Pharmacogenomic update on multiple sclerosis: a focus on actual and new therapeutic strategies.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of central nervous system comprising several subtypes. Pharmacological treatment involves only few drugs. Among these, interferon beta (IFN-ß) and glatiramer acetate were the most used. Although evidence supports the efficacy of these agents in treating MS symptoms, actual studies allowed to introduce new innovative drugs in clinical practice. Applying pharmacogenetic approach to MS, IFN-ß and several other immune pathways were abundantly investigated. Numerous reports identified some promising therapy markers but only few markers have emerged as clinically useful. This may be partially due to differences in clinical and methodological criteria in the studies. Indeed, responder and non-responder definitions lack standardized clinical definition. The goal of this review is to treat advances in research on the pharmacogenetic markers of MS drugs and to highlight possible correlations between type of responses and genetic profile, with regard to clinical and methodological discrepancies in the studies.

Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management.

Toll-like receptors (TLR) are important innate immune proteins for the identification and clearance of invading pathogen. TLR signal through adaptor proteins, most commonly myeloid differentiation primary response gene 88 (MyD88). Inappropriate response of specific TLR has been implicated in certain autoimmune diseases, such as multiple sclerosis (MS). Activation of TLR2, TLR4, TLR7 and TLR9 plays a role in experimental allergic encephalomyelitis (EAE), a murine model of MS, while TLR3 activation protects from disease. Therefore, TLR-modulation could be an important adjuvant to current treatments. Here, we focus on TLR involved in EAE and MS pathogenesis highlighting specific components targeting TLR that might offer further therapeutic possibilities.

Peripheral expression of key regulatory kinases in Alzheimer's disease and Parkinson's disease.

Alteration of key regulatory kinases may cause aberrant protein phosphorylation and aggregation in Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we investigated expression and phosphorylation status of glycogen synthase kinase 3 (GSK-3), protein kinase B (Akt) and tau protein in peripheral blood lymphocytes of 20 AD, 25 PD patients and 20 healthy controls. GSK-3 was increased in AD and PD patients. In these latter, GSK-3 levels were positively correlated with daily L-Dopa intake. Phosphorylated Akt expression was augmented in both groups; total Akt levels were increased only in AD patients and were positively correlated with disease duration and severity. Total and phosphorylated tau were increased only in AD, with phospho-tau levels being positively correlated with levels of total tau, Akt, and disease duration. No correlations between protein levels and clinical variables were found in PD patients. Investigation of peripheral changes in the expression of specific kinases may, therefore, lead to the development of innovative biomarkers of neurodegeneration, particularly for AD.

[Use of mechanical staplers for the solution of proctological problems. Our experience with 122 patients]. / Uso della suturatrice meccanica nella risoluzione di problematiche proctologiche. Nostra esperienza relativa a 122 pazienti.

The Longo technique using a circular stapler has changed haemorrhoid therapy. Thanks to the advent of this technique for treating haemorrhoids without excision, we can now successfully eliminate the mechanism responsible for their pathogenesis. The aims of circumferential stapled anoplasty are to correct the anodermal prolapse and restore the haemorrhoidal cushions to their anatomical position. Furthermore, with a few variants the technique can be utilised for other proctological problems, such as obstructed defecation in rectocele and incomplete internal prolapse (or rectal intussusception). The authors report on their experience in a consecutive series of 122 cases undergoing circular stapled anoplasty for haemorrhoids, associated in 10 cases with rectocele or rectal intussuscep-tion, analysing early and late complications after an accurate follow-up. The procedure can be performed with local or spinal anaesthesia. The operation lasted on average 19 minutes. There were few complications: early bleeding (4.9%), late bleeding (0.8%), mild stricture (2.5%) and thrombosis of external piles (8.2%). This new surgical technique is effective and rapid, causes only minimal postoperative pain and could be proposed as an alternative to traditional surgery also in the day surgery setting.

[Carcinoid tumor of the appendix. A not especially rare entity]. / Il tumore carcinoide dell'appendice. Un'entità non proprio rara.

Carcinoid tumors arise from neuroendocrine system and one of their preferred sites is the appendix. Most of appendiceal carcinoids almost always are clinically silent and are incidentally found at histological examination. For this reason, histological examination of the appendix is recommended in every case of the appendicectomy. Prognostic factors are: tumor stage, histologic pattern and differentiation. The authors present 6 cases of appendiceal carcinoid tumor, clinically silent and found at histologic examination (3 cases of appendicectomy for acute appendicitis, 3 cases of appendicectomy associated with abdominal surgical interventions for other pathology) and compare their experience with the most recent literature on this subject. The conclusion is drawn that the size of this tumor is the main factor that surgeons must consider for the choice of surgical treatment. Incidental, clinical silent, small (less than 2 cm in size) appendiceal carcinoid tumors can be treated by appendicectomy, and they do not need follow-up. Greater (more than 2 cm in size) appendiceal carcinoid tumors, in young patients must be treated with a right hemicolectomy and they need follow-up (periodically radiological, ultrasonographic and endoscopic examinations, tumor markers) because there is the possibility of recurrence or metastases.

Anal fistulas with recess above the anal levators.

The Authors present their experience with anal fistulas with recess above the levators. They mainly analyze the diagnostic, clinical, instrumental and therapeutic problems which this type of anal fistula may present.

Local recurrence of rectal cancer: anterior resection versus abdomino-perineal resection.

Local recurrences of rectal cancer after surgical therapy are a mainly diagnostic and therapeutic problem. The Authors report their experience in local recurrences of rectal cancer. They consider anterior resection versus abdomino-perineal resection, the type of anastomosis and the stage of primary disease. Follow-up is discussed emphasizing early diagnosis for local recurrences.

Perforations of the extraperitoneal rectum during barium enema.

Rectal injuries during barium enema are uncommon but not unusual complications. Radiologists and surgeons must be able to recognize them, as early diagnosis is essential for effective treatment. The Authors discuss various aspects of problems arising from rectal perforation, and report their experience on seven cases.

[Preoperative ultrasonic diagnosis of metastasis to the cervical lymph nodes from otorhinolaryngeal neoplasms]. / Valutazione ecotomografica preoperatoria delle metastasi ai linfonodi cervicali da neoplasie di pertinenza otorinolaringoiatrica.

The results of a study on 30 patients with ear, nose and throat cancers are discussed; a comparison of clinical, ultrasound and histological findings for the preoperatory evaluation of the cervical lymph nodes has been carried out. Ultrasound technique is an excellent method of investigation for the staging "N" of such neoplasms; its contribution is very important for the following therapeutic program.

Effect of monovalent cation ionophores on lymphocyte cellular metabolism.

The effect of valinomycin, nigericin and gramicidin on the cellular O2 consumption and on ATP content has been investigation. It has been found that while valinomycin and nigericin interfere with mitochondrial functions, gramicidin D does not show any appreciable effect. These results are explained in terms of the differing abilities of ionophores to redistribute among intracellular membranes.

[True aneurysms late complications of revascularization operations in the femoropopliteal tract]. / Aneurismi veri: complicanza tardiva degli interventi di rivascolarizzazione nel tratto femoropopliteo.

The Authors report three cases of true aneurysms following arterial reconstructive surgery in the femoropopliteal tract. One time it was an autologous venous graft and two times of an endarterectomized artery. At surgery the suture line was intact; so the differential diagnosis with false aneurysms was made. This complication is very rare (less than 1%). That natural history and the treatment are reviewed.