Biotinylated chitosan macromolecule based nanosystems: A review from chemical design to biological targets.

World Health Organization estimates that 30-50% of cancers are preventable by healthy lifestyle choices, early detection and adequate therapy. When the conventional therapeutic strategies are still regulated by the lack of selectivity, multidrug resistance and severe toxic side effects, nanotechnology grants a new frontier for cancer management since it targets cancer cells and spares healthy tissues. This review highlights recent studies using biotin molecule combined with functional nanomaterials used in biomedical applications, with a particular attention on biotinylated chitosan-based nanosystems. Succinctly, this review focuses on five areas of recent advances in biotin engineering: (a) biotin features, (b) biotinylation approaches, (c) biotin functionalized chitosan based nanosystems for drug and gene delivery functions, (d) diagnostic and theranostic perspectives, and (e) author's inputs to the biotin-chitosan based tumour-targeting drug delivery structures. Precisely engineered biotinylated-chitosan macromolecules shaped into nanosystems are anticipated to emerge as next-generation platforms for treatment and molecular imaging modalities applications.

Carboxymethyl guar gum nanoparticles for drug delivery applications: Preparation and preliminary in-vitro investigations.

Carboxymethyl guar gum (CMGG) synthesized from commercially available polysaccharide was formulated into nanoparticles via ionic gelation using trisodium trimetaphosphate (STMP) as cross-linking agent. Characterisation using a range of analytical techniques (FTIR, NMR, GPC, TGA and DLS) confirmed the CMGG structure and revealed the effect of the CMGG and STMP concentration on the main characteristics of the obtained nanoformulations. The average nanoparticle diameter was found to be around 208 nm, as determined by dynamic light scattering (DLS) and confirmed by scanning electron microscopy (SEM) and nanoparticle tracking analysis (NTA). Experiments using simulated gastric and intestinal fluids evidenced significant pH-dependent drug release behaviour of the nanoformulations loaded with Rhodamine B (RhB) as a model drug (loading capacity in excess of 83%), as monitored by UV-Vis. While dose-dependent cytotoxicity was observed, the nanoformulations appeared completely non-toxic at concentrations below 0.3 mg/mL. Results obtained so far suggest that carboxymethylated guar gum nanoparticles formulated with STMP warrant further investigations as polysaccharide based biocompatible drug nanocarriers.

Silica nanoparticles: preparation, characterization and in vitro/in vivo biodistribution studies.

BACKGROUND: The current progress in pharmaceutical nanotechnology field has been exploited in the design of functionalized radiolabelled nanoparticles that are able to deliver radionuclides in a selective manner to improve the outcome of diagnosis and treatment. Silica nanoparticles (SNPs) have been widely developed for biomedical applications due to their high versatility, excellent functional properties and low cost production, with the possibility to control different topological parameters relevant for multidisciplinary applications. PURPOSE: The aim of the present study was to characterize and evaluate both in vitro, by microscopy techniques, and in vivo, by scintigraphic imaging, the biodistribution of silica nanostructures derivatives (Cy5.5 conjugated SNPs and (99m)Tc radiolabelled SNPs) to be applied as radiotracers in biomedicine. METHODS: SNPs were synthesized by hydrolysis and condensation of silicon alkoxides, followed by surface functionalization with amino groups available for fluorescent dye and radiolabelling possibility. RESULTS: Our data showed the particles size distribution (200-350 nm), the surface charge (negative for bare and fluorescent SNPs and positive for amino SNPs), polydispersity index (broad distribution), the qualitative composition and the toxicity assessments (safe material) that made the obtained SNPs candidates for in vitro/in vivo studies. A high uptake of fluorescent SNPs in all the investigated organs was evidenced by confocal microscopy. The (99m)Tc radiolabelled SNPs biodistribution was quantified in the range of 12-100% counts/g organ using the scintigraphic images. CONCLUSIONS: The obtained results reveal improved properties, namely, reduced toxicity with a low level of side effects, an improved biodistribution, high labelling efficiency and stability of the radiolabelled SNPs with potential to be applied in biomedical science, particularly in nuclear medicine as a radiotracer.

Flaxseed lignan wound healing formulation: characterization and in vivo therapeutic evaluation.

Flaxseed lignans are a natural source of useful biologically active components that show a diverse spectrum of health-promoting properties. The valuable effects of the phenolic molecules are mainly due to their antioxidant activity by preventing oxidative stress and stimulate collagen synthesis, therefore, providing benefits to the skin. The present work highlights the development of flaxseed extract formulation as novel wound healing agent. The recognition of key structural features within flaxseed extract was crucial for the design and development of the therapeutic cream. Chromatographic analyses were employed for bioactive compounds identification and quantification. Folin-Ciocalteu method determined the total phenolic content and the antioxidant properties were evaluated by DPPH assay. The storage and loss modulus and tan δ were calculated for cream rheological properties evaluation. In vitro diffusion capacity and in vivo wound healing activity of phenolic cream were evaluated on Wistar rats. The collective properties and healing effect of the flaxseed suggested wound healing capacity.

Anal endosonography and fistulography for fistula-in-ano.

PURPOSE: In this study, a comparison was made of the accuracy and clinical usefulness of anal endosonography and fistulography in the preoperative classification of fistulas-in-ano. MATERIALS AND METHODS: A total of 113 patients with a clinical diagnosis of cryptoglandular fistula-in-ano who were awaiting surgery were included in this retrospective review. Patients were preoperatively investigated by anal endosonography and/or modified fistulography by inserting a Foley catheter into the rectum and a metal ring close to the anus. The catheter and ring served as radiopaque anal markers. Fistula classification obtained by the two diagnostic modalities was compared with surgical classification as the criterion standard. RESULTS: Endoanal ultrasound and fistulography identified 82.8% and 100% of primary tracks, 79% and 74.2% of internal openings, 98% and 91.8% of secondary tracks and 92.9% and 87.8% of abscesses, respectively. CONCLUSIONS: Anal endosonography and fistulography with radiopaque markers are important complements to surgical exploration for investigating anal sepsis and may be of value to the surgeon in planning a therapeutic strategy.

Colonic total and segmental transit times in healthy Italian adults.

PURPOSE: This study was done to determine colonic transit times in healthy Italian adults. MATERIALS AND METHODS: Institutional review board approval and informed patient consent were obtained. Colonic segmental radiopaque markers were counted and transit times calculated in 36 healthy subjects studied using a technique involving daily radiopaque marker ingestion and single radiological visit, with oral administration of 8-10 ml of a thick barium paste as a colonic trace for the marker count. Two independent radiologists counted the marker twice. Observer agreement was assessed using comparison analysis. RESULTS: There was very good observer agreement for the segmental marker counts. The upper limit for colonic transit times was: 45.6 h in the colon as a whole, 31.2 h in the right colon, 19.2 h in the left colon and 16.8 h in the rectosigmoid. Colonic transit times were not gender-related. CONCLUSIONS: In healthy subjects, a barium trace affords optimal visibility of the different colonic segments, enabling accurate location of all markers and thus providing an anatomy-related, repeatable and reproducible fluoroscopic segmental marker count. We suggest that the reference values for normal colonic transit times could be adopted for Italian people irrespective of gender.

Set-up and statistical validation of a new scoring system for obstructed defaecation syndrome.

OBJECTIVE: There is no objective means to assess the obstructed defaecation syndrome (ODS), to allow evaluation of outcome or to compare the efficacy of treatment including surgery. The study aimed to validate a disease-specific index to quantify severity to allow assessment of the results of treatment in clinical trials, to permit comparison between them. METHOD: Seventy-six patients with ODS and 30 healthy controls entered the study after proctologic and ano-rectal physiological investigation. Hirschsprung's disease and slow transit constipation were excluded. An eight-item questionnaire with four or five possible answers was administered by two independent researchers at two different times. The ODS score was the sum of all points with a maximum possible of 31 points. Agreement between the two operators was evaluated by the Kappa coefficient for each single item. The coefficient of repeatability (CR) was assessed by the Bland and Altman plot. The internal consistency was evaluated by the Crohnbach-alpha test. A cluster analysis was carried out on each clinical finding. The Mann-Whitney U-test was used to compare median ODS score between patients and controls. RESULTS: The ODS score of the two operators was normally distributed and strongly correlated (r = 0.89). The correlation coefficient between the score assigned to each item by two operators ranged from 0.79 to 0.98. The degree of agreement between the operators was good and the two methods were reproducible (CR = 3.13). There was a significant difference between the mean ODS score for patients and controls (t = 20.70, P < 0.001). The Crohnbach alpha value for internal reliability was +0.513. Cluster analysis showed a different profile between cluster 1 (a nonhomogenous group including rectocoele, intussusception or perineal descent), and cluster 2 (pelvic dysynergia). CONCLUSION: The ODS score offers a validated severity of disease index in grading the severity of disease and monitoring the efficacy of therapy.

Reinterventions after complicated or failed stapled hemorrhoidopexy.

BACKGROUND: Stapled hemorrhoidopexy has become increasingly popular over the past five years, mainly because of the assumption that it is associated with less pain. However, persistent tags and recurrence might represent a problem, because piles are not excised and severe complications requiring surgery have been occasionally reported. The aim of the present study is to analyze the causes for and the outcome of reintervention following either severely complicated or failed stapled hemorrhoidopexy. METHODS: A total of 232 primary stapled hemorrhoidopexies and 65 reinterventions after stapled hemorrhoidopexy were performed by the authors in five centers devoted to colorectal surgery. Twelve patients of the latter group had the stapled hemorrhoidopexy performed in one of these centers. Thirty-five were males and 30 were females. The mean age was 50 (range, 29-81) years. In all cases the primary indication for stapled hemorrhoidopexy was either third-degree or fourth-degree symptomatic hemorrhoids. In all patients submitted to reoperation the diagnosis of either severely complicated or failed stapled hemorrhoidopexy was made. The clinical history of all of these patients was carefully studied and all underwent inspection, digital exploration, and proctoscopy. After the reintervention, proctoscopy was performed in 61 patients (92 percent) after a median follow-up of 5.5 (range, 1-36) months. RESULTS: Our reoperation rate after stapled hemorrhoidopexy was 11 percent. The most frequent indications for reintervention were persistent, severe anal pain (visual analog pain score higher than 7) in 29 patients (45 percent), severe postoperative bleeding in 20 (31 percent), anal fissure in 16 (21 percent), prolapsing piles in 12 (18 percent), rectal polyp in 11 (16 percent), anorectal sepsis in 11 (16 percent), and fecal incontinence in 7 (11 percent). Thirteen different types of reintervention were needed. Excisional hemorrhoidectomy, removal of staples, and fissurectomy and/or internal sphincterotomy were the most frequent operation (n = 41). A decrease in anal pain, as measured by visual analog pain score, was observed one month after reintervention, compared with that measured preoperatively (from 5.6 +/- 3.6 to 3.0 +/- 2.9) (P < 0.001). Bleeding requiring treatment occurred in six cases (10 percent), anal stricture requiring dilation occurred in three (5 percent), and fecal incontinence in three (5 percent). Proctoscopy showed no recurrences in 52 cases (80 percent) after the reintervention. CONCLUSION: Pain and bleeding mostly caused by piles, fissures, and retained staples were the most frequent causes for reoperation after stapled hemorrhoidopexy. Reintervention was associated with a high bleeding and soiling rate, but was effective in treating pain and other symptoms in the majority of patients. Because of the wide spectrum of different interventions required, a failed or complicated stapled hemorrhoidopexy might be better treated by an experienced colorectal surgeon.

Bleeding, incontinence, pain and constipation after STARR transanal double stapling rectotomy for obstructed defecation.

BACKGROUND: The STARR double stapling procedure (DSP), i. e. transanal anteroposterior rectotomy, has been recently reported as a low-morbidity and effective operation for the treatment of rectocele and internal rectal mucosal prolapse (R-IMP) causing obstructed defecation. We report the postoperative complications and recurrence of symptoms following this novel operation. PATIENTS AND METHODS: Fourteen chronically constipated women with RIMP, aged 36-72 years, presented with either severe complications or recurrence of symptoms following DSP performed by means of two circular staplers. All were followed for a median period of 12 months (range, 2-24) after DPS. RESULTS: Severe rectal bleeding occurred in two cases postoperatively. Persistent severe anal pain was reported by seven patients, all presenting with anxiety. Four of them were multiparous. Three patients had fecal incontinence, both had vaginal deliveries. R-IMP recurred in six, obstructed defecation in seven cases. Four patients needed reintervention, one for suturing the bleeding area, one excising the recurrent prolapse, one for colpocele and one for rectal stricture. Four patients required biofeedback training for non-relaxing puborectalis and two needed psychotherapy. CONCLUSION: Parity, spastic floor syndrome and psychoneurosis seem to be the risk factors predisposing to failure of DSP, which may be followed by severe complications and early recurrence of symptoms requiring reoperation.

Complications after stapled hemorrhoidectomy: can they be prevented?

Stapled hemorrhoidectomy (SH), a new approach to the treatment of hemorrhoids, removes a circumferential strip of mucosa about four centimeters above the dentate line. A review of 1,107 patients treated with SH from twelve Italian coloproctological centers has revealed a 15% (164/1,107) complication rate. Immediate complications (first week) were: severe pain in 5.0% of all patients, bleeding (4.2%), thrombosis (2.3%), urinary retention (1.5%), anastomotic dehiscence (0.5%), fissure (0.2%), perineal intramural hematoma (0.1%), and submucosal abscess (0.1%). Bleeding was treated surgically in 24%, with Foley insertion 15%; and by epinephrine infiltration in 2%; 53% of patients with bleeding received no treatment and 6% needed transfusion. One patient with anastomotic dehiscence needed pelvic drainage and colostomy formation. The most common complication after 1 week was recurrence of hemorrhoids in 2.3% of patients, severe pain (1.7%), stenosis (0.8%), fissure (0.6%), bleeding (0.5%), skin tag (0.5%), thrombosis (0.4%), papillary hypertrophy (0.3%) fecal urency (0.2%), staples problems (0.2%), gas flatus and fecal incontinence (0.2%), intramural abscess, partial dehiscence, mucosal septum and intussusception (each <0.1%). Recurrent hemorrhoids were treated by ligation in 40% and by Milligan-Morgan procedure in 32%. All hemorrhoidal thromboses were excised. Anal stenoses were treated by dilatation in 55% and by anoplasty in 45%. Fissure was treated by dilatation in 57%. Most complications (65%) occurred after the surgeon had more than 25 case experiences of stapled hemorrhoidectomy. The most common complication in the first 25 cases of the surgeon's experience was bleeding (48%). Even though SH appears to be promising, we feel that a multicenter randomized study with a long-term follow-up comparing SH and banding is necessary before recommending the procedure. Most complications can be avoided by respecting the rectal wall anatomy in the execution of the procedure.

Multicentre retrospective analysis of the outcome of artificial anal sphincter implantation for severe faecal incontinence.

BACKGROUND: A new prosthetic device, the Action artificial anal sphincter, has recently been introduced for treating severe faecal incontinence. The results of this procedure in 28 patients are presented. METHODS: The patients underwent operation for severe faecal incontinence in four Italian university hospitals and patients were reviewed after a median follow-up of 19 (range 7-41) months. RESULTS: Early infections occurred in four patients, requiring removal of the device in three. Dehiscence of the perineal wound occurred in nine patients. After activation of the device, the cuff had to be removed in a further four patients (for rectal erosion in two, anal pain in one and late infection in one). The cuff was accidentally broken in one patient. A new anal cuff was repositioned successfully in two patients. Overall, five patients had complete removal of the device and two removal of the cuff only. Twenty-one patients available for long-term evaluation had a major improvement in faecal continence. Median resting anal pressure increased from 27 mmHg before surgery to 32 mmHg after operation. Preoperative squeeze pressure was 42 mmHg while maximum postoperative anal pressure with the activated device was 67 mmHg. The median American Medical System incontinence score decreased significantly from 98.5 to 5.5 (P < 0.001). Similar figures were observed using the Continence Grading Scale (from 14.9 to 2.6; P < 0.001). Twelve patients developed symptoms of obstructed defaecation while two patients complained of anal pain. CONCLUSION: Improved continence was achieved after neosphincter implantation in three-quarters of the patients. Early infection and rectal erosion, together with difficulty in evacuating, are still major concerns with this technique.

Neuromodulation for fecal incontinence: outcome in 16 patients with definitive implant. The initial Italian Sacral Neurostimulation Group (GINS) experience.

PURPOSE: Sacral nerve modulation appears to offer a valid treatment option for some patients with fecal incontinence and functional defects of the internal anal sphincter or of the striated muscle. METHODS: Sixteen patients with fecal incontinence (4 males; mean age, 51.4 (range, 27-79) years) with intact or surgically repaired (n = 1) anal sphincter underwent permanent sacral nerve stimulation implant. Cause was traumatic in two patients, and associated disorders included scleroderma (2 patients) and spastic paraparesis (1 patient); eight (50 percent) of the patients also had urinary incontinence, and two (12.5 percent) had nonobstructive urinary retention. All patients were selected on the basis of positive findings from at least one peripheral nerve evaluation. The stimulating electrode was positioned in the S2 (1 patient), S3 (14 patients), or S4 (1 patient) sacral foramen. RESULTS: Mean follow-up was 15.5 (range, 3-45) months. Mean preimplant Williams score decreased from 4.1 +/- 0.9 (range, 2-5) to 1.25 +/- 0.5 (range, 1-2) (P = 0.01, Wilcoxon test), and the number of incontinence accidents for liquid or solid stool in 14 days decreased from 11.5 +/- 4.8 (range, 2-20) before implant to 0.6 +/- 0.9 (range, 0-2) at the last follow-up. Important manometric data were an increase in mean maximal pressure at rest of 37.7 +/- 14.9 mmHg (implantable pulse generator 49.1 +/- 18.7, P = 0.04) and in mean maximal pressure during squeeze (prestimulation 67.3 +/- 21.1 mmHg, implantable pulse generator 82.6 +/- 21.0, P = 0.09). CONCLUSIONS: Neuromodulation can be considered an option for fecal incontinence. However, an accurate clinical and instrumental evaluation and careful patient selection are required to optimize outcome.

[Sclerotherapy and elastic ligation of hemorrhoids]. / La scleroterapia e la legatura elastica delle emorroidi.

In the treatment of haemorrhoids all procedures may have good results, if indications are correct. Injection treatment has the best indication for I and II degree bleeding piles, the rubber band ligation for II and III degree piles; this procedure is very effective when associated to cryosurgery. All operations for haemorrhoids must be avoided in Crohn disease.

Does surgery resolve outlet obstruction from rectocele?

In order to ascertain whether plastic surgery for rectocele is of value in the treatment of outlet obstruction, a retrospective study was made of 21 women complaining of difficulty in expelling faeces: 13 patients (group A) underwent surgery with transanal longitudinal plication of the anterior rectal wall (Block's technique), and 8 patients (group B) had colpoperineoplasty which, in 2, was associated with bladder-neck suspension following the Raz-Peyrera technique for urinary incontinence. The mean follow-up was 24.2 +/- 18.7 and 36.8 +/- 17.8 months respectively. In 11 group A patients (80.9%) and 6 group B patients (75%) cure, or an improvement, was achieved. Of the remaining 4 patients (19%), recurrent rectocele was found in 2 (one group A and one group B) and intestinal transit time tests detected colonic constipation in one group A and in one group B patient. It is concluded that surgery can resolve outlet obstruction from rectocele, but Block's technique is preferable because it is more straight-forward and easier.

Does acetylsalicylic acid interfere with stimulated pancreatic secretion? An experimental study in the rat.

To evaluate the effect of the prostaglandin inhibitor acetylsalicylic acid (ASA) on rat exocrine pancreas secretion, three groups of rats were administered ASA by infusion: Groups 1-3, 50, 100, and 200 mg/kg body wt, respectively; Group 4 received saline. Twenty minutes later these ASA-pretreated groups were given intraarterial secretin (18 CU/kg) and cholecystokinin (CCK) (18 micrograms/kg). In an additional three groups of seven rats each, saline solution rather than secretin-CCK was given after ASA pretreatment. Pancreatic juice was collected every 10 min by means of a chronic pancreatic fistula. Bicarbonate and protein concentrations were measured and variations in outputs observed. No significant variations were found in the bicarbonate concentrations and outputs of rats with different types of pharmacological treatment, while protein concentrations and outputs were found to vary with time and type of experiment. There was, however, no interaction between these two variables. At lower ASA dosages, the bicarbonate and protein concentrations and outputs of secretin-CCK-stimulated rats were higher than the basal values and the levels of rats without hormonal stimulation. At higher dosages, no difference was found between the two groups. In conclusion, ASA seems to interfere with stimulated pancreatic exocrine secretion of proteins, even when its effect on bicarbonate concentration is factored in, and its effect seems to be present at the highest dosages considered in the study. Among the various hypotheses that may explain this phenomenon, an antagonizing effect of ASA on secretin-CCK action should be the first to be considered.

Can proctological procedures resolve perianal pruritus and mycosis? A prospective study of 23 cases.

Twenty-three patients with pruritus ani associated with anal mycosis underwent primary treatment of a concurrent anal disorder. The anal disorders included haemorrhoids (n = 9), fissure (n = 8), anal spasm without fissure (n = 5), and occult mucosal prolapse (n = 1). Pretreatment investigation of faeces for parasites was negative. The glucosal tolerance test and white blood cell count were normal in all cases. Culture of skin smears from the perianal region was positive for Candida only in 16 patients, Dermatophytes only in 6 and a combination of both in 1 patient. Following the appropriate proctological procedure, pruritus resolved or markedly improved in 20 patients. The remaining three patients required antifungal treatment with econazole. Two of these, however, continued to complain of pruritus. It is suggested that in patients with pruritus ani associated with perianal mycosis, antimycotic therapy should be used only if fungal infection persists after treatment of the underlying proctological disease.