Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder.

INTRODUCTION: CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain-penetrant molecule that was reported to selectively inhibit group I p21-activated kinases (PAKs), serine/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis. METHODS: The effects of treatment with FRAX486 on CDD-related alterations were assessed in vitro (100 nM for 48 h) on primary hippocampal cultures from Cdkl5-knockout male mice (Cdkl5-KO) and in vivo (20 mg/Kg, s.c. for 5 days) on Cdkl5-KO heterozygous females (Cdkl5-Het). RESULTS: The in vitro treatment with FRAX486 completely rescued the abnormal neuronal maturation and the number of PSD95-positive puncta in Cdkl5-KO mouse neurons. In vivo, FRAX486 normalized the general health status, the hyperactive profile and the fear learning defects of fully symptomatic Cdkl5-Het mice. Systemically, FRAX486 treatment normalized the levels of reactive oxidizing species in the whole blood and the fasting-induced hypoglycemia displayed by Cdkl5-Het mice. In the hippocampus of Cdkl5-Het mice, treatment with FRAX486 rescued spine maturation and PSD95 expression and restored the abnormal PAKs phosphorylation at sites which are critical for their activation (P-PAK-Ser144/141/139) or for the control cytoskeleton remodeling (P-PAK1-Thr212). CONCLUSIONS: Present results provide evidence that PAKs may represent innovative therapeutic targets for CDD.

Stimulation of the Serotonin Receptor 7 Restores Brain Histone H3 Acetylation and MeCP2 Corepressor Protein Levels in a Female Mouse Model of Rett Syndrome.

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene, characterized by severe behavioral and physiological impairments for which no cure is available. The stimulation of serotonin receptor 7 (5-HT7R) with its selective agonist LP-211 (0.25 mg/kg/day for 7 days) was proved to rescue neurobehavioral alterations in a mouse model of RTT. In the present study, we aimed at gaining insight into the mechanisms underpinning the efficacy of 5-HT7R pharmacological stimulation by investigating its epigenetic outcomes in the brain of RTT female mice bearing a truncating MeCP2 mutation. Treatment with LP-211 normalized the reduced histone H3 acetylation and HDAC3/NCoR levels, and increased HDAC1/Sin3a expression in RTT mouse cortex. Repeated 5-HT7R stimulation also appeared to strengthen the association between NCoR and MeCP2 in the same brain region. A different profile was found in RTT hippocampus, where LP-211 rescued H3 hyperacetylation and increased HDAC3 levels. Overall, the present data highlight a new scenario on the relationship between histone acetylation and serotoninergic pathways. 5-HT7R is confirmed as a pivotal therapeutic target for the recovery of neuronal function supporting the translational value of this promising pharmacological approach for RTT.

Uterine Fundus Remodeling after Hysteroscopic Metroplasty: A Prospective Pilot Study.

The septate uterus is the most common congenital uterine malformation and is treated by hysteroscopic metroplasty. There are few studies on the fundal uterine changes that occur after surgery. We designed a pilot prospective observational study to evaluate by three-dimensional transvaginal ultrasound (3D-TVS) the changes not only of the internal fundal uterine profile, but also of the external one, after hysteroscopic metroplasty. Sixty women who underwent hysteroscopic metroplasty for partial or complete uterine septum (U2a and U2b subclasses of ESHRE/ESGE classification) were enrolled. We performed 3D-TVS after surgery confirming optimal removal of the septum. However, at ultrasound follow-up after three months, we observed a significant increase (p < 0.001) in the residual septum (Zr) (3.7 mm (95% CI: 3.1-4.4)), the myometrial wall thickness (Y) (2.5 mm (95% CI: 2.0-3.0)) and the total fundal wall thickness (Y + Zr) (6.2 mm (95% CI: 5.5-6.9)). Forty-three patients (72%) required a second step of hysteroscopic metroplasty. Moreover, the shape of uterine fundus changed in 58% of cases. We actually observed a remodeling of the uterine fundus with modifications of its external and internal profiles. Therefore, we propose to always perform a second ultrasound look at least three months after the metroplasty to identify cases that require a second- step metroplasty.

Comparison of Hysteroscopic Cesarean Scar Defect Repair with 26 Fr Resectoscope and 16 Fr Mini-resectoscope: A Prospective Pilot Study.

STUDY OBJECTIVE: Several studies have been published on hysteroscopic treatment of cesarean scar defect using the 26 Fr resectoscope. This study compared the effects of the 26 Fr resectoscope with those of the 16 Fr mini-resectoscope in terms of efficacy, safety profile, and peri- and postoperative complications. DESIGN: A prospective cohort study. SETTING: Tertiary care university hospital (S. Orsola-Malpighi, Bologna, Italy). PATIENTS: Three hundred and nine women having symptoms and with a cesarean scar defect diagnosis were divided into 2 groups according to a temporal criterion: from March 2012 to March 2015, 155 consecutive women (control group) underwent isthmoplasty with the 26 Fr resectoscope (Karl Storz, Tuttlingen, Germany), whereas from April 2015 to March 2018, 154 consecutive women (study group) underwent isthmoplasty with the 16 Fr mini-resectoscope (Gubbini system, Tontarra Medizintechnik, Tuttlingen, Germany). INTERVENTIONS: One hundred and fifty-five women (control group) underwent isthmoplasty with the 26 Fr resectoscope, and 154 women (study group) underwent isthmoplasty with the 16 Fr mini-resectoscope. The so-called "channel-like" 360° endocervical resection technique was applied. MEASUREMENTS AND MAIN RESULTS: The isthmoplasty time with the 2 resectoscopes, excluding cervical dilatation, was similar (p = .25), whereas the overall surgical time was shorter in the case of the mini-resectoscope. The use of the 16 Fr mini-resectoscope was significantly associated with a reduced volume of distension medium used (p <.001) and a lower fluid absorption (p <.001). A significant increase (p = .01) in postoperative complications in the control group (9/155; 5.8%) compared with the study group (1/154; 0.7%) was also found. No significant reduction in discharge time was observed between the 2 groups (p = .13). Patient satisfaction immediately after surgery was significantly higher (p <.001) in the study group than in the control group. CONCLUSION: Isthmoplasty with a 16 Fr mini-resectoscope seems to be as effective as isthmoplasty with a 26 Fr resectoscope in reducing postmenstrual abnormal uterine bleeding and suprapubic pelvic pain. It is associated with a significant reduction in overall surgical time owing to the non-necessity of performing cervical dilatation. The 16 Fr mini-resectoscope facilitates surgery in small anatomical spaces such as the cervical canal and reduces the complication rate linked to blind maneuvers not respecting the uterine anatomy.

Conservative hysteroscopic treatment of stage I well differentiated endometrial cancer in patients with high surgical risk: a pilot study.

OBJECTIVE: To report hysteroscopic treatment combined with levonorgestrel-releasing intrauterine device (LNG-IUD) to treat women with early well differentiated endometrial cancer (EC) at high surgical risk. METHODS: Nine women diagnosed with stage IA, grade 1 endometrioid EC which was contraindicated or refused standard treatment with external beam radiation therapy with or without brachytherapy were enrolled in our prospective study. Endo-myometrial hysteroscopic resection of the whole uterine cavity and the placement of LNG-IUD for 5 years was performed. Response rate, perioperative complications, and recurrence of disease were evaluated. RESULTS: None had intra or post-operative complications and all were discharged no later than the third day of hospitalization. After 6 months from surgery, all the women showed a complete regression of the lesion. All the women completed the 5 years follow-up and in no case was detected sign of recurrence. Two women died for causes unrelated to the tumor or the ongoing therapy. CONCLUSION: The alternative treatment with endo-myometrial hysteroscopic resection and LNG-IUD in women with stage IA, grade 1 endometrioid EC showed initial encouraging outcomes in terms of effectiveness and safety.

Percutaneous electrochemotherapy in the treatment of portal vein tumor thrombosis at hepatic hilum in patients with hepatocellular carcinoma in cirrhosis: A feasibility study.

AIM: To treated with electrochemotherapy (ECT) a prospective case series of patients with liver cirrhosis and Vp3-Vp4- portal vein tumor thrombus (PVTT) from hepatocellular carcinoma (HCC), in order to evaluate the feasibility, safety and efficacy of this new non thermal ablative technique in those patients. METHODS: Six patients (5 males and 1 female), aged 61-85 years (mean age, 70 years), four in Child-Pugh A and two in Child-Pugh B class, entered our study series. All patients were studied with three-phase computed tomography (CT), contrast enhanced ultrasound (CEUS) and ultrasound-guided percutaneous biopsy of the thrombus before ECT. All patients underwent ECT treatment (Cliniporator Vitae®, IGEA SpA, Carpi, Modena, Italy) of Vp3-Vp4 PVTT in a single session. At the end of the procedure a post-treatment biopsy of the thrombus was performed. Scheduled follow-up in all patients entailed: CEUS within 24 h after treatment; triphasic contrast-enhanced CT and CEUS at 3 mo after treatment and every six months thereafter. RESULTS: Post-treatment CEUS showed complete absence of enhancement of the treated thrombus in all cases. Post-treatment biopsy showed apoptosis and necrosis of tumor cells in all cases. The follow-up ranged from 9 to 20 mo (median, 14 mo). In 2 patients, the follow-up CT and CEUS demonstrated complete patency of the treated portal vein. Other 3 patients showed a persistent avascular non-tumoral shrinked thrombus at CEUS and CT during follow-up. No local recurrence was observed at follow-up CT and CEUS in 5/6 patients. One patient was lost to follow-up because of death from gastrointestinal hemorrage 5 wk after ECT. CONCLUSION: In patients with cirrhosis, ECT seems effective and safe for curative treatment of Vp3-Vp4 PVTT from HCC.

Hysteroscopic myomectomy: techniques and preoperative assessment.

Even if usually asymptomatic, uterine myomas have been associated with a number of clinical issues such as abnormal uterine bleeding (AUB), heavy menstrual bleeding (HMB), infertility, recurrent pregnancy loss, especially when these masses are submucous. Golden standard treatment for symptomatic submucous fibroids has long been considered their laparotomic removal or a total hysterectomy. The development of endoscopy has made these fibroids accessible and removable from the inner surface of uterus. Hysteroscopy arose as a diagnostic technique, but then it also became an alternative surgical technique for many diseases, offering therapeutic and irreplaceable possibilities of treatment, avoiding major surgery on the one hand, and allowing the correction of pathologies specifically related to female fertility, on the other hand. Excision by slicing has been described as traditional resectoscopic submucosal myomectomy, but today there are new procedures among which the operator can choose, that allow overcoming the initial limitations of the traditional resectoscopic myomectomy in clinical practice.

Should the myometrial free margin still be considered a limiting factor for hysteroscopic resection of submucous fibroids? A possible answer to an old question.

OBJECTIVE: To evaluate the feasibility of the hysteroscopic resection of type II submucous fibroids regardless of the myometrial free margin separating them from the serosa and to report the dynamic changes the margin undergoes after the various phases of resection. DESIGN: A prospective observational study. SETTING: A tertiary-level university hospital. PATIENT(S): Thirteen women with single type II submucous fibroids of ≤ 5 cm in diameter regardless of the myometrial free margin. INTERVENTION(S): Hysteroscopic myomectomy and ultrasound evaluation of myometrial free margin before and after each phase of the procedure. MAIN OUTCOME MEASURE(S): The possibility of a complete one-step resection, the incidence of intraoperative or postoperative complications, and the analysis of the dynamic changes occurring in myometrial free margin. RESULT(S): Complete resection was performed successfully in all patients. No complications were registered. The myometrial free margin decreased on the distension of the uterine cavity and then increased progressively and significantly after the various phases of resection. CONCLUSION(S): In selected cases and in experienced hands, hysteroscopic myomectomy of type II submucous fibroids may be performed successfully and safely regardless of the myometrial free margin. Myometrial free margin increases progressively with each step of the procedure probably leading to an increasing margin of safety.

Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review.

BACKGROUND: Drug-Induced Hypersensitivity Syndrome (DIHS) is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug). We present a case of DISH and we review studies on the clinical features and treatment of DIHS, and on its pathogenesis in which two elements (Herpesvirus infection and the drug) interact with the immune system to trigger such a syndrome that can lead to death in about 20% of cases. CASE PRESENTATION: We report the case of a 26-year old woman with fever, systemic maculopapular rash, lymphadenopathy, hepatitis and eosinophilic leukocytosis. She had been treated with antibiotics that gave no benefit. She was taking escitalopram and lamotrigine for a bipolar disease 30 days before fever onset. Because the patient's general condition deteriorated, betamethasone and acyclovir were started. This treatment resulted in a mild improvement of symptoms. Steroids were rapidly tapered and this was followed with a relapse of fever and a worsening of laboratory parameters. Human herpesvirus 6 (HHV-6) DNA was positive as shown by PCR. Drug-Induced Hypersensitivity Syndrome (DIHS) was diagnosed. Symptoms regressed on prednisone (at a dose of 50 mg/die) that was tapered very slowly. The patient recovered completely. CONCLUSIONS: The search for rare causes of fever led to complete resolution of a very difficult case. As DIHS is a rare disease the most relevant issue is to suspect and include it in differential diagnosis of fevers of unknown origin. Once diagnosed, the therapy is easy (steroidal administration) and often successful. However our case strongly confirms that attention should be paid on the steroidal tapering that should be very slow to avoid a relapse.

Tenofovir and its potential in the treatment of hepatitis B virus.

Recent literature is reviewed about treatment of chronic hepatitis B virus (CHB), focusing on tenofovir disoproxil fumarate (TDF; Viread((R))), among the nucleotide and nucleoside analogs. TDF pharmacokinetics and pharmacodynamics, activity in respect of hepatitis B virus (HBV) multi-drug-resistant mutations, efficacy in treatment-naïve and treatment-experienced patients, and side effects are described. The most predictive response factors to TDF therapy are discussed and all available combination therapies to optimize clinical outcome in the various patient profiles are analyzed, such as compensated and/or decompensated cirrhotic patients. The use of TDF in pregnancy, and prophylaxis after exposure to HBV and post-liver transplantation are also evaluated.