Biological therapy downregulates the heterodimer S100A8/A9 (calprotectin) expression in psoriatic patients.

The pathophysiology of psoriasis is very complex and involves an interplay between immune cells and keratinocytes. The keratinocyte production of calprotectin (S100A8/A9), induced by the inflammatory psoriatic milieu, may be involved in initiating immune cell invasion, as well as in propagating inflammation. However, the exact role of calprotectin in psoriasis remains unclear. Therapeutic approaches utilizing adalimumab, etanercept and ustekinumab are widely used in psoriatic treatment, but their anti-inflammatory mechanisms are not fully understood. The aim of this study was to investigate, by immunohistochemical analysis, the expression of the heterocomplex S100A8/A9 in lesional skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. Our results showed that S100A8/A9, absent or present at very low level in skin biopsies from healthy subjects, is dramatically upregulated in each epidermal layer from psoriatic patients. Interestingly, calprotectin was mainly localized in keratinocyte nuclei from psoriatic patients, suggesting a role of S100A8/A9 in keratinocyte nuclear function. Furthermore, we have shown that the biological treatment induced a drastic reduction of S100A8/A9 expression in skin biopsies from treated patients, correlating with PASI reduction. Our results suggest that calprotectin may play a crucial role as a significant marker of inflammation in psoriasis, and that its reduction of expression may be considered a favourable prognostic marker in psoriasis.

Laparoscopic treatment of mucinous adenocarcinoma of jejunum associated with celiac disease. Case report.

Mucinous adenocarcinoma of the small bowel is very rare, and only few cases have been described in the literature. Association of this tumor with celiac disease has never been published. The authors report a unique case of jejunal mucinous adenocarcinoma in which a concomitant celiac disease has been histologically recognized. The difficult diagnosis, the role of laparoscopic surgery and the relationship between small bowel tumors and celiac disease are discussed. A 49-year-old man presented with recurrent melena, nausea, vomiting and anemia. A stenosis of the jejunum was documented by means of CT scan and video capsule enteroscopy. A laparoscopy was scheduled. A tumor, found in the first jejunal loop, was removed by laparoscopic surgery. Histopathology revealed a rare mucinous adenocarcinoma associated with epithelial changes secondary to celiac disease. Although small bowel tumors are rare entity, in patients with celiac disease complaining of symptoms related to altered intestinal transit or occult bleeding, an appropriate work-up should be planned for diagnosis. Mucinous type intestinal adenocarcinoma, even if never published before, could be observed. Laparoscopic surgery is often essential for the diagnosis and treatment.

BRAF(V600E) mutation and the biology of papillary thyroid cancer.

BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.

Central nervous system adverse effects of new antiepileptic drugs. A meta-analysis of placebo-controlled studies.

OBJECTIVE: Systematic review and meta-analysis of the most frequent treatment-emergent central nervous system adverse events (CNS AEs) of new antiepileptic drugs (AEDs) from double-blind, add-on, placebo-controlled studies conducted in adult epileptic patients and identification of dose-adverse effect relationships. METHODS: Trial reports found by searching Medline and journals. Outcome was the number of patients complaining of treatment-emergent CNS AEs. Sixteen predefined CNS AEs were considered. Risk differences (RDs) were calculated for individual studies and summary statistics estimated using the random effect model. Predefined CNS AEs in patients treated with active drug (broken down into dose levels) or placebo were extracted and the RDs (95% CI) for CNS AEs were calculated. RESULTS: Thirty-six suitable studies identified. No meta-analysis was possible for oxcarbazepine and tiagabine (only one study each included). For these drugs RDs were calculated from single studies. Gabapentin was significantly associated with somnolence 0.13 (0.06-0.2) and dizziness 0.11 (0.07-0.15); lamotrigine with dizziness 0.11 (0.05-0.17), ataxia 0.12 (0.01-0.24) and diplopia 0.12 (0.00-0.24); levetiracetam with somnolence 0.06 (0.01-0.11); pregabalin with somnolence 0.11 (0.07-0.15), dizziness 0.22 (0.16-0.28), ataxia 0.10 (0.06-0.14) and fatigue 0.04 (0.01-0.08); topiramate with somnolence 0.09 (0.04-0.14), dizziness 0.06 (0.00-0.11), cognitive impairment 0.14 (0.06-0.22) and fatigue 0.06 (0.01-0.12); zonisamide with somnolence 0.06 (0.02-0.11) and dizziness 0.06 (0.00-0.12). The dose-response relationship was analysed only for those CNS AEs significantly associated with the AED. CONCLUSIONS: No comparison between drugs was possible. One CNS AE was significantly more frequent for levetiracetam, two for zonisamide and gabapentin, three for lamotrigine and four for pregabalin and topiramate.

[Buschke Scleredema, case report]. / Scleredema di Buschke, contributo casistico.

Buschke Scleredema is a rare connective tissue disorder of unknown aetiology, characterized by thickening of the dermis whose characteristics may mainly to mime systemic sclerosis, eosinophilic fasciitis and cutaneous amyloidosis. Scleredema may be associated with a history of an antecedent febrile illness, diabetes mellitus, or blood dyscrasia. Scleredema can be classified into three clinical groups; each has a different history, course, and prognosis. Each one of these share reduction in chest articular movements and limitation of limbs movements. The skin histology is characterised by thickened dermis and increased spaces between large collagen bundles due to increased deposition of mucopolysaccharide in the dermis. Differential diagnosis can be made considering the typical clinical features and the histologic peculiarity. No therapy has been found effective. The authors describe a case of Buschke Scleredema successfully treated by steroids and colchicine. Clinical evaluation of skin induration and thickness as well as ultrasonography were performed at baseline and after treatment.

Negative/low expression of the Met/hepatocyte growth factor receptor identifies papillary thyroid carcinomas with high risk of distant metastases.

To investigate the clinical impact of Met/hepatocyte growth factor receptor (HGF-R) expression in thyroid cancer we studied 163 thyroid carcinomas (129 papillary, 21 follicular, and 13 anaplastic) from patients followed-up for 25-147 months postthyroidectomy. Forty-nine thyroid adenomas were also studied. Met/HGF-R expression was evaluated by semiquantitative immunohistochemistry, measuring both the proportion (scale of 0-5) and the intensity (scale, 0-5) of stained cells and calculating a total score (scale of 0-10). Met/HGF-R was absent in the normal thyroid tissue, absent or focally expressed in follicular and anaplastic tumors, and expressed at various levels in most papillary carcinomas, including microcarcinomas. Papillary carcinomas were thus categorized as having negative/low Met/HGF-R (n = 50; total score, < or = 5) or high Met/HGF-R expression (n = 70; total score, > 5). High Met/HGF-R was inversely associated with vascular invasion (P = 0.0308), but not with other prognostic factors. Negative/low Met/HGF-R expression was the most effective predictor by multivariate Cox analysis of distant metastases (hazard ratio = 9.71; P = 0.0036), higher than extrathyroid invasion (hazard ratio = 4.25; P = 0.0181), age (< or = 45 vs. > 45 yr; hazard ratio = 3.99; P = 0.0099), and vascular invasion (hazard ratio = 3.19; P = 0.0358). These findings suggest a role for Met/HGF-R in papillary thyroid cancer and its clinical use to select patients with a high risk of distant metastases.

In situ evidence of neoplastic cell phagocytosis by macrophages in papillary thyroid cancer.

We evaluated the occurrence, tissue distribution, and prognostic value of tumor-associated macrophages in 121 papillary thyroid carcinomas using immunohistochemical staining with anti-CD68 antibody in archival paraffin-embedded sections. Lymphocytic infiltration and dendritic cell presence were also evaluated. Three groups were identified according to the presence and characteristics of macrophages: 1) tumors without evidence of infiltrating macrophages: (n = 35); 2) tumors with infiltrating macrophages but no evidence of neoplastic cells phagocytosis (n = 68); and 3) tumors with infiltrating macrophages and in situ evidence of active neoplastic cell phagocytosis (n = 18). Neoplastic cell phagocytosis by macrophages was positively correlated with both lymphocytic infiltration and dendritic cells (P = 0.0000), whereas it was negatively correlated with vascular invasion (P = 0.0032). Distant metastases developed in none of the 18 tumors with neoplastic cell phagocytosis, but occurred in 15 of 103 of the remaining tumors (P = 0.0647) and were significantly and negatively associated with lymphocytic infiltration or dendritic cells. The present study indicates, therefore, that immune reaction, involving neoplastic cell phagocytosis by macrophages and lymphocytic infiltration, plays a role in the development of distant metastases in patients with papillary thyroid cancer.

Smooth-pursuit eye movement and saccadic intrusions in obsessive-compulsive disorder.

Although several reports agree that smooth-pursuit eye movement (SPEM) is abnormal in some obsessive-compulsive disordered (OCD) patients, differences between treatments and lack of accuracy in control selection make the results controversial. Although reduced gain seems the most accepted abnormality, the characteristics of saccadic disruption of smooth pursuit are as yet unspecified. SPEMs in 21 OCD patients (DSM-III-R) and 21 healthy subjects recruited from the community were studied through a multiple target velocity task . The two groups were individually matched on age, gender, and level of education. None of the subjects had a history of substance dependence apart from the smokers who refrained from smoking in the 2 hours prior to the test. A significantly lower SPEM gain and increased number and frequency of anticipatory saccades (ASs) was found in OCD patients as compared with control subjects. No relationship emerged between eye movement abnormalities and clinical variables explored.

Smooth-pursuit eye movements: alterations in Alzheimer's disease.

Smooth-pursuit eye movements induced by targets moving at constant velocities (from 5 to 100 deg/sec) were recorded from 13 patients with Alzheimer's disease (AD) and from 11 healthy subjects. Four variables were evaluated to quantify the patients' response to the eye movement tests: (1) average peak velocity of smooth-pursuit; (2) percent target matching index after saccade removal (percent ratio between the area of the velocity curve of smooth-pursuit eye movement after saccade removal and the area of target velocity) which is related to the eye performance for each value of target velocity; (3) total amplitude of anticipatory saccades; (4) total number of anticipatory saccades. Compared to the controls, AD patients were found to have significantly lower values of average peak velocity of smooth pursuit and of percent target matching index and a significantly increased number and amplitude of anticipatory saccades. A discriminant stepwise analysis indicated that 5 oculographic variables were significantly associated with the patient's clinical condition (healthy volunteer or AD patient). These statistics yielded an equation for predicting the patient's status according to which the percentage of cases classified correctly was 82.6% in the overall group (n = 23). The predictive performance was similar between the healthy volunteers subgroup (81.8%, n = 11) and the AD subgroup (83.3%, n = 12). The discriminant score was significantly correlated with the score resulting from the MiniMental test (r = 0.67). A significant correlation was also found between the MiniMental score and the number of anticipatory saccades (r = -0.61). No significant correlation was present between the gain of smooth pursuit and the patients' cognitive decline.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral nervous system involvement in systemic sclerosis: the median nerve as target structure.

OBJECTIVES: To investigate the frequency and the main electrophysiological characteristics of the canalicolar passage nerve involvement in patients with systemic sclerosis (SSc). METHODS: Thirty-two SSc patients were enrolled in the study, classified according to the type (diffuse or limited) and the duration (> / < 5 years) of the disease. Sensory-motor nerve conduction studies (NCS) of the upper and lower limbs, in particular at the critical canalicolar points, were conducted by recording the Compound Muscular Action Potential (CMAP) and the Sensory Action Potential (sNAP). The following parameters were evaluated: Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity; distal and proximal latency of the CMAP and the onset and peak latency of the sNAP; peak-peak amplitude and negative-peak area of the CMAP and sNAP; and the Terminal Latency Index (TLI) (Terminal Distance/MCNV x Distal latency). RESULTS: Four (12.5%) patients had a distal neuropathy of the upper limbs (one with monolateral and two with bilateral involvement of the median nerve and one bilateral involvement of the ulnar nerve). Fourteen (43.7%) patients showed a decrement of the median nerve TLI and seven (21.8%) of either the median or the ulnar nerve (Table I). Motor and sensitive conduction velocity and latency studies did not show a statistical difference between SSc patients and controls. The amplitude and area of the CMAP (distal and proximal), sNAP and of the median nerve TLI were significantly decreased in patients with respect to controls. CONCLUSION: Distal mononeuropathy of the median nerve was the most frequent result in our patients. The involvement of the peripheral nervous system seems to be strictly topographical, following the modifications of the tissues and vascular tone (Raynaud's phenomenon) at the upper acral level. The neurophysiological alterations detected in our study at the wrist level may not be linked merely to a compressive event but also to microvascular involvement. Nerve involvement closely connected with the pathogenesis and distribution of SSc should be considered when peripheral nervous system involvement is the initial symptom of the disease.

Changes in bit-mapped contingent negative variation (CNV) activity due to initial normal involutional processes of the human brain.

Bit-color mapped multicomponent CNV complexes and RTs to S2 evoked with a simple warned CNV/RT paradigm were recorded and measured in 20 selected right-handed very healthy volunteers (10 young adults and 10 presenile subjects, mean age 28.3 and 59.6, respectively). EEG and CNV components (post S1, N1, P2, P3; early CNV; N1200; late CNV; CNV resolution) were recorded from Fz, C3, Cz, C4, P3, Pz, and P4 referenced to linked mastoid electrodes. EOG, RT and stimuli were also recorded. The presenile group differed significantly from the younger group in the auditory post-S1 N1 and early (O-wave) and late (P-wave) CNV complex components. A progressive amplitude reduction limited to frontal leads between O-wave and P-wave, the lowest point being reached in the P-wave, was characteristic in the presenile group. Moreover, presenile subjects showed relatively flat CNV waveshapes of low amplitude and, on the whole, performed a little less well than young ones. This finding suggests that the statistically significant changes in auditory post-S1 N1 and CNV activity recorded in our presenile subjects, without any appreciable deficits in behavioral or mental performance, could be alerting signs of early brain involutional processes related to minimal and subclinical decline in orienting, attentiveness and response preparation capabilities. If such is the case, and it could be confirmed in a larger sample of very healthy subjects, these age-related changes in the presenium might prove to be of considerable practical importance for clinical research.

Topographic CNV activity mapping, presenile mild primary cognitive decline and Alzheimer-type dementia.

The CNV complex evoked with a standard paradigm (S1-2 sec-S2-motor response) and reaction time (RT) to the imperative signal (S2) were recorded and measured in 12 patients with initial presenile idiopathic cognitive decline (PICD), 12 with presenile Alzheimer-type dementia (PAD) and 10 healthy age-matched controls. Significant group differences were obtained for measures of some CNV components, particularly of the late pre-S2 CNV. No significant CNV activity, very prolonged RTs and sometimes characteristic post-imperative negative variations (PINV) were observed in the majority of patients with PAD. These results suggest that similar CNV complex and RT changes to those observed in our patients may constitute a valuable clue in the study of pathophysiological brain functioning in the early stages of presenile idiopathic mental deterioration.

[A rare case of drug-induced hepatitis]. / Un raro caso di epatite acuta da farmaci.

This paper describes a case of drug-induced hepatitis that onset in a patient who was hospitalised in our department after administration of calcium heparin. The rarity of the case was shown not only by the very short time elapsed between cause (drug administration) and effect (bio-humoral changes detected), but also by the histology results of the liver biopsy. This latter confirmed that mechanisms of idiosyncrasy, which may cause liver cell necrosis, can occur after administration of any drug.

Comparison of two nonlinear models for fitting saccadic eye movement data.

Saccadic eye movements are rapid shifts in the direction of gaze which are being studied increasingly for clinical and pharmacological purposes. The evaluation of the relationship between amplitude and peak velocity of these ocular movements (the so-called 'main sequence' plot) is particularly useful for characterising the saccade pattern in individual patients. This relationship is nonlinear and the peak velocity tends to achieve an asymptote for high values of amplitude. Since a standard parametrisation of the main sequence based on specific mathematical models has not yet been achieved, in the present study two simple models based on the Michaelis-Menten equation and on an exponential equation are proposed together with their implementation on a microcomputer. Two microcomputer programs are described which estimate the model parameters from the experimental data of the patients using a weighted nonlinear least-squares fit. The two procedures have been tested and compared in a series of 23 healthy volunteers. The following results (mean +/- S.D.) were obtained: Michaelis-Menten model. Km (degrees) = 31.2 +/- 7.7, Vmax (degrees/s) = 841.0 +/- 165.5, root-mean-squared error(%) = 6.0 +/- 1.6; exponential model. K (degrees) = 23.4 +/- 4.6, Vmax (degrees/s) = 578.0 +/- 97.4, root-mean-squared error(%) = 5.4 +/- 1.6. The two techniques of parametrisation provided similar indices of intra-individual variability in 4 healthy volunteers. In conclusion, our methods for saccade parametrisation can be regarded as simple but efficient tools for facilitating research on these ocular movements.

[Angiomyolipoma of the kidney]. / L'angiomiolipoma del rene.

The renal angiomyolipoma is a rare, benign, no epithelial neoplasm. It is frequently associated with tuberous sclerosis, above all in young patients. It may be under an asymptomatic form, especially if it deals of a small volume neoplasm, and sometimes it becomes evident only when it occurs an haemorrhagic complication. When we have a sure diagnosis and a small tumor, the treatment is preservative; on the contrary it is surgical either for big symptomatic neoplasms or haemorrhagic complications. The authors report a clinical case of renal angiomyolipoma in a pregnant patient, who had an haemorrhagic complication and was treated with nephrectomy.

Presacral myelolipoma. A case report.

Presacral myelolipoma is a rare benign tumour composed of fat and haemopoietic tissue. Ultrasound, computed tomography and magnetic resonance imaging are of help to achieve the diagnosis, but pathologic confirmation is mandatory. The Authors report an asymptomatic case whose diagnosis has been achieved by means of CT scan-guided percutaneous needle biopsy. Unnecessary surgical treatment was avoided in this case. Clinical approach and role of surgery are discussed.

[Heterotopy of gastric glands in the submucosa of the stomach]. / L'eterotopia di ghiandole gastriche nella sottomucosa dello stomaco.

Heterotopic gastric glands in the submucosa of the stomach is underestimated condition. It is still controversial whether the lesion is caused by inflammation or maldevelopment. Pathologists must recognized this entity and distinguish it from adenocarcinoma in biopsies. The case of a 37 year old man, unusual as to the appearance of local growth, is reported.

[Pneumatosis cystoides intestinalis]. / La pneumatosi cistica intestinale.

Pneumatosis Cystoides Intestinalis. Pneumatosis Cystoides Intestinalis is usually associated with intrinsic disease of the bowel. A case of the ileum associated with duodenal ulcer and a case of the large bowel associated with diverticular disease are reported. It was an unexpected finding in both patients. The histiocytic origin of the cells which line the gas cysts and the pathogenesis are discussed.

Eye movements and orienting of attention in patients with visual neglect.

The aim of the present study was to assess the relationship between overt and covert orienting of attention in visual neglect patients with parietal and fronto-parietal lesions. Two stimuli were presented at eccentricities of 8° or 20° to the left (LVF) or right (RVF) visual fields and the patient was required to maintain fixation on the central mark and to respond only manually upon the appearance of the stimulus. Neglect patients with fronto-parietal lesion showed a lack of oculomotor control and the presence of leftward eye movements without corresponding attentional shifts. Neglect patients with parietal lesions did not show this phenomenon. They rarely responded ocularly and manually to LVF stimuli, whereas they were unable to inhibit an automatic ocular orienting reaction towards RVF stimuli. When a RVF stimuli triggered both ocular and attentional shifts, the pattern of responses revealed a retinal eccentricity effect. Patients were more accurate to respond to stimuli located at 8° than 20°. In contrast, when a RVF stimuli triggered only attentional shifts, the results showed the attentional gradient effect (Iiidavas, 1990). Patients were more accu- rate to respond to stimuli located at 20° than 8°. Therefore, the results of the present study seem to suggest a functional dissociation of the mechanisms subserving attentional and gaze orienting and a differential role played by the frontal and parietal lobes in overt visual orienting.