Combined evaluation of prolactin-induced peptide (PIP) and extracellular signal-regulated kinase (ERK) as new sperm biomarkers of FSH treatment efficacy in normogonadotropic idiopathic infertile men.

PURPOSE: Nearly, 40% of the causes of male infertility remain idiopathic. The only suggested treatment in idiopathic oligo- and/or asthenozoospermia in normogonadotropic patients is the FSH. In the current clinical practice, efficacy is exclusively assessable through semen analysis after 3 months of treatment. No molecular markers of treatment efficacy are appliable in clinical practice. The aim of the present work is to evaluate the combination of extracellular signal regulated kinase (ERK) 1 and 2 and prolactin inducible peptide (PIP) as potential markers of idiopathic infertility and FSH treatment efficacy. METHODS: Western blot and confocal microscopy were performed to analyze the modulation of PIP and ERK1/2 in idiopathic infertile patients (IIP) sperm cells. Taking advantage of mass spectrometry analysis, we identified these proteins unequivocally in sperm cells. RESULTS:  We demonstrated a significant decrease of both PIP protein and of ERK1/2 levels in spermatozoa obtained from IIP in comparison to healthy fertile patients (HFP). Conversely, we reported a significant increase of these markers comparing infertile patients before and after 3 months of FSH treatment. Importantly, this correlated with an increase in total number of sperm and sperm motility after FSH treatment. Finally, we identified of PIP and ERK2 proteins in sperm samples by proteomic analysis. CONCLUSIONS: The combined evaluation of ERK1/2 and PIP proteins might represent a useful molecular marker to tailor FSH treatment in the management of male normogonadotropic idiopathic infertility.

Families in quarantine for COVID-19 in Italy. Resilience as a buffer of parental distress and problematic children's emotions and behaviors.

The pandemic of Covid-19 has had a high impact on people's lives and especially on families. In Italy, in 2020, the several forced closures led families to live indoors to manage anxiety and distress. It was considered appropriate to investigate which protective factors, like parental resilience, can mitigate the negative impact of pandemic-related distress on family life. We have conducted two online surveys during different national lockdowns for Covid-19. The first survey was conducted immediately after the disruption of the virus and the second one after nine months. We measured parental resilience and distress, anxiety, problematic behaviors, and somatization of their children (as assessed by the parents). The aim was to investigate the protective role of parental resilience in mitigating parental distress and in turn problematic emotional states and behavior of their children. Mediation analyses confirmed the hypothesis that parental resilience lowers parental distress and consequently the anxiety and behavioral disorders of their children in both acute distress (first study) and chronic distress (second study) situations. Such results suggest that the improvement of parents' resilience can buffer the negative impact of pandemic-related parental distress and children's behavioral problems on both occasions. The need for focused interventions and treatments aimed to reinforce parental resilience is discussed. Targeted prevention and support strategies are needed now, and early in case of future health crises.

Salmonella Paratyphi A Outer Membrane Vesicles Displaying Vi Polysaccharide as a Multivalent Vaccine against Enteric Fever.

Typhoid and paratyphoid fevers have a high incidence worldwide and coexist in many geographical areas, especially in low-middle-income countries (LMIC) in South and Southeast Asia. There is extensive consensus on the urgent need for better and affordable vaccines against systemic Salmonella infections. Generalized modules for membrane antigens (GMMA), outer membrane exosomes shed by Salmonella bacteria genetically manipulated to increase blebbing, resemble the bacterial surface where protective antigens are displayed in their native environment. Here, we engineered S Paratyphi A using the pDC5-viaB plasmid to generate GMMA displaying the heterologous S Typhi Vi antigen together with the homologous O:2 O antigen. The presence of both Vi and O:2 was confirmed by flow cytometry on bacterial cells, and their amount was quantified on the resulting vesicles through a panel of analytical methods. When tested in mice, such GMMA induced a strong antibody response against both Vi and O:2, and these antibodies were functional in a serum bactericidal assay. Our approach yielded a bivalent vaccine candidate able to induce immune responses against different Salmonella serovars, which could benefit LMIC residents and travelers.

Dietary intake of advanced glycation end products (AGEs) and changes in body weight in European adults.

PURPOSE: Advanced glycation end products (AGEs) can be formed in foods by the reaction of reducing sugars with proteins, and have been shown to induce insulin resistance and obesity in experimental studies. We examined the association between dietary AGEs intake and changes in body weight in adults over an average of 5 years of follow-up. METHODS: A total of 255,170 participants aged 25-70 years were recruited in ten European countries (1992-2000) in the PANACEA study (Physical Activity, Nutrition, Alcohol, Cessation of smoking, Eating out of home in relation to Anthropometry), a sub-cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition). Body weight was measured at recruitment and self-reported between 2 and 11 years later depending on the study center. A reference database for AGEs was used containing UPLC-MS/MS-measured Nε-(carboxymethyl)-lysine (CML), Nε-(1-carboxyethyl)-lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) in 200 common European foods. This reference database was matched to foods and decomposed recipes obtained from country-specific validated dietary questionnaires in EPIC and intake levels of CEL, CML, and MG-H1 were estimated. Associations between dietary AGEs intake and body weight change were estimated separately for each of the three AGEs using multilevel mixed linear regression models with center as random effect and dietary AGEs intake and relevant confounders as fixed effects. RESULTS: A one-SD increment in CEL intake was associated with 0.111 kg (95% CI 0.087-0.135) additional weight gain over 5 years. The corresponding additional weight gain for CML and MG-H1 was 0.065 kg (0.041-0.089) and 0.034 kg (0.012, 0.057), respectively. The top six food groups contributing to AGEs intake, with varying proportions across the AGEs, were cereals/cereal products, meat/processed meat, cakes/biscuits, dairy, sugar and confectionary, and fish/shellfish. CONCLUSION: In this study of European adults, higher intakes of AGEs were associated with marginally greater weight gain over an average of 5 years of follow-up.

Determinants of 20-year non-progression to Type 2 diabetes in women at very high risk: the E3N cohort study.

AIMS: To identify the most important determinants associated with not developing Type 2 diabetes in women considered to be at very high risk. METHODS: Between 1995 and 2014, we followed 402 women from the E3N cohort study who were considered to be at very high risk of Type 2 diabetes based on the D.E.S.I.R. score. We then computed a classification and regression tree model to identify, among a large set of risk factors, the top risk factors associated with not having Type 2 diabetes at the end of the follow-up. RESULTS: During follow-up, 117 women (29%) were diagnosed with Type 2 diabetes, while 285 (71%) were still free of the disease in 2014. A low Western dietary pattern score was the top characteristic associated with not developing Type 2 diabetes, as only 20% of the women at very high risk in the E3N study with that characteristic developed Type 2 diabetes (compared with 29% overall). In women with a moderate or high Western dietary pattern score, the most important characteristic associated with not developing Type 2 diabetes was a high total dietary antioxidant capacity, as only 26% of these women ultimately developed Type 2 diabetes. CONCLUSIONS: We showed that the top characteristic associated with not developing Type 2 diabetes, despite being at very high risk, was a healthy diet, characterized by limiting Western dietary habits, but with a high intake of antioxidant-rich foods. This underscores the importance of diet in the prevention of Type 2 diabetes in people at high risk.

Effect of nutrient deprivation on the expression and the epigenetic signature of sirtuin genes.

BACKGROUND AND AIM: Over the last decades advances in understanding the molecular bases of the close relationship between nutrition, metabolism, and diseases have been impressive. However, there are always novel frontiers coming up and epigenetics is one of these. Sirtuins, are pivotal factors in the control of metabolic pathways according to nutrient availability. In the present study we evaluated the effect of nutrient deprivation on expression, DNA methylation and chromatin status of the sirtuin genes. METHODS AND RESULTS: We performed these studies in mouse hepatoma cells, that were grown in standard medium, or in media containing low glucose concentration, or no glucose, or no amino acids. We applied quantitative real-time PCR to cDNA, methylation-enriched DNA and nuclease-treated DNA in order to evaluate gene expression, DNA methylation, and chromatin condensation, respectively. This study shows that the expression of sirtuin genes varies following nutrient deprivation. Moreover, we observed that changes of DNA methylation and chromatin condensation occur at the transcription start site of sirtuin genes following nutrient deprivation. CONCLUSIONS: Epigenetic mechanisms may have a role in the sirtuin response to nutrient deprivations in cultured hepatoma cells. Replicating these results in vivo to achieve a comprehensive understanding of the epigenetic control of sirtuin expression following nutrient deprivations might open up novel therapeutic possibilities to cure metabolic diseases and promote human health.

Ventriculoperitoneal shunt malfunction: analysis of abdominal causes.

BACKGROUND: Ventriculoperitoneal (VP) shunt is the most common neurosurgical procedure to treat obstructive and communicating hydrocephalus in children and adults but failure are frequent. The knowledge of risk factors related to abdominal shunt failure is useful to avoid complications. PATIENTS AND METHODS: We analyze retrospectively 86 adults patients affected by obstructive and communicating hydrocephalus operated for VP shunt at our Institution. Statistical analysis was performed in order to correlate shunt malfunctioning with type of abdominal approach (trocar vs mini-laparotomy), perioperative infective status, sex, bowel distention and length of surgical time. RESULTS: Factors statistically significant for surgical shunt revision were the use of trocar (univariate analisys p=0,029 and multivariate p= 0,035) and high infective risk (univariate analisys p=0,028 and multivariate p= 0,038). No statistical significant association was observed between shunt revision and sex, bowel distension and operative length time. CONCLUSIONS: To avoid postoperative shunt malfunctions especially in peritoneum the mini-laparotomy is the approach of choice. Surgery must be performed when infective status is healed.

Spontaneous chronic subdural hematoma in young adult: the role of missing coagulation facto.

AIM: Chronic subdural hematoma (CSDH) is typically in elderly and rarely in young people. To prevent complications and re-bleeding after surgical treatment of CSDH it is important to assess the risk factors as coagulation disorders especially in young patients (below 65 years) with no history of head trauma, alcohol abuse or anticoagulant therapy. PATIENTS AND METHODS: This study consists of 16 patients (12 males, 4 females) with age ranging from 27 to 59 years (median 48,25 years) operated for CSDH. All patients are submitted to routine coagulation parameters pre-operatively and complete screening for unknown coagulation deficit in the follow-up. RESULTS: Factor VII was altered in 6 out of 16 patients and one patient had the alteration of the Von Willebrand factor. Recurrence occurred in 4 out of 16 patients and all of these patients were positive for factor VII deficiency. Three pts were in therapy with ASA. No patients were alcoholists or suffered from hematological disease. CONCLUSION: In this study we documented that the decreased activity of VII factor may play a role in the pathophysiology and recurrence of spontaneous CSDH in young adults. We suggest that for young patients aged under 65 y.o. suffered from CSDH the screening of coagulation factors is useful to planning a safely and correct surgical therapy.

Assessing human exposure to inorganic arsenic in high-arsenic areas of Latium: a biomonitoring study integrated with indicators of dietary intake.

BACKGROUND: In Latium (central Italy), arsenic concentrations exceeding the regulatory limit of 10 µg/L for drinking water are present in groundwater from a large area of volcanic origin. At least in part of the area, high arsenic concentrations have been detected also in soil and phytoavailable geogenic arsenic enters the food chain. As a result, local population may be exposed to inorganic arsenic via water and also through consumption of food with higher than background arsenic concentrations. METHODS: A cross sectional study was conducted to assess inorganic arsenic exposure and metabolism in 269 residents of 27 municipalities in the provinces of Viterbo, Rome and Latina. Total arsenic in toenails and the sum of inorganic arsenic and methylated metabolites in urine, the latter determined by HPLC-ICP-MS, were used as biomarkers of inorganic arsenic exposure. All the subjects involved in the study provided samples of the water(s) used for drinking and cooking as well as detailed information on water use. To get an insight into dietary intake from locally-processed food, inorganic arsenic in bread samples collected in affected municipalities of the three provinces was determined and compared to background levels of samples from reference areas. RESULTS: 30% of the sample used bottled water or resorted to water treatment in order to lower the arsenic content <10 µg/L (Group 1), 51% of the sample drank bottled water and used tap water with an arsenic content exceeding 10 µg/L for cooking only (Group 2), 19% of the sample used tap water with an arsenic content exceeding 10 µg/L for both drinking and cooking (Group 3). Nail arsenic was higher for Group 2 and 3 compared to Group 1, whereas all groups had higher nail arsenic than the reference group. The sum of inorganic arsenic and related metabolites in urine was higher in Group 3 than in the other two groups, and higher in Group 2 compared to Group 1. White bread from the study area showed significantly higher inorganic arsenic levels compared to samples from reference areas. CONCLUSIONS: Use of toenail arsenic as biomarker of long-term exposure allowed to retrospectively reconstruct exposure irrespective of recent modifications due to changes in water use. In Group 3, urinary concentration of inorganic arsenic and metabolites exceeded the upper limit of the reference concentration range for the Italian population. Inter-individual variability of the efficiency of arsenic metabolism in the study population was substantial indicating that a subgroup of the population is more susceptible to the toxic effects of inorganic arsenic owing to a lower methylation capability.

Trends of human brucellosis in Italy, 1998-2010.

SUMMARY: We describe the epidemiological trends and spatial distribution of human brucellosis in Italy over 13 years (1998-2010). In the study period 8483 cases were notified in Italy, with a relevant decrease (-89%) from 1998 to 2010. Most cases were notified in southern Italy (Campania, Apulia, Calabria, Sicily). In these regions we observed relevant differences in the risk of brucellosis at province level. Cases were distributed with a seasonal pattern, male patients represented 60% of the cases and no significant differences were observed between age groups. We modelled the underreporting rate that ranged between 2 and 21 (average 12·5). According to our estimates the true number of cases would have ranged from 41 821 to 155 324 providing a far more severe picture of human brucellosis in Italy than the one provided by the surveillance system.

Effect and safety of duodenal levodopa infusion in advanced Parkinson's disease: a retrospective multicenter outcome assessment in patient routine care.

Duodenal levodopa infusion represents an effective strategy to manage motor and non-motor complications in patients with advanced Parkinson's disease (PD). However, most published clinical series regard small numbers of patients and do not exceed 1 year follow-up. In this multi-national observational cohort study conducted in seven specialised PD clinics and university hospitals we assessed long-term safety and outcome of chronic treatment with intra-duodenal levodopa infusions in a large population of patients with advanced PD. The starting population consisted of 98 treated patients (safety population). We report clinical outcomes of 73 patients with subsequent efficacy assessment(s) (efficacy population) over a follow-up period up to 2 years. Follow-up periods and collection of clinical observations varied based on individual routine care program. At last follow-up there was a significant (p ≤ 0.05) reduction in duration of "Off" periods as well as dyskinesia duration and severity that was associated with an improvement of quality of life. Twenty three patients (25.3 % of the safety population) withdraw, due to adverse drug reaction (5), procedure and device related events (7), compliance (3) and lack of efficacy (8). The mean duration for last value reported after baseline (LV) was 608 ± 292 days (median: 697 days). Our results demonstrate significant and sustained benefit over a long observation period in motor complications and in quality of life following a change from oral pulsatile to continuous levodopa delivery. The relatively large number of withdrawals reflects the current use of duodenal levodopa infusion in very advanced PD patients.

Doppler flow analysis of the palmaris superficial branch of the radial artery in postmenopausal women with acroparesthesia: the role of hormone therapy. A pilot study.

METHOD: Twenty-three patients with acroparesthesia were submitted to clinical evaluation and color Doppler analysis of the uterine artery and palmaris superficial branch of the radial artery. Thirteen women (Group I) were submitted to hormone treatment with drospirenone 2 mg + estradiol emidrate 1 mg. Ten patients refused the treatment and served as controls (Group II). The patients were studied at baseline and after 6 months' therapy. RESULTS: After 6 months of hormone therapy, the resistances of the uterine artery and palmaris superficial branch of the radial artery significantly decreased in Group I patients. This was associated with the complete disappearance of paresthesic symptoms in 12/13 (92%) of the treated patients. In patients belonging to Group II, the paresthesia remained unchanged. CONCLUSION: Hormone therapy with drospirenone may increase the forearm/hand blood flow, and favor the amelioration of paresthesia.

The correlation between exaggerated fluid in lumbar facet joints and degenerative spondylolisthesis: prospective study of 52 patients.

BACKGROUND: Magnetic resonance imaging (MRI) is often used to evaluate low back pain; however, MRI in the supine position does not always reveal degenerative spondylolisthesis. The existence of a linear correlation between increased fluid in the facet joints seen on the supine axial T2 MRI of the lumbosacral spine and lumbar instability seen on standing lateral flexion-extension lumbosacral radiographs has recently been reported. The objective of this prospective study was to determine the incidence of increased fluid in the lumbar facet joints seen on the supine axial T2 MRI, and to evaluate the correlation of this finding with radiographic evidence of lumbar instability. MATERIALS AND METHODS: We prospectively analyzed weight-bearing flexion-extension lumbosacral radiographs and lumbosacral MRI in the supine position for 52 patients (mean age 64.7 years) seen at our institution for low back pain and/or radiculopathy. The statistical analysis was performed with Fisher's exact test. A difference was considered statistically significant if P < 0.05. RESULTS: In all but 5 of the 52 patients, degenerative disc disease and facet joint disease were observed on the supine MRI of the lumbosacral spine. Fifteen patients had exaggerated fluid in the lumbar facets on the axial T2 MRI (28.8%). Radiographic signs of degenerative lumbar spondylolisthesis were observed in 12 patients (23.1%), and the degenerative spondylolisthesis was not evident on the supine sagittal MRI in 10 of these 12 patients (83.3%). Among these 12 patients, the axial T2 MRI showed exaggerated fluid in the facet joints at the corresponding level in 8 patients (66%). Increased fluid in the lumbar facet joints was present on the supine axial T2 MRI in 7 patients (13.4%), even though there were no radiographic signs of corresponding lumbar instability. CONCLUSION: We observed a statistical correlation between increased fluid in the lumbar facet joints on the supine axial T2 MRI and degenerative spondylolisthesis seen on standing lateral flexion-extension lumbosacral radiographs.

Deep brain stimulation in patients with long history of drug resistant epilepsy and poor functional status: Outcomes based on the different targets.

BACKGROUND: Deep brain stimulation (DBS) is a widely used surgical procedure for the treatment of patients with drug resistant epilepsy (DRE) and several anatomical target have been described. Indications for DBS includes patients with focal, partial seizure and those for which resective or disconnective surgery are contraindicated, such as involvement of eloquent cortex or significant comorbidities. Despite the SANTE trial has clearly indicated the efficacy of DBS of anterior nucleus of the thalamus (ANT), specific indications regarding the best anatomical target and outcome in patients with severe disability are lacking. Here we described our case series of patients underwent DBS of three different target including ANT, centromedian thalamic nucleus (CMN) and subthalamic nucleus (STN). METHOD: Six patients with DRE have been treated with DBS of ANT (n = 3), STN (n = 2) and CMN (n = 1). Outcome has been expressed as seizures frequency reduction and patients functional status after surgery with a follow-up of 5-11 years. RESULTS: Four out of six patients show no reduction of seizures frequency after DBS implant with one case of increasing atypical absence. Two cases, one ANT and one CMN, show a significant reduction of seizures frequency of 50-60%. No patients improve relative to functional outcome and one showed psychiatric symptoms worsening. CONCLUSIONS: For patients with DRE and severe functional disability, DBS may reduce seizure frequency in some cases, but it does not improve functional outcome.

Chlamydophila pneumoniae infection in patients undergoing carotid artery stent.

Although several reports have correlated Chlamydophila pneumoniae (CP) infection with carotid endarterectomy and coronary stent, no data have been reported on the potential relationship between this pathogen and carotid artery stenting (CAS). Hence, we evaluated 47 subjects, 27 symptomatic and 20 asymptomatic, before CAS intervention and during the follow up, for the presence of CP DNA and anti-CP antibodies, including chlamydial HSP60 (Cp-HSP60). Before stent placement, CP DNA was detected exclusively in symptomatic patients, all of whom were also positive for CP IgG and IgA and 85.7 percent of them also had CP-HSP60 antibodies. At the follow-up, all CP DNA positive and 11 out of the 13 symptomatic patients with Cp-HSP60 antibodies became negatives. In contrast, no change was observed for CP- IgA antibodies. Despite the small number of patients, the present study advocates an important role of CP infection in symptomatic patients with carotid artery disease. Our findings also suggest that stent placement and/or therapy might have a role in favouring resolution of inflammation, though not affecting persistence of CP infection.

Acetaminophen plus codeine compared to ketorolac in polytrauma patients.

INTRODUCTION: The management of pain in polytrauma patients is mandatory. While non-steroidal anti-inflammatory drugs (NSAIDs) represent the most used drugs in polytrauma patients, their use may be associated with an increased risk of haemorrhage. Opioids may represent a valid alternative to NSAIDs either alone or in combination with acetaminophen. Whether their efficacy is comparable to that produced by NSAIDs in polytrauma patients has never been studied. PATIENTS AND METHODS: 60 polytrauma patients were enrolled for this study. 30 patients were treated with acetaminophen 1000 mg plus codeine 60 mg tid for 24 hours (Group A), while the remaining 30 with ketorolac 10 mg qid for 24 hours (Group B). Pain intensity has been evaluated using an analogical visual scale (VAS) ranging from 0 (no pain) to 10 (very severe pain). The level of pain was valuated at enrolment (TO) as well as after 2 (T2), 12 (T12) and 24 (T24) hours from the starting of the analgesic therapy. Results obtained by the group A were compared with those reported by the group B. RESULTS: T0: Group A mean score was 6.4 +/- 1.5 compared with 6.6 +/- 1.5 of Group B (p= ns); T2: Group A mean score was 3.4 +/- 2.8, compared with 3.5 +/- 2.4 of group B (p = ns); T12: Group A mean score was 3.4 +/- 3.4, compared with 3.5 +/- 3 of Gorup B (p = ns); T24: Group A mean score was 2.9 +/- 1.5, compared to 3.0 +/- 1.6 of Group B (p = ns). All those drugs determined a significant reduction of pain intensity during the course of therapy. CONCLUSIONS: Acetaminophen plus codeine is effective in pain control in polytrauma patients at least in our series. It may represent a valid alternative to NSAIDs, especially in patients with a documented haemorrhage or with a high hemorrhagic risk.

Primary Dural Lymphoma: Clinical Cases and Literature Review.

Primary dural lymphoma (PDL) is an extranodal non-Hodgkin lymphoma that accounts for less than 1% of all central nervous system lymphomas. Primary dural lymphoma grows from the dura mater, and it is often diagnosed as meningioma or acute subdural hematoma due to its radiological characteristics. Surgery is the gold standard of therapy; in many patients, PDL is relatively benign with good outcome. Authors report their experience in three patients affected by extranodal non-Hodgkin lymphoma (PDL) mimicking a meningioma.

Cognitive and linguistic outcomes after awake craniotomy in patients with high-grade gliomas.

BACKGROUND: Preservation of language and cognition is crucial in glioma surgery, as they are crucial aspects of daily life functioning. Several studies claimed that awake surgery in eloquent areas is demanded in low and high-grade gliomas. Cognitive and language outcome has been less investigated in high-grade gliomas compared to low-grade. METHOD: We analyzed the neuropsychological and neuro-oncological outcome of nineteen patients (from a cohort of forty patients) who underwent fully awake surgery for resection of malignant tumors located in eloquent areas. RESULTS: Post-surgery, linguistic functions were unchanged in 80 % of patients. Slight impairments in memory and executive functions were observed in about 50 % of patients. Survival rate at one year follow-up was 89 %. Results showed that awake procedure is safe, well tolerated and related with good linguistic outcome similar to low-grade gliomas. The majority of patients reported a good outcome in term of quality of life. CONCLUSIONS: Our results confirm that awake surgery is associated to good cognitive and linguistic clinical outcome also in malignant tumors.

Blindsight following visual cortex deafferentation disappears with purple and red stimuli: a case study.

We employed a redundant signal effect (RSE) paradigm to ascertain the role of the superior colliculus (SC) in blindsight. The RSE consists of the speeding of reaction time (RT) to double versus single stimuli. One patient with a unilateral lesion of the optic radiation and consequent hemianopia showed a RSE with pairs of visual stimuli presented across the vertical meridian despite seeing only stimuli in the intact hemifield. However, when, instead of achromatic stimuli we used short or long wavelength stimuli the implicit RSE disappeared. This result raises the possibility that implicit chromatic processing in the affected hemifield might have a different neural substrate following deafferentation with respect to lesion of the primary visual cortex.

MDM4 (MDMX) and its Transcript Variants.

MDM family proteins are crucial regulators of the oncosuppressor p53. Alterations of their gene status, mainly amplification events, have been frequently observed in human tumors.MDM4 is one of the two members of the MDM family. The human gene is located on chromosome 1 at q32-33 and codes for a protein of 490aa. In analogy to MDM2, besides the full-length mRNA several transcript variants of MDM4 have been identified. Almost all variants thus far described derive from a splicing process, both through canonical and aberrant splicing events. Some of these variants are expressed in normal tissues, others have been observed only in tumor samples. The presence of these variants may be considered a fine tuning of the function of the full-length protein, especially in normal cells. In tumor cells, some variants show oncogenic properties.This review summarizes all the different MDM4 splicing forms thus far described and their role in the regulation of the wild type protein function in normal and tumor cells. In addition, a description of the full-length protein structure with all known interacting proteins thus far identified and a comparison of the MDM4 variant structure with that of full-length protein are presented. Finally, a parallel between MDM4 and MDM2 variants is discussed.