MP nor PBr could accelerate wound healing when compared with untreated control monolayers. CONCLUSIONS: In PV, MP and PBr exert their curative effects in part by enhancing the regeneration properties of keratinocytes. Indeed, our data suggest that both drugs can specifically counterbalance the detrimental effects of PV serum on keratinocyte wound healing. These findings provide an explanation for the efficacy of MP and PBr in the treatment of PV lesions in human skin and oral mucosa.

At least three phosphorylation events induced by pemphigus vulgaris sera are pathogenically involved in keratinocyte acantholysis.

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.

Oral manifestations of adverse drug reactions: guidelines.

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.

Mucocutaneous pemphigus vulgaris carrying high-titre antidesmoglein 1 antibodies with skin lesions resembling pemphigus erythematosus.

Patients with pemphigus vulgaris (PV) who have both antidesmoglein (Dsg)1 and anti-Dsg3 antibodies usually develop flaccid blisters on skin and mucous membranes. We report a case of PV with crusting skin lesions resembling pemphigus erythematosus, the localized variant of pemphigus foliaceus (PF). Notably, the patient had high titres of anti-Dsg1 IgG, as assessed by ELISA. We then established an in vitro model of pemphigus, and found that patient's serum was able to induce suprabasilar acantholysis in mouse skin culture. However, epidermal splitting also occurred within the granular layer, suggesting that the pathogenic potential of such a high-titre anti-Dsg1 serum was intermediate between PV and PF. Thus, the levels of anti-Dsg1 antibodies could play a role in determining the clinical phenotype of pemphigus.

Internalization of non-clustered desmoglein 1 without depletion of desmoglein 1 from adhesion complexes in an experimental model of the autoimmune disease pemphigus foliaceus.

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.

Metalloproteinase 9 is the outer executioner of desmoglein 3 in apoptotic keratinocytes.

OBJECTIVE: To investigate the specific matrix metalloproteinases (MMPs) targeting desmoglein 3 (Dsg3) in apoptotic keratinocytes. METHOD: Inhibitor studies on cultured keratinocytes and Western blot analysis. RESULTS: Blocking of MMP-9 activity strongly reduces shedding of Dsg3 from cell surface. MMP-2 has a less relevant role in the cleavage of Dsg3 while other MMPs, such as MMP-1, -3, and -8, do not target Dsg3. CONCLUSION: Apoptic keratinocytes impair the extracellular domain of cell surface Dsg3 by MMP-9 activity. The discovery of a specific targeting of Dsg3 could be useful to understand the pathophysiology of diseases in which Dsg3 is affected.

Matrix metalloproteinase gene expression in oral lichen planus: erosive vs. reticular forms.

BACKGROUND: Oral lichen planus (OLP) is an autoimmune disease of unknown aetiology. The pathogenesis is characterized by apoptosis of basal keratinocytes, triggered by contact between CD8+ -activated lymphocytes and an unknown antigen expressed on the surface of the basal cells. Basement membrane (BM) degradation, which allows lymphocytes to migrate, involves proteolytic enzymes known as matrix metalloproteinases (MMPs). OBJECTIVES: This study aimed to evaluate the expression of a series of MMPs in biopsies from OLP patients, to reveal correlations with different clinical forms of OLP. METHODS: Twenty-six patients diagnosed with OLP (14 reticular and 12 erosive) were studied, together with seven healthy patients as negative controls. RESULTS: Reverse transcriptase polymerase chain reaction (RT-PCR) showed that the overall levels of expression of MMP mRNAs were higher in erosive lichen planus (E-OLP) than in the reticular forms (R-OLP). Moreover, MMP-1 and MMP-3 may be principally associated with erosion development. The expression of specific tissue inhibitors of metalloproteinases (TIMPs) was also evaluated. CONCLUSIONS: The different clinical appearances of OLP are associated with significant differences in MMP mRNA levels.

Burning mouth syndrome (BMS): evaluation of thyroid and taste.

BACKGROUND: Burning mouth syndrome (BMS) is a chronic, intraoral burning sensation seen mainly in middle-aged and post-menopausal females, without identifiable oral lesions or abnormal laboratory findings, but often associated with psychogenic disorders such as depression. The latter can have a range of causes, including hormonal. OBJECTIVE: Since there may be connections between BMS, psychogenic changes, hormonal changes and taste abnormalities, we have examined aspects of taste and thyroid function. PATIENTS AND METHODS: We selected 50 patients with BMS (study group) and 50 healthy subjects (control group) and analysed their ability to taste bitter, acid and spicy substances and analysed their thyroid function and Undertook thyroid echography. RESULTS: Taste sensation was normal in all controls. However, 30 of the patients with BMS reported ageusia for bitter taste and 2 had ageusia for acid. The use of pepper sauce (Tabasco) (spicy substance) produced a strong burning to the tongue in 28 patients of the BMS group but only in 10 controls. No control patients showed abnormality of thyroid function or echograpic abnormality. Five patients in the BMS group had biochemical evidence of hypothyroidism, 4 patients had raised levels of thyroid auto-antibodies and, of the 41 remaining BMS patients, most (34) had thyroid echographic changes indicative of nodularity. CONCLUSIONS: Hypothyroidism may be responsible for a negative influence on taste and consequent increase in trigeminal sensorial sensation (tactile, thermal and painful sensation).

Burning mouth syndrome (BMS): evaluation of thyroid and taste

BackgroundBurning mouth syndrome (BMS) is a chronic, intraoral burning sensation seen mainly in middle-aged and post-menopausal females, without identifiable oral lesions or abnormal laboratory findings, but often associated with psychogenic disorders such as depression. The latter can have a range of causes, including hormonal. ObjectiveSince there may be connections between BMS, psychogenic changes, hormonal changes and taste abnormalities , we have examined aspects of taste and thyroid function.. Patients and methodsWe selected 50 patients with BMS (study group) and 50 healthy subjects (control group) and analysed their ability to taste bitter, acid and spicy substances and analysed their thyroid function and Undertook thyroid echography. ResultsTaste sensation was normal in all controls. However, 30 of the patients with BMS reported ageusia for bitter taste and 2 had ageusia for acid. The use of pepper sauce ( Tabasco®) (spicy substance) produced a strong burning to the tongue in 28 patients of the BMS group but only in 10 controls. No control patients showed abnormality of thyroid function or echograpic abnormality.Five patients in the BMS group had biochemical evidence of hypothyroidism, 4 patients had raised levels of thyroid auto-antibodies and, of the 41 remaining BMS patients, most (34) had thyroid echographic changes indicative of nodularity. ConclusionsHypothyroidism may be responsible for a negative influence on taste and consequent increase in trigeminal sensorial sensation (tactile, thermal and painful sensation)

Recurrent herpes labialis: a pilot study of the efficacy of zinc therapy.

BACKGROUND: The objective of this study was to investigate the effect of zinc on recurrent herpes labialis. MATERIALS/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.

Burning mouth syndrome: the efficacy of lipoic acid on subgroups.

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.

Maternal MTHFR variant forms increase the risk in offspring of isolated nonsyndromic cleft lip with or without cleft palate.

The pathogenesis of cleft lip with or without cleft palate (CL/P) is complex; its onset could be due to the interaction of various genetic and environmental factors. Recently MTHFR functional polymorphisms were found to increase the risk of this common malformation; however, this finding is still debated. We investigated 110 sporadic CL/P patients, their parents and 289 unrelated controls for c.665C>T (commonly known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala) polymorphism in the MTHFR gene. Transmission disequilibrium test (TDT) showed no distortion in allele transmission. Nevertheless, association studies revealed significant differences in allele frequencies between mothers of CL/P patients and controls. This work supports the hypothesis that a lower MTHFR enzyme activity in pregnant women, mostly related to the c.665C>T variant form, is responsible for a higher risk of having CL/P affected offspring.

[Microbial environmental monitoring in the dental surgery room]. / Monitoraggio microbiologico ambientale nello studio odontoiatrico.

The aim of our study is to analyse the contamination level of air, water and hard surfaces before and after works activities in a dental clinic. Four different methods are detected for the sampling of the hard surfaces: contact plates, nitrocellulose membranes, swab and mask system, bioluminometer. Our results are overall satisfactory, but few critical situations related to some practice, were observed. In comparing the four methods of sampling the hard surfaces, the use of bioluminometer although referring to indirect indices, appears to give results comparable to those obtained with the contact plates and nitrocellulose membranes, which determine the microbiologic count. Contact plates and nitrocellulose membranes appear to be of more friendly use and show same results.

Orofacial cleft in Southern Italy.

AIM: Cleft lip and palate or orofacial cleft (OFC) is one of the most common congenital malformations. The average incidence is around 1 every 1 000 live births. Different types of cleft lip and palate exist: cleft lip (CL), cleft lip and alveolus (CLA), cleft lip, alveolus and palate (CLP), and cleft palate only (CPO). Genetic studies on human samples have demonstrated that OFC has a heterogeneous genetic background and environmental factors also contribute to disclose this malformation. Because of the complex aetiology of OFC, studies on different and homogeneous populations can be useful in detecting environmental and genetic factors involved in the onset of this disease. The aim of the present study is to evaluate the relation between gender, type of cleft and affected side in a group of patients in Southern Italy. METHODS: Six hundred and fifty patients were enrolled in this retrospective study. They were operated at the Dental Clinic of the Second University of Naples in the period 1980-2002. Gender, type of cleft and affected side were analysed by means of the "Test for comparing two proportions". RESULTS: Among the analysed variables it was statistically demonstrated that overall CLP is more frequent in males as well as bilateral CLP whereas overall CPO is more frequent in females as well as right microform of CL. CONCLUSION: The identification of gender related subtypes of cleft is in accordance with data reported in similar studies on different populations and confirms that OFC is an heterogeneous disease even in a homogeneous ethnic group.

Pemphigus vulgaris with oral involvement: evaluation of two different systemic corticosteroid therapeutic protocols.

BACKGROUND: Pemphigus vulgaris is a potentially life-threatening disease characterized by cutaneous and mucosal blistering. Systemic corticosteroids remain the mainstay of therapy, transforming an invariably fatal disease into one with a mortality that is now less than 10%. Nevertheless, oral lesions are often recalcitrant and corticosteroid therapy can provoke adverse effects. OBJECTIVE: To determine whether two different regimens of systemic corticosteroid therapy based on prednisone gave different benefits. METHOD: We examined two different regimens of systemic corticosteroid therapy based on prednisone in an open study. Ten patients (group A) were treated with systemic corticosteroids, in a therapeutic protocol made up of orally administered prednisone. Ten matched patients (group B) were treated with systemic corticosteroids alternating a pulse of intravenous betamethasone with orally administered prednisone. RESULTS AND CONCLUSIONS: The pulse protocol appeared to have some advantages both in a shorter time to resolution of symptoms and oral lesions, and in terms of minor adverse effects.

Idiopathic dysgeusia; an open trial of alpha lipoic acid (ALA) therapy.

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.