Sinecatechins ointment as a potential novel treatment for usual type vulval intraepithelial neoplasia: a single-centre double-blind randomised control study.

OBJECTIVE: To compare the safety and efficacy of 10% sinecatechins (Veregen® ) ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). DESIGN: A Phase II double-blind randomised control trial. SETTING: A tertiary gynaecological oncology referral centre. POPULATION: All women diagnosed with primary and recurrent uVIN. METHODS: Eligible patients were randomised 1:1 to receive either sinecatechins or placebo ointment (applied three times daily for 16 weeks) and were followed up at 2, 4, 8, 16, 32 and 52 weeks. MAIN OUTCOME MEASURES: The primary outcome measure, recorded at 16 and 32 weeks, was histological response (HR). Secondary outcome measures included clinical (CR) response, toxicity, quality of life and pain scores. RESULTS: There was no observed difference in HR between the two arms. However, of the 26 patients who were randomised, all 13 patients who received sinecatechins showed either complete (n = 5) or partial (n = 8) CR, when best CR was evaluated. In placebo group, three patients had complete CR, two had partial CR, six had stable disease and two were lost to follow up. Patients in the sinecatechins group showed a statistically significant improvement in best observed CR as compared with the placebo group (P = 0.002). There was no difference in toxicity reported in either group. CONCLUSION: Although we did not observe a difference in HR between the two treatment arms, we found that 10% sinecatechins application is safe and shows promise in inducing clinical resolution of uVIN lesions and symptom improvement, thus warranting further investigation in a larger multicentre study. TWEETABLE ABSTRACT: A randomised control study indicating that sinecatechins ointment may be a novel treatment for uVIN.

Effects of branched chain amino acid supplementation on patient care outcomes in adults and children with liver cirrhosis: A systematic review.

BACKGROUND & AIMS: Malnutrition is highly prevalent in chronic liver disease (CLD) due to alterations in nutrient utilization, malabsorption and poor intake. Low serum concentrations of branched chain amino acids (BCAA) in the presence of elevated aromatic acid concentrations is commonly observed in adult and children with liver cirrhosis and is associated with malnutrition and other adverse patient outcomes. The efficacy of BCAA supplementation has not been well established in adults and children with CLD. The purpose of this review was to critically evaluate the literature regarding the impact of BCAA supplementation related to changes in body composition, muscle strength, liver biomarkers, medical and hepatic complications (hepatic encephalopathy (HE), ascites, edema) and patient care outcomes (event free survival, health related quality of life, length of hospitalization). METHODS: A total of 40 articles retrieved from PubMed or Web of Science databases (1989-2017) were included. RESULTS: BCAA supplementation may be beneficial in improving muscle strength, ascites and edema with potential clinically significant improvements in HE in adult liver patients. In children, limited data have shown that BCAA supplementation may exert favourable effects on weight, fat mass, fat free mass and serum albumin level. CONCLUSIONS: Heterogeneity of study findings attributed to variability in BCAA dose (total, relative proportions), duration, disease severity and lack of uniformity in tools used for assessing patient outcomes limit overall conclusions. Longitudinal studies examining the efficacy of BCAA supplementation as a therapeutic treatment of malnutrition in chronic liver disease is warranted.

Repurposing Zidovudine in combination with Tigecycline for treating carbapenem-resistant Enterobacteriaceae infections.

The global emergence of carbapenem-resistant Enterobacteriaceae (CRE) presents a significant clinical concern, prompting the WHO to prioritize CRE as a top priority pathogen in their 2017 global antibiotic-resistant bacteria priority list. Due to the fast-depleting antibiotic arsenal, clinicians are now resorting to using once-abandoned, highly toxic antibiotics such as the polymyxins and aminoglycosides, creating an urgent need for new antibiotics. Drug repurposing, the application of an approved drug for a new therapeutic indication, is deemed a plausible solution to this problem. A total of 1,163 FDA-approved drugs were screened for activity against a clinical carbapenem- and multidrug-resistant E. coli isolate using a single-point 10 µM assay. Hit compounds were then assessed for their suitability for repurposing. The lead candidate was then tested against a panel of clinical CREs, a bactericidal/static determination assay, a time-kill assay and a checkerboard assay to evaluate its suitability for use in combination with Tigecycline against CRE infections. Three drugs were identified. The lead candidate was determined to be Zidovudine (azidothymidine/AZT), an oral anti-viral drug used for HIV treatment. Zidovudine was shown to be the most promising candidate for use in combination with Tigecycline to treat systemic CRE infections. Further experiments should involve the use of animal infection models.

Long-term outcomes of sacral nerve stimulation for faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) has proven short- to medium-term effectiveness for the treatment of faecal incontinence (FI); fewer long-term outcomes have been presented and usually in small series. Here, the long-term effectiveness of SNS was evaluated in a large European cohort of patients with a minimum of 5 years' follow-up. METHODS: Prospectively registered data from patients with FI who had received SNS for at least 5 years from ten European centres were collated by survey. Daily stool diaries, and Cleveland Clinic and St Mark's incontinence scores were evaluated at baseline, after implantation and at the last follow-up. SNS was considered successful when at least 50 per cent symptom improvement was maintained at last follow-up. RESULTS: A total of 407 patients underwent temporary stimulation, of whom 272 (66·8 per cent) had an impulse generator implanted; 228 (56·0 per cent) were available for long-term follow-up at a median of 84 (i.q.r. 70-113) months. Significant reductions in the number of FI episodes per week (from median 7 to 0·25) and summative symptom scores (median Cleveland Clinic score from 16 to 7, St Mark's score from 19 to 6) were recorded after implantation (all P < 0·001) and maintained in long-term follow-up. In per-protocol analysis, long-term success was maintained in 71·3 per cent of patients and full continence was achieved in 50·0 per cent; respective values based on intention-to-treat analysis were 47·7 and 33·4 per cent. Predictive analyses determined no significant association between pretreatment variables and successful outcomes. Risk of long-term failure correlated with minor symptom score improvement during the temporary test phase. CONCLUSION: SNS remains an effective treatment for FI in the long term for approximately half of the patients starting therapy.

Value of sacral nerve stimulation in the treatment of severe faecal incontinence: a comparison to the artificial bowel sphincter.

OBJECTIVE: Sacral nerve stimulation (SNS) is a recent treatment option in the management of severe faecal incontinence (FI) that offers promising results. The aim of this study was to compare SNS to artificial bowel sphincter (ABS) implanted patients to assess the rationale of this approach in achieving satisfying functional results and improved quality of life (QoL). METHOD: Among 27 patients tested (December 2001 and April 2004), 15 patients were successfully managed with SNS. They were compared to 15 matched patients implanted with ABS in a previous period (control group). Assessment of continence level (Cleveland Clinic score), constipation score (Knowles, Eccersley, Scott Score) and QoL (Short-Form 36) were prospectively collected. RESULTS: Both groups were comparable for clinical parameters (age, gender, anal testing and aetiology of incontinence) and anal physiology. The mean postoperative continence score was significantly higher in the SNS group [9.4 (+/-3.3) vs 5.7 (+/-3.9), P < 0.01]; however, the mean constipation score was higher in the ABS group (6.3 +/- 6.3 vs 12.8 +/- 5.7, P < 0.01). The mean QoL score was similar in both groups. The mean follow-up after implantation was 15 (+/-9) months in the SNS group, and 43 (+/-33) months in the ABS group. CONCLUSION: In this study, SNS offers satisfying results in terms of QoL, similar to that of ABS. Although it seems to be less effective in restoring continence level, symptoms of outlet obstruction are more frequent after ABS. This SNS approach should be proposed as a first-line treatment of FI in selected patients. ABS should remain an option that can improve function.

Optimizing electrode implantation in sacral nerve stimulation--an anatomical cadaver study controlled by a laparoscopic camera.

BACKGROUND AND AIM: Sacral nerve stimulation is the therapy of choice in patients with neurogenic faecal and urine incontinence, constipation and some pelvic pain syndromes. The aim of this study is to determine the best insertion angles of the electrode under laparoscopic visualization of the sacral nerves. MATERIALS AND METHODS: Five fresh cadaver pelvises were dissected through an anterior approach of the presacral space, exposing the ventral sacral roots. Needles and electrodes were inserted into the S3 foramen. Both right and left sides were used, with the traditional percutaneous procedure. The validation was done by a laparoscopic camera controlling the position of the needle and electrode on the nerve. The angles were assessed with a goniometer and were confirmed in two living patients. RESULTS: The mean angle of insertion in the sagittal plane was 62.9+/-3 degrees (range, 59-70). In the axial plane, the mean angle for the left side was 91.7+/-13.5 degrees (range, 80-110) and 83.2+/-7.7 degrees for the right side (range, 75-95). These angles resulted in the optimal placement of the leads along the S3 sacral root, in all these cases. CONCLUSIONS: This study allows direct visualization during the placement of the needle and electrode, thus permitting accurate calculations of the best angle of approach during the surgical procedure in sacral nerve stimulation. These objective findings attempt to standardize this technique, which is often performed with the aid of intra-operative fluoroscopy but still leaving a lot to chance. These insertion angles should help to find more consistent and reproducible results and thus improved outcome in patients.

Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid).

We have studied the effects in three rodent models of generalised convulsive or absence epilepsy of two antagonists of group I metabotropic glutamate receptors that are selective for the mGlu1 receptor. LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid) have been administered intracerebroventricularly (i.c.v.) to DBA/2 mice and lethargic mice (lh/lh), and focally into the inferior colliculus of genetically epilepsy prone rats (GEPR). In DBA/2 mice both compounds produce a rapid, transient suppression of sound-induced clonic seizures (LY 367385: ED50 = 12 nmol, i.c.v., 5 min; AIDA: ED50 = 79 nmol, i.c.v., 15 min). In lethargic mice both compounds significantly reduce the incidence of spontaneous spike and wave discharges on the electroencephalogram, from <30 to >150 min after the administration of AIDA, 500 nmol, i.c.v., and from 30 to >150 min after the administration of LY 367385, 250 nmol, i.c.v. LY 367385, 50 nmol, suppresses spontaneous spike and wave discharges from 30 to 60 min. In genetically epilepsy prone rats both compounds reduce sound-induced clonic seizures. LY 367385, 160 nmol bilaterally, fully suppresses clonic seizures after 2-4 h. AIDA is fully effective 30 min after 100 nmol bilaterally. It is concluded that antagonists of mGlu1 receptors are potential anticonvulsant agents and that activation of mGlu1 receptors probably contributes to a variety of epileptic syndromes.

A survey of infections in stereotactic surgery.

In 365 consecutive intracranial stereotactic procedures over a 6-year period, there were three postoperative infections; 1 case of increased neurological deficit and 1 of fatality. Staphylococcus aureus was the most common organism involved; however, multiple organisms were seen in 2 cases. Multiplicity of organisms necessitated the use of a broad spectrum of antibiotics in the preoperative and postoperative periods. The method described has permitted an infection rate which compares favorably to other reports in the literature. Perioperative antibiotics, antibiotic-containing irrigation solutions, and careful attention to sterile techniques seem to be instrumental in maintaining a low infection rate in our study. Since the new spheroid design has been used, there have been no infections.

Stereotaxic treatment of seizure disorder.

Individuals with intractable epilepsy have a murky existence, fraught with medical helplessness, social rejection and personal despair. Drugs control many, but unfortunately not all, cases of epilepsy. An attempt to elucidate on the indications, selections and rationale for the stereotaxic interruption is made. Three cases of intractable epilepsy treated by stereotaxic Fields of Forel Interruptions are reported with special emphasis on pre and postoperative evaluations. Based on the data so far available, it appears that a significant number of patients with medically intractable epilepsy who are not candidates for "standard" neurosurgical interventions, can be helped further by stereotaxic interruptions with minimal morbidity.