Mitoxantrone in relapsing-remitting and rapidly progressive multiple sclerosis: Ten-year clinical outcomes post-treatment with mitoxantrone.

BACKGROUND: Mitoxantrone (MTX) has been used as an effective disease modifying treatment (DMT) in multiple sclerosis (MS). Evidence from studies demonstrates benefits of reduced relapse rates, MRI disease activity and disability progression in patients treated with MTX. While effective, MTX use has been limited due to potential adverse effects (AE) ranging from mild to potentially life-threatening AEs such as cardiotoxicity, bone marrow suppression and hematological malignancies. In this study we aimed to review the long-term clinical efficacy, tolerability, and AE profile of treatment with MTX in patients both with relapsing-remitting and rapidly progressive MS over a 10-year follow-up period. METHODS: We collected prospective data of 70 patients with relapsing-remitting and rapidly progressive MS treated with MTX and followed-up over a 10-year period. Expanded disability status scale (EDSS) scores and annualized relapse rates (ARR) were assessed 1 year prior to MTX treatment, and at different time points (1, 2, 3, 5 and 10 years) during follow-up. We recorded the time to first relapse and 0.5-point EDSS increase to assess efficacy. We also obtained frequency data on AEs and patients withdrawn from treatment. RESULTS: 70 patients were started on treatment with MTX with 53 patients (34 relapsing-remitting MS, 19 progressive disease) completing the course. Mean EDSS progressed from 5.5 to 6.5 in the relapsing-remitting group and 6.7 to 9.0 in the progressive group over the study period. ARR in the RRMS group reduced at all time points from 2.2 prior to MTX to 0.3 by year 10. We reported 3 significant AEs, one chicken pox and subsequent acute promyelocytic leukemia, one left ventricular systolic dysfunction, one pancytopenia. The commonest AE reported was nausea/vomiting in 28 (40%) patients. Seventeen patients (5 relapsing-remitting, 12 progressive disease) stopped treatment. In fifteen (87%) of these this was due to lack of efficacy. In the remaining 2 patients, MTX was stopped due to one patient developing chicken pox and the other developing first-degree heart block. CONCLUSION: Our study demonstrated that MTX is an effective disease modifying treatment for relapsing-remitting MS with a well-established risk profile. While MTX is now used less frequently, many MS and neurology services continue to follow-up patients who have been treated with MTX previously. Therefore, understanding the long-term effects risks and benefits remains relevant in this patient group. MTX is also a low-cost treatment in comparison to other high efficacy MS disease-modifying treatments and this may be beneficial in low resource settings.

The potential roles of strigolactones and brassinosteroids in the autoregulation of nodulation pathway.

BACKGROUND AND AIMS: The number of nodules formed on a legume root system is under the strict genetic control of the autoregulation of nodulation (AON) pathway. Plant hormones are thought to play a role in AON; however, the involvement of two hormones recently described as having a largely positive role in nodulation, strigolactones and brassinosteroids, has not been examined in the AON process. METHODS: A genetic approach was used to examine if strigolactones or brassinosteroids interact with the AON system in pea (Pisum sativum). Double mutants between shoot-acting (Psclv2, Psnark) and root-acting (Psrdn1) mutants of the AON pathway and strigolactone-deficient (Psccd8) or brassinosteroid-deficient (lk) mutants were generated and assessed for various aspects of nodulation. Strigolactone production by AON mutant roots was also investigated. KEY RESULTS: Supernodulation of the roots was observed in both brassinosteroid- and strigolactone-deficient AON double-mutant plants. This is despite the fact that the shoots of these plants displayed classic strigolactone-deficient (increased shoot branching) or brassinosteroid-deficient (extreme dwarf) phenotypes. No consistent effect of disruption of the AON pathway on strigolactone production was found, but root-acting Psrdn1 mutants did produce significantly more strigolactones. CONCLUSIONS: No evidence was found that strigolactones or brassinosteroids act downstream of the AON genes examined. While in pea the AON mutants are epistatic to brassinosteroid and strigolactone synthesis genes, we argue that these hormones are likely to act independently of the AON system, having a role in the promotion of nodule formation.

Auxin influences strigolactones in pea mycorrhizal symbiosis.

Hormone interactions are essential for the control of many developmental processes, including intracellular symbioses. The interaction between auxin and the new plant hormone strigolactone in the regulation of arbuscular mycorrhizal symbiosis was examined in one of the few auxin deficient mutants available in a mycorrhizal species, the auxin-deficient bsh mutant of pea (Pisum sativum). Mycorrhizal colonisation with the fungus Glomus intraradices was significantly reduced in the low auxin bsh mutant. The bsh mutant also exhibited a reduction in strigolactone exudation and the expression of a key strigolactone biosynthesis gene (PsCCD8). Strigolactone exudation was also reduced in wild type plants when the auxin content was reduced by stem girdling. Low strigolactone levels appear to be at least partially responsible for the reduced colonisation of the bsh mutant, as application of the synthetic strigolactone GR24 could partially rescue the mycorrhizal phenotype of bsh mutants. Data presented here indicates root auxin content was correlated with strigolactone exudation in both mutant and wild type plants. Mutant studies suggest that auxin may regulate early events in the formation of arbuscular mycorrhizal symbiosis by controlling strigolactone levels, both in the rhizosphere and possibly during early root colonisation.

Long-distance signaling and the control of branching in the rms1 mutant of pea.

The ramosus (rms) mutation (rms1) of pea (Pisum sativum) causes increased branching through modification of graft-transmissible signal(s) produced in rootstock and shoot. Additional grafting techniques have led us to propose that the novel signal regulated by Rms1 moves acropetally in shoots and acts as a branching inhibitor. Epicotyl interstock grafts showed that wild-type (WT) epicotyls grafted between rms1 scions and rootstocks can revert mutant scions to a WT non-branching phenotype. Mutant scions grafted together with mutant and WT rootstocks did not branch despite a contiguous mutant root-shoot system. The primary action of Rms1 is, therefore, unlikely to be to block transport of a branching stimulus from root to shoot. Rather, Rms1 may influence a long-distance signal that functions, directly or indirectly, as a branching inhibitor. It can be deduced that this signal moves acropetally in shoots because WT rootstocks inhibit branching in rms1 shoots, and although WT scions do not branch when grafted to mutant rootstocks, they do not inhibit branching in rms1 cotyledonary shoots growing from the same rootstocks. The acropetal direction of transport of the Rms1 signal supports previous evidence that the rms1 lesion is not in an auxin biosynthesis or transport pathway. The different branching phenotypes of WT and rms1 shoots growing from the same rms1 rootstock provides further evidence that the shoot has a major role in the regulation of branching and, moreover, that root-exported cytokinin is not the only graft-transmissible signal regulating branching in intact pea plants.

A prospective evaluation of surgeon performed sonography as a screening test in blunt abdominal trauma.

INTRODUCTION: Sonography has found a role in the evaluation of patients with abdominal injury. However, the accuracy of sonography as performed by non-radiologists remains controversial. This study aims to determine the accuracy of focused abdominal sonography for trauma when performed by surgeons. MATERIALS AND METHOD: Over a 1-year period, 48 patients with abdominal injury were initially evaluated for free intraperitoneal fluid by sonography. These tests were performed by 2 surgeons who had received instructions and performed a minimum of 30 examinations. Sonographic findings were then compared with other diagnostic modalities including computed tomography (CT) scan, diagnostic peritoneal lavage and exploratory laparotomy. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for sonography were found to be 0.86, 0.92, 0.89, 0.90 and 0.89, respectively. Although not specifically sought for, 2 cases of solid organ injury and 1 haemothorax, which were missed in initial examinations and X-rays, were detected on sonography. CONCLUSION: In conclusion, our initial experience suggests that local surgeons can perform a focused sonographic examination for trauma with acceptable accuracy. Although sonography lacks the sensitivity of diagnostic peritoneal lavage and the accuracy of CT scan, the diagnostic algorithm for abdominal trauma should include sonography as a screening test.

Bile duct injuries during laparoscopic cholecystectomy: a collective experience of four teaching hospitals and results of repair.

BACKGROUND: Laparoscopic cholecystectomy has been performed in Singapore since 1990 and, up until the end of 1997, a total of 4445 procedures had been performed in the four major teaching hospitals. Although bile duct injuries were thought to have increased following the introduction of laparoscopic cholecystectomy, there have been no reviews done on the incidence of these injuries in the Singapore context. METHODS: The present retrospective review aimed to audit the rate of bile duct injuries in the four major teaching hospitals in Singapore and to document the results of management of these injuries. RESULTS: Of the 4445 procedures performed, there were 19 (0.43%) cases of bile duct injuries. These involved the common hepatic duct (n = 8), common bile duct (n = 10), and the right hepatic duct (n = 1). The underlying gall bladder pathology included non-inflamed gall bladders (n = 10), acute cholecystitis (n = 4), Mirrizzi's syndrome (n = 3) and mucocele of the gall bladder (n = 2). Transection of the duct accounted for the majority of the injuries. Eleven bile duct injuries were identified at the time of operation. These were primarily repaired over a T tube (n = 4) or by a bilio-enteric bypass (n = 7). The remainder were diagnosed at a median of 7 days (range: 1-556 days) after surgery with a presentation of jaundice or pain. These were repaired by bilio-enteric anastomosis (n = 7) and closure over a T tube (n = 1). Three patients developed strictures subsequently, two following bilio-enteric repair after delayed diagnosis and one following immediate primary repair over a T tube. One patient developed intrahepatic stones and required a left lateral segmentectomy. CONCLUSIONS: The experience of a 0.43% bile duct injury rate is comparable to the best results from most large series in the West. Inflammation at Calot's triangle is an important associated factor for injury. Early recognition and prompt repair affords good results, and hepaticojejunostomy is recommended as the repair of choice.

Ambulatory anorectal surgery--is it feasible locally?

Currently, anorectal procedures are done in an inpatient setting in most local hospitals. This study examines the feasibility of performing these procedures in an outpatient setting. Patients (age range 16 to 65 years) with anorectal complaints requiring surgery were randomized into 2 groups of 40 patients each. Procedures performed included haemorrhoidectomy, fistulotomy, lateral sphincterectomy, excision of rectal polyps and examination under anaesthesia. The first group was managed in the conventional inpatient setting with regional anaesthesia. The second group was done on an ambulatory basis with local anal block. Intravenous and oral ketorolac was used for postoperative pain control and patients were discharged about 4 hours postoperatively. No complications were noted in the second group while the first group had 2 cases of acute urine retention requiring temporary catheterisation and 2 cases of significant bleeding requiring hospitalisation. Pain and satisfaction scores for both groups were similar. Anorectal surgery can be performed in an outpatient setting locally with safety and efficacy. The cost savings can be significant.

Abdominal surgery in human immunodeficiency virus (HIV) infected patients--early local experience.

The prevalence of human immunodeficiency virus (HIV) infection is increasing in Singapore. The surgical experience, however, remains limited. A retrospective review of 13 HIV-positive patients requiring abdominal surgery within Singapore was done. There were 4 females and 9 males with age ranging from 21 to 44 years. Operations included appendicectomy, colectomy, splenectomy, intestinal bypass, gastrostomy and exploratory laparotomy. Pathologic findings directly related to HIV infection were found in two-fifths (5 out of 13) of these patients. A low CD4+ count or signs of full-blown acquired immunodeficiency syndrome (AIDS) were not associated with a higher likelihood of HIV-related pathology; neither did it preclude a successful outcome. There were 2 early postoperative deaths, both with HIV-related pathology. Five of our patients who survived their abdominal surgery died on follow-up with a median survival of 17 months. In patients with typical surgical problems, e.g. appendicitis and torsion of the ovary, early surgery allows for rapid recovery similar to normal surgical patients. Care of these patients is best provided by surgeons with experience and interest in this condition together with infectious diseases physicians. Even palliative surgery offers a respite from acute and often severe problems and improves the quality of life significantly. Two patients with AIDS presented with sepsis and diffuse abdominal tenderness. Subsequent laparotomy revealed only primary bacterial peritonitis. For patients with AIDS and non-localizing abdominal signs, alternative non-invasive diagnostic modalities such as computed tomographic (CT) scan should be considered.

Evaluation of the Phene Plate generalized microplate for metabolic fingerprinting and for measuring fermentative capacity of mixed bacterial populations.

The Phene Plate (PhP) generalized microplate for metabolic fingerprinting and for measuring the fermentative capacity of intestinal bacteria was evaluated. Twelve bacterial species, representing those commonly found in the intestine of humans and animals were employed. Mixtures of bacteria were inoculated in duplicate onto the PhP microplates. Anaerobic conditions were achieved by either incubating the plates under nitrogen atmosphere or by covering the microplates with mineral oil before incubation. Different metabolic fingerprints based on the pattern of substrate utilization were obtained for each bacterial mixture. Metabolic responses of bacterial samples were similar under both anaerobic conditions although the rate of carbohydrate utilization was higher in plates covered with mineral oil. A fermentative capacity value based on the number and the degree of fermented carbohydrates was established for each mixture which differed as the composition of the mixture changed but in general it was higher in samples with more bacterial species. The PhP generalized microplate may thus be used for studying the functional status and metabolic potential of intestinal floras.

Case report of acute splenic and superior mesenteric vein thrombosis and its successful medical management.

We report a case of a 27-year-old pregnant patient who presented with severe colicky abdominal pain, diarrhoea and fever. She was initially treated for gastroenteritis. She later requested a termination of the pregnancy. Abdominal X-rays showed small bowel dilatation. A dynamic computed tomographic scan was performed and showed a splenic and superior mesenteric vein thrombosis. This was confirmed by colour duplex scanning and angiography. Anticoagulation with heparin was associated with dramatic relief of the symptoms and complete recanalisation of both veins. Surgical intervention was avoided.