Therapy for Unhealed Gastrocutaneous Fistulas in Rats as a Model for Analogous Healing of Persistent Skin Wounds and Persistent Gastric Ulcers: Stable Gastric Pentadecapeptide BPC 157, Atropine, Ranitidine, and Omeprazole

Objective This study focused on unhealed gastrocutaneous fistulas to resolve whether standard drugs that promote healing of gastric ulcers may simultaneously have the same effect on cutaneous wounds, and corticosteroid aggravation, and to demonstrate why peptides such as BPC 157 exhibit a greater healing effect. Therefore, with the fistulas therapy, we challenge the wound/growth factors theory of the analogous nonhealing of wounds and persistent gastric ulcers. Methods The healing rate of gastrocutaneous fistula in rat (2-mm-diameter stomach defect, 3-mm-diameter skin defect) validates macro/microscopically and biomechanically a direct skin wound/stomach ulcer relation, and identifies a potential therapy consisting of: (i) stable gastric pentadecapeptide BPC 157 [in drinking water (10 μg/kg) (12 ml/rat/day) or intraperitoneally (10 μg/kg, 10 ng/kg, 10 pg/kg)], (ii) atropine (10 mg/kg), ranitidine (50 mg/kg), and omeprazole (50 mg/kg), (iii) 6-alpha-methylprednisolone (1 mg/kg) [intraperitoneally, once daily, first application at 30 min following surgery; last 24 h before sacrifice (at postoperative days 1, 2, 3, 7, 14, and 21)]. Results Greater anti-ulcer potential and efficiency in wound healing compared with standard agents favor BPC 157, efficient in inflammatory bowel disease (PL-14736, Pliva), given in drinking water or intraperitoneally. Even after 6-alpha-methylprednisolone aggravation, BPC 157 promptly improves both skin and stomach mucosa healing, and closure of fistulas, with no leakage after up to 20 ml water intragastrically. Standard anti-ulcer agents, after a delay, improve firstly skin healing and then stomach mucosal healing, but not fistula leaking and bursting strength (except for atropine). Conclusion We conclude that BPC 157 may resolve analogous nonhealing of wounds and persistent gastric ulcers better than standard agents.     

Gastric Pentadecapeptide BPC 157 and Short Bowel Syndrome in Rats

The gastric pentadecapeptide BPC 157, which was shown to be safe as an antiulcer peptide in trials for inflammatory bowel disease (PL14736, Pliva), successfully healed intestinal anastomosis and fistula in rat. Therefore, we studied for 4 weeks rats with escalating short bowel syndrome and progressive weight loss after small bowel resection from fourth ileal artery cranially of ileocecal valve to 5 cm beneath pylorus. BPC 157 (10 μg/kg or 10 ng/kg) was given perorally, in drinking water (12 ml/rat/day) or intraperitoneally (once daily, first application 30 min following surgery, last 24 h before sacrifice). Postoperatively, features of increasingly exhausted presentation were: weight loss appearing immediately regardless of villus height, twofold increase in crypt depth and fourfold increase in muscle thickness within the first week, jejunal and ileal overdilation, and disturbed jejunum/ileum relation. In contrast, constant weight gain above preoperative values was observed immediately with BPC 157 therapy, both perorally and parenterally, and villus height, crypt depth, and muscle thickness [inner (circular) muscular layer] also increased, at 7, 14, 21, and 28 days. Moreover, rats treated with pentadecapeptide BPC 157 showed not different jejunal and ileal diameters, constant jejunum-to-ileum ratio, and increased anastomosis breaking strength. In conclusion, pentadecapeptide BPC 157 could be helpful to cure short bowel syndrome.     

Lower extremity free flap reconstruction outcomes using venous coupler

Background: Microvascular anastomotic coupling devices have been available to microsurgeons for over 20 years. Many studies have validated the efficacy of these devices for venous anastomosis. To date, there have been no large reports of their success in the anatomical region with the highest free flap failure rate, the lower extremity. Methods: A retrospective review of 67 consecutive patients who underwent lower extremity microvascular reconstruction performed from August 2003 to September 2010 was performed. Patient charts were reviewed for age, sex, medical comorbidities, etiology of defect, location of defect, flap type, anastomotic technique, complications, flap survival, and limb salvage outcome. Results: No patients returned to the operating room to have an arterial or venous anastomosis revised. Despite 100% vascular anastomosis patency rates in 67 consecutive lower extremity free flaps, flap survival rate was 95.5%. Total complication rate (13.4%) was due to two partial and one complete flap loss, three infections, two skin graft loses, and one hematoma. There were no intraoperative or perioperative complications involving the use of a microvascular anastomotic coupling device itself. Thirty‐day and long term limb salvage rate was 97% and 92.5%, respectively. Conclusion: Microvascular anastomotic coupling devices create effective venous anastomoses in lower extremity microvascular reconstruction. Thus, it presents an important tool in the armamentarium for lower extremity microsurgical reconstruction. © 2011 Wiley‐Liss, Inc. Microsurgery 2011.     

Characterisation of Twelve Newly Synthesised N-(substituted Phenyl)-2-chloroacetamides with QSAR Analysis and Antimicrobial Activity Tests

In this study we screened twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides for antimicrobial potential relying on quantitative structure-activity relationship (QSAR) analysis based on the available cheminformatics prediction models (Molinspiration, SwissADME, PreADMET, and PkcSM) and verified it through standard antimicrobial testing against Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Candida albicans. Our compounds met all the screening criteria of Lipinski’s rule of five (Ro5) as well as Veber’s and Egan’s methods for predicting biological activity. In antimicrobial activity tests, all chloroacetamides were effective against Gram-positive S. aureus and MRSA, less effective against the Gram-negative E. coli, and moderately effective against the yeast C. albicans. Our study confirmed that the biological activity of chloroacetamides varied with the position of substituents bound to the phenyl ring, which explains why some molecules were more effective against Gram-negative than Gram-positive bacteria or C. albicans. Bearing the halogenated p-substituted phenyl ring, N-(4-chlorophenyl), N-(4-fluorophenyl), and N-(3-bromophenyl) chloroacetamides were among the most active thanks to high lipophilicity, which allows them to pass rapidly through the phospholipid bilayer of the cell membrane. They are the most promising compounds for further investigation, particularly against Gram-positive bacteria and pathogenic yeasts.Key Words: N-substituted amides, antimicrobial potential, quantitative analysis of chemical structure and activity relationship     

Breast cancer patients with brain metastases or leptomeningeal disease: 10‐year results of a national cohort with validation of prognostic indexes

Development of brain metastasis (BM) and leptomeningeal (LM) disease in breast cancer (BC) patients indicates poor prognosis and impairs patients’ quality of life. Prognostic survival scores for BM can help predict expected survival in order to choose the most appropriate treatment. The aim of our study was to analyze national data for BC patients treated with radiation therapy for BM/LM disease and validate the applicability of different survival prognostic scores. We retrospectively evaluated medical records of 423 BC patients with BM/LM disease receiving radiation therapy between April 2005 and December 2015. Patients were classified by BC Recursive Partitioning Analysis (B‐RPA), Breast Graded Prognostic Assessment (Breast‐GPA), Modified Breast Graded Prognostic Assessment (MB‐GPA), and Simple Survival score for patients with BM from BC (SS‐BM). Overall survival (OS) was calculated from the development of BM/LM disease to death or last follow‐up date. After a median follow‐up of 7.5 years, the median OS was 6.9 months (95% CI 5.5‐7.8, range 0‐146.4) and 1‐ and 2‐year survival rates were 35% and 17%, respectively. Survival analysis showed significant differences in median OS regarding biologic subtypes (P < 0.0001), as follows: 3.2 (95% Confidence Interval (CI) 2.5‐3.9), 3.9 (95% CI 2.3‐5.6), 7.1 (95% CI 4.3‐9.8), 12.1 (95% CI 8.3‐15.9), and 15.4 (95% CI 8.8‐22.1) months for primary triple‐negative BC (TNBC), Luminal B HER2‐negative, Luminal A, HER2‐enriched, and Luminal B HER2‐positive tumors, respectively. Good Karnofsky Performance Status (KPS), single metastasis, and absence of LM or extracranial disease all demonstrated better OS in univariate and multivariate analysis. All four employed prognostic indexes provided good prognostic value in predicting survival. SS‐BM and MB‐GPA showed the best discriminating ability (Concordance indexes C were 0.768 and 0.738, respectively). This study presents one of the largest single‐institution series validating prognostic scores for BC patients with BM/LM. SS‐BM and MB‐GPA proved to be useful tools in the clinical decision‐making process.     

Fatal toxic epidermal necrolysis and severe granulocytopenia following therapy with cefuroxime

Toxic epidermal necrolysis (TEN) is one of the most threatening adverse reactions to various drugs. No case of concomitant occurrence TEN and severe granulocytopenia following the treatment with cefuroxime has been reported to date. Herein we present a case of TEN that developed eighteen days of the initiation of cefuroxime axetil therapy for urinary tract infection in a 73-year-old woman with chronic renal failure and no previous history of allergic diathesis. The condition was associated with severe granulocytopenia and followed by gastrointestinal hemorrhage, severe sepsis and multiple organ failure syndrome development. Despite intensive medical treatment the patient died. The present report underlines the potential of cefuroxime to simultaneously induce life threatening adverse effects such as TEN and severe granulocytopenia. Further on, because the patient was also taking furosemide for chronic renal failure, the possible unfavorable interactions between the two drugs could be hypothesized. Therefore, awareness of the possible drug interaction is necessary, especially when given in conditions of their altered pharmacokinetics as in case of chronic renal failure.     

Computer-assisted surgery and computer-assisted telesurgery in otorhinolaryngology

Surgical preparation is enhanced by the availability of computer-generated three-dimensional models that allow surgeons to explore the surgical field in various projections prior to an actual operation. In fact, with adequate computed tomography images, an entire operation can be simulated beforehand so that surgeons can plan the safest and most effective approach and be prepared to avoid or overcome obstacles during the actual procedure. Also, computer technology allows surgeons to conduct remote consultations and to even perform telesurgery--that is, to operate on a patient from a great distance. In this article, we describe our experience with computer-assisted local and remote endoscopic sinus surgery in Croatia.