S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy.

Despite advances in our understanding of the mechanisms underlying the progression of chronic kidney disease and the development of fibrosis, only limited efficacious therapies exist. The calcium binding protein S100A8/A9 is a damage-associated molecular pattern which can activate Toll-like receptor (TLR)-4 or receptor for advanced glycation end-products (RAGE). Activation of these receptors is involved in the progression of renal fibrosis; however, the role of S100A8/A9 herein remains unknown. Therefore, we analysed S100A8/A9 expression in patients and mice with obstructive nephropathy and subjected wild-type and S100A9 knock-out mice lacking the heterodimer S100A8/A9 to unilateral ureteral obstruction (UUO). We found profound S100A8/A9 expression in granulocytes that infiltrated human and murine kidney, together with enhanced renal expression over time, following UUO. S100A9 KO mice were protected from UUO-induced renal fibrosis, independently of leucocyte infiltration and inflammation. Loss of S100A8/A9 protected tubular epithelial cells from UUO-induced apoptosis and critical epithelial-mesenchymal transition steps. In-vitro studies revealed S100A8/A9 as a novel mediator of epithelial cell injury through loss of cell polarity, cell cycle arrest and subsequent cell death. In conclusion, we demonstrate that S100A8/A9 mediates renal damage and fibrosis, presumably through loss of tubular epithelial cell contacts and irreversible damage. Suppression of S100A8/A9 could be a therapeutic strategy to halt renal fibrosis in patients with chronic kidney disease.

Trends of thyroid function and autoimmunity to 5 years after the introduction of mandatory iodization in Italy.

Background. Mandatory iodine fortification of salt was introduced in Italy in 2005. The purpose of our study is to estimate the trend of thyroid diseases in Italy before and after mandatory iodization in Italy. Methods. 7976 patients (6802 females; 1174 males) were examined between 2003 and 2010. We divided the patients into categories according to their clinical diagnosis. Later, we evaluated for each patient if there was the positivity for antibodies anti TPO. Finally, we collected data about TSH values of all patients who did not use therapy for thyroid disease at the time of the examination. To evaluate the differences percentages for categorical variables, χ2-Pearson test was used; to evaluate the percentage differences of TSH values we used the Kruskal-Wallis test. Values were considered statistically significant at p < 0.05. Results. We considered diagnosis of "toxic adenoma / goiter", diagnosis of "Graves' disease" and diagnosis of "hyperthyroidism / thyrotoxicosis" before and after the introduction of mandatory iodization in Italy, to demonstrate the possible presence of iodine-induced hyperthyroidism. Diagnosis of toxic adenoma / goiter before 2005 were 3.7%, while after 2005 they were reduced to 3.1%. Diagnosis of Graves' disease before 2005 were 2.4%, and they remained unchanged after 2005. Finally, diagnosis of hyperthyroidism / thyrotoxicosis decreased from 2.5% to 2.1%. Comparing these results, there were no significant differences (P = 0.261) between the percentages of diagnosis of hyperthyroidism before and after the introduction of mandatory iodization. We considered diagnosis of Hashimoto's thyroiditis before and after 2005 to demonstrate a link between the administration of iodine and thyroid autoimmunity. Prevalence of Hashimoto's thyroiditis between 2003 and 2005 was 37%; prevalence between 2006 and 2010 dropped to 34.7%. This small difference has a borderline statistical significance (P = 0.049). Stratifying TSH values from year to year, we found a small increase in TSH value, which, in any case, remains in the normal range. TSH values passed from 1.37 in 2003, to 1.61 in 2010. Although this increase is modest, it is statistically significant (P values < 0.001). Conclusion. In this study there isn't a connection between iodine fortification and iodine-induced hyperthyroidism, and between iodine fortification and Hashimoto's thyroiditis. This small increase of TSH values can not find a clear explanation yet. We considered several mechanisms to explain this phenomenon: alterations of Na/I symporter reduce intracellular levels of iodine, and cause a state of hypothyroidism; excessive levels of iodine can increase apoptosis of thyrocytes, as it is demonstrated by several studies; interference from external agents (endocrine disruptors).

A case of hypersensitivity to progesterone presenting as an eczematous eruption.

Hypersensitivity to progesterone is a rare condition, and it represents a hypersensitivity reaction to endogenous progesterone. Here we report a case of a woman who presented to our attention for evaluation of a rash for a few years on her posterior elbows, forearms, and right lateral lower extremity. We report this case because it describes a rare clinical entity, with an atypical clinical presentation pemphigoid-like, that is rarely described in literature.

Chemical research on red pigments after adverse reactions to tattoo.

Currently, the incidence of tattooing is on the rise compared to the past, especially among adolescents, and it leads to the urgency of monitoring the security status of tattooing centers, as well as to inform people about the risks of tattoo practice. In our clinical experience, 20% of tattooed patients presented adverse reactions, like allergic contact dermatitis, psoriasis with Koebner's phenomena and granulomatous reactions, with the latter most prevalent and most often related to red pigment. Adverse reactions to tattoo pigments, especially the red one, are well known and described in literature. Great attention has to be focused on the pigments used, especially for the presence of new substances, often not well known. For this reason, we decided to perform a study on 12 samples of red tattoo ink, obtained by patients affected by different cutaneous reactions in the site of tattoo, to analyze their chemical composition.

Chronic idiophatic urticaria and Helicobacter pylori: a specific pattern of gastritis and urticaria remission after Helicobacter pylori eradication.

Chronic urticaria (CU) is defined as the occurrence of spontaneous wheals for a duration of more than 6 weeks and is the most frequent skin disease, with prevalence ranging between 15 and 25%, and is a seriously disabling condition, with social isolation and mood changes causing a significant degree of dysfunction and quality of life impairment to many patients. The main clinical features of CU are the repeated occurrence of transient eruptions of pruritic wheals or patchy erythema on the skin that last less than 24 hours and disappear without sequelae. CU is often defined as chronic idiopathic urticaria (CIU) because the causes of CU remain unknown in the great majority (70-95%) of patients. Drugs, food, viruses, alimentary conservative substances or inhalant substances often seem to be involved in determining CIU skin flare. Despite a general agreement that bacteria infections and parasitic infestations can be involved in the pathogenesis of CIU, proven evidence of these relationships is lacking. The aim of the present study is to evaluate the prevalence of Helicobacter pylori (Hp) infection, and the extension and severity of gastritis in a group of CIU patients compared to controls and to evaluate the effectiveness of eradication of Hp on the CIU symptomatology, and the role of Hp infection in pathogenesis of CIU.

Psoriasiform dermatitis in a non-psoriatic patient treated with adalimumab.

Anti-TNF drugs may be associated with various adverse reactions including cutaneous ones. We describe the case of a 45-year-old woman affected by undifferentiated spondyloarthritis who presented a localized psoriasiformis dermatitis during treatment with adalimumab, without any medical history of psoriasis.

Effects of oral hyposensitization therapy with nickel on haemoglobin and haematocrit values in sensitized patients.

Nickel deficiency leads to reduced iron content in organs and to reduced hemoglobin levels and haematocrit counts. We carried out a clinical trial of oral hyposensitization therapy with low doses of nickel on a group of 20 patients affected by systemic allergy to this sensitizer element and with a chronic relapsing low hemoglobin level and haematocrit count. We obtained interesting results on maintaining these values in treated patients.

Laser removal of tattoos.

In Western countries the phenomenon of "tattooing" is expanding and tattoos are considered a new fashion among young people. In this paper we briefly trace the history of tattooing, the techniques used, the analysis of pigments used, and their possible adverse reactions. We also carried out a review of the international literature on the use of Q-switched laser in tattoo removal and its complications, and we describe our experience in the use of this technique.

CD63 cell expression detected by flow-cytometric determination of basophil activation in allergic patients.

Flow cytometry analysis of in vitro activated basophils (BATs) based on the detection of CD63 up-regulation on basophil membrane provides the physician and the clinical laboratory with a novel diagnostic approach, proposed as a promising alternative method for in vitro diagnosis of IgE and non-mediated reactions. We performed an optimized flow cytometric procedure to assess CD63 expression on activated basophils on twenty allergic patients, and compared the results with specific IgE determination (RAST) and skin testing (Prick test).

Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families.

Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder of skeletal muscle characterized by disturbance of intracellular calcium homeostasis in the sarcoplasmic reticulum. Mutations of the ryanodine receptor 1 (RYR1) gene account for most cases, with some studies claiming up to 86% of mutations in this locus. However, RYR1 gene is large and variants are common even in the normal population. We examined 54 families with MH susceptibility and 21 diagnosed with equivocal MH. Thirty-five were selected for an anesthetic reaction, whereas the remainder for hyperCKemia. In these, we studied all 106 exons of the RYR1 gene. When no mutation was found, we also screened: sodium channel voltage-gated, type IV alpha subunit (SCN4A), calcium channel voltage-dependent, L type, alpha 1S subunit (CACNA1S), and L-type voltage-gated calcium channel alpha 2/delta-subunit (CACNL2A). Twenty-nine different RYR1 mutations were discovered in 40 families. Three other MH genes were tested in negative cases. Fourteen RYR1 amino acid changes were novel, of which 12 were located outside the mutational 'hot spots'. In two families, the known mutation p.R3903Q was also observed in malignant hyperthermia-nonsusceptible (MHN) individuals. Unexpectedly, four changes were also found in the same family and two in another. Our study confirms that MH is genetically heterogeneous and that a consistent number of cases are not due to RYR1 mutations. The discordance between in vitro contracture test status and the presence of a proven causative RYR1 mutation suggests that the penetrance may vary due to as yet unknown factors.

Anetoderma: evidence of the relationship with autoimmune disease and a possible role of macrophages in the etiopathogenesis.

Anetoderma is a benign condition characterized by round or oval macular lesions with focal loss of dermal elastic tissue resulting in localized areas of flaccid or herniated saclike skin. Often, the anetoderma is associated with immuno-mediated pathogenetic mechanism. In this article, we describe the association between anetoderma and autoimmune diseases, by underlining the role and the action of macrophages as a possible etiopathogenesis.

Allergy to nickel: first results on patients administered with an oral hyposensitization therapy.

Nickel sulphate allergy is the most common contact allergy. In fact, nickel sulphate is an ubiquitous element, contained in various objects and food; it occurs in igneous rocks, as a free metal and together with iron, but it is also a component of living organism, mainly vegetables. We carried out a clinical trial of oral hyposensitization therapy with low doses of nickel in a group of 67 patients affected by systemic allergy to this sensitizer element. We obtained good results on consequent tolerance to nickel in treated patients.

A Case of Ketron-Goodman Disease.

Pagetoid reticulosis (PR) is a rare form of cutaneous T-cell lymphoma [Mod Pathol 2000;13:502-510]. Two variants of the disease are described: the localized type Woringer-Kolopp disease (WKD) and the disseminated type Ketron-Goodman disease (KGD). KGD may have disseminated lesions, high rate of recurrence and a guarded prognosis [Mod Pathol 2000;13:502-510]. In patients with KGD, therefore, long-term observation is necessary. Disappearance of cutaneous lesions does not mean resolution of the disease [J Am Acad Dermatol 2002;47:183-186]. Herein we report the case of an 84-year-old man with erythematous patches of the trunk and the upper and lower extremities in whom the diagnosis of KGD was made. We describe this case for the rarity of this pathology and for the good response to therapy (IFN).

Follow-up of patients tested for malignant hyperthermia susceptibility.

BACKGROUND AND OBJECTIVE: Malignant hyperthermia is an inherited disorder of skeletal muscle characterized by muscle contracture and hypermetabolic crisis following exposure to halogenated anaesthetics and depolarizing muscle relaxants. We planned this follow-up to get more information about the safety of non-triggering anaesthesia in susceptible patients; the safety of the use of trigger agents in non-susceptible patients and any minor sequelae following the biopsy. METHODS: A questionnaire was sent to 244 patients tested for susceptibility between 1998 and 2004 enquiring about sequelae from the biopsy, subsequent experience with anaesthesia and difficulties encountered because of the investigation. RESULTS: Replies were received from 129 patients. Thirty-four complained about sequelae from the biopsy: 10 reported headache and nausea; 16 experienced pain and a lack of strength in the biopsed leg and 8 found the scar less than satisfactory. Ten patients found it difficult to find a diagnostic centre. Eighteen reported problems and/or delay when they had needed a subsequent anaesthetic. Fourteen patients found the anaesthesiologist reluctant to anaesthetize them and four experienced a delay. Forty-three patients received anaesthesia since their biopsy. Complete medical records were available for 24 anaesthetic exposures in 23 patients. No documented perioperative complications occurred. Only three non-susceptible patients received one trigger agent. CONCLUSIONS: It is safe to use trigger-free anaesthesia in susceptible patients. The difficulties encountered by patients to be anaesthetized and the management of the majority of non-susceptible patients during general anaesthesia show the need of more accurate educational programmes and methods for promoting patient-centred care.

Asymptomatic cores and paracrystalline mitochondrial inclusions in CADASIL.

Three siblings with genetically assessed cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with core-like lesions and mitochondrial abnormalities in muscles are described. Involvement of the Ryanodine receptor 1 gene was excluded. In the current cases, the relation between molecular genetic lesion and muscle fiber abnormalities remains to be determined, but the Notch3 gene may influence mitochondrial metabolism.

Model of extreme hypoglycemia in dogs made ketotic with (R,S)-1,3-butanediol acetoacetate esters.

The rationale behind this study is that controlled starvation of poorly differentiated (anaplastic) fast-growing tumor cells, but not host cells, might be possible in vivo. The energy metabolism of anaplastic tumor cells, but not host cells, is largely dependent on carbohydrate metabolism at all times. Therefore depleting plasma of carbohydrate fuels could place these tumor cells at a significant metabolic disadvantage. Hence an animal model was developed in which all cells would be required to oxidize fatty acids, ketoacids, and/or 1,3-butanediol to satisfy their energy needs. To achieve this aim, one would need ketosis, severe hypoglycemia, and low lactatemia. Anesthetized normal dogs were infused with somatostatin and a mixture of (R,S)-1,3-butanediol monoacetoacetate and (R,S)-1,3-butanediol diacetoacetate; these latter compounds are nonionized precursors of ketoacids. They were infused at 90% of the dog's caloric requirement. After establishment of a moderate ketosis (2-3 mM) over < 100 min, a severe degree of hypoglycemia (close to 0.5 mM) without rebound and without hyperlactatemia was induced by infusing insulin and dichloroacetate. Tracer kinetic measurements showed 1) a 20% decrease in the rate of appearance of glucose, 2) 50 and 62% increases in glycerol and nonesterified fatty acid rates of appearance, reflecting stimulation of lipolysis, and 3) no change in the rate of glutamine appearance. We suggest that this model may prove useful for selectively starving those cancer cells that are unable to utilize fat-derived fuels while preserving nutrient supply to vital organs.