C2 by-pass: Cross-talk between the complement classical and alternative pathways.

Several disorders associated with the total or partial absence of components of the human complement system are known. Deficiencies of classical pathway (CP) components are generally linked to systemic lupus erythematosus (SLE) or SLE-like syndromes. However, only approximately one-third of patients who lack C2 show mild symptoms of SLE. The relatively high frequency of homozygous C2 deficiency without or with minor disease manifestation suggests that there might be a compensatory mechanism which allows the activation of the CP of complement without the absolute requirement of C2. In this study we show that factor B (FB), the C2 homologue of the alternative pathway (AP) of complement, can substitute for C2. This was confirmed by using C4b as immobilised ligand and FB as analyte in Surface Plasmon Resonance (BIACORE). C2 binding to the immobilised C3b-like molecule C3(CH3NH2) was not seen. The estimated binding constant for C4bB complex formation was 2.00 * 10-5 [M]. We were further able to demonstrate that C4b supports the cleavage of Factor B by Factor D. Finally, cleavage of 125I-C3 by C4bBb was evaluated and gave strong evidence that the "hybrid" convertase C4bBb can cleave and activate C3 in vitro. Cleavage activity is very low, but consistent with some of the "C2-bypass" observations of others.

Multiple sclerosis and neuromyelitis optica spectrum disorders in Malaysia: A comparison in different ethnic groups.

We performed a retrospective observational analytical study looking at the frequencies and characteristics of multiple sclerosis(MS) and neuromyelitis optica spectrum disorders(NMOSD) in consecutive patients with idiopathic inflammatory demyelinating disease (IIDDs) attending three centers (2009-2017). Of 523 patients with IIDDs, there were 173 patients with NMOSD and 230 patients with MS. The percentage of NMOSD: IIDDs was 33%. The percentage of NMOSD:Total MS and NMOSD cohort was 43%. Of 141 seropositive NMOSD patients, 134(95%) were from the three main ethnic groups. The percentage of seropositive NMOSD to IIDDs and to combined MS and NMOSD was 26.9% and 35% respectively. Ratios of MS to NMOSD were nearly equal at 1.3 to 1.0, reinforcing the high ratio of NMOSD to MS in Asia. Nearly half of the Chinese cohort were seropositive ie; 71/141 (50%) with the remainder being Malays; 56/141 (39.7%) and Indians; 7/141 (5%). Amongst the other indigenous groups seropositivity was seen in 2 each of Iban, Bajau, Kadazan descent as well as one of Bidayuh origin. Comparatively, seropositivity in NMOSD is commoner amongst the Chinese compared to the Malays (p ≤ 0.005) and Indians, p ≤ 0.05 with ratios as high as 10:1. In the MS group of 230 subjects, 123(53.5%) were Malays (ratio of MS:NMOSD of 2:1), 41(17.8%) were Chinese, (ratio of MS:NMOSD of 0.5:1.0) and 54 (23.5%)were Indians (ratios of MS:NMOSD of 5:1 amongst the Indians). The remainder from East Malaysia were made up of 2 each of Kadazans, Ibans and Bajaus including 3 each of Bidayuh and Eurasian descent. Comparatively, in the NMOSD and MS cohorts a female preponderance was noted more so amongst Chinese NMOSD patients, with rare familial occurrence in both but more in Malay MS/NMOSD patients. This study also highlighted some of the inter-ethnic differences in presentation of MS and NMOSD amongst the 3 main ethnic races in Malaysia and confirms indigenous races having MS/NMOSD which needs further research. It also reviewed current literature on similar inter-ethnic differences world wide. To conclude, MS and NMOSD are the commonest demyelinating diseases seen in Malaysia with interesting inter-ethnic differences and similarities.

Complement research in the 18th-21st centuries: Progress comes with new technology.

The complement system has been studied for about 120 years. Progress in defining this large and complex system has been dependent on the research technologies available, but since the introduction of protein chromatography, electrophoresis, and antibody-based assay methods in the 1950s and 60s, and sequencing of proteins and DNA in the 70s and 80s, there has been very rapid accumulation of data. With more recent improvements in 3D structure determination (nmr and X-ray crystallography), the structures of most of the complement proteins have now been solved. Complement research since 1990 has been greatly stimulated by the discoveries of the multiple proteins in the lectin pathway, the strong association of Factor H, C3, Factor B allelic variants with adult macular degeneration and atypical haemolytic uremic syndrome, and the introduction of the anti-C5 monoclonal antibody as a therapy for paroxysmal nocturnal hemoglobinuria and atypical haemolytic uremic syndrome. Potential new roles for complement in tissue development and the search for novel therapeutics suggest a very active future for complement research.

Establishment of lipiodol as a fertility treatment - prospective study of the complete innovative treatment data set.

BACKGROUND: Our randomised controlled trial (RCT) found that a hysterosalpingogram (HSG) with the oil-soluble contrast medium (OSCM) lipiodol improves pregnancy rates amongst couples with unexplained and endometriosis-related infertility. These results were supported by the findings of our observational study of the first 100 women to undergo the procedure after it was offered as an innovative treatment in New Zealand from September 2003. AIM: To further assess the safety and efficacy of lipiodol procedures and present together the complete data set of the procedures performed in our RCT and those performed as innovative procedures (n = 296) prior to it being offered as a standard fertility treatment. METHODS: Women with infertility underwent a therapeutic lipiodol procedure by HSG technique with fluoroscopy X-ray screening. Primary outcomes were clinical pregnancy within six months of the procedure and live birth. RESULTS: The overall pregnancy rate for the 296 women was 40.2%. The live birth/ongoing pregnancy rate was 31.4%. The pregnancy rates for women under the age of 40 with endometriosis and unexplained infertility were 51.1 and 31.4%, respectively. CONCLUSION: Lipiodol can now be considered a standard treatment for both unexplained and endometriosis-related infertility. The precise mechanism behind the fertility-enhancing effect of lipiodol has yet to be elucidated. This study supports a mechanism of effect on the endometrium with possible enhanced receptivity of the endometrium to embryo implantation.

Core temperature falls during laparotomy in infants with necrotizing enterocolitis.

AIM OF THE STUDY: Intraoperative hypothermia may have a detrimental clinical effect. Preterm infants undergoing laparotomy for necrotizing enterocolitis (NEC) are particularly at risk. We investigated the relationship between intraoperative temperature and morbidity and outcome in infants with NEC. METHODS: A review of all laparotomies for NEC (n = 82, 69 infants) performed between Jan 2008 and Jan 2011 in our institution was done. Relationships between intraoperative temperature and intra- and postoperative fluid and blood product requirements, postoperative clinical status (sequential organ failure assessment [SOFA] score) and outcome were determined. Data (mean [range]) were compared using paired t-test and regression analysis. RESULTS: Data were available for 52 laparotomies (49 infants). The lowest intraoperative core temperature was significantly lower than the preoperative temperature (peri-op 34.9 °C [31.5-37.0] vs. pre-op 37.0 °C [35.8-38.0]; p < 0.0001). There was a statistically significant inverse relationship between mean intraoperative temperature and intraoperative blood transfusion requirement (p = 0.01). There were no statistically significant relationships between intraoperative temperature and other blood product or volume requirements, postoperative infective complications, change in SOFA score following surgery, length of stay, or mortality. CONCLUSIONS: During laparotomy for NEC, there is a significant and profound drop in core temperature. The effect of this on short-term morbidity and long-term outcome (e.g., neurodevelopment) warrants further investigation.

The changing trend of diverticular disease in a developing nation.

AIM: Left-sided diverticular disease (LDD) is associated with reduced dietary intake, whereas right-sided diverticular disease (RDD) is more common amongst Oriental populations. We aimed to determine whether the prevalence, site and distribution of diverticular disease in our Oriental population has changed over the past two decades. METHOD: A total of 1663 barium enema studies performed between January 2001 and August 2002 were reviewed retrospectively. The site of disease was correlated with age, gender and ethnicity of the patient. RESULTS: Forty-five per cent of patients in the study population had diverticular disease. Older patients were more likely to have LDD, whereas the Chinese ethnic group was more likely to have RDD. Right-sided diverticular disease peaks at in the sixth decade, while for LDD this occurred in the seventh and eighth decades. Right-sided diverticular disease was more common in all age groups overall. When compared with two barium enema studies carried out in Singapore two decades earlier, there was a statistically significant increase in the incidence of RDD and LDD. CONCLUSION: There is a positive association of RDD and LDD with Chinese race and increasing age. There is an increasing incidence of both LDD and RDD compared with two decades previously.

Chronic anastomotic sinus after low anterior resection: when can the defunctioning stoma be reversed?

AIM: Anastomotic leakage after low anterior resection may incompletely resolve, resulting in sinus tracts that persist on repeated contrast studies. This case series evaluated the factors that may contribute to sinus healing or to safe reversal of the defunctioning ileostomy. METHOD: All patients (n = 8) who developed an anastomotic sinus after low anterior resection over an 8-year period were identified from a prospective database. RESULTS: All patients had been treated with low anterior resections with defunctioning stomas for rectal carcinoma [median follow up 43.5 (13-84) months]. Two patients with an unhealed subclinical leak had the stoma reversed successfully. Of the six patients with clinical leakage, two healed spontaneously, one healed after application of fibrin glue, one developed an anastomotic stricture that was successfully treated by dilatation with subsequent stoma reversal, and one developed recurrent cancer and was not reversed. One patient underwent reversal, despite persistence of the sinus, followed by rectal perforation requiring laparotomy and faecal diversion. Bowel function was satisfactory where the sinus healed spontaneously, but poor where reversal was carried out without sinus healing. CONCLUSION: Tracks that persist for longer than 1 year are unlikely to heal, but the stoma can be reversed if there had been a subclinical leak previously. A persistent anastomotic sinus leading to a cavity may not be suitable for stoma closure.

Initial outcomes from universal newborn hearing screening in Avon.

OBJECTIVE: The Avon Area Health Authority was a first-phase site for introduction of universal newborn screening in the UK. The aims of this study were: to review the programme's results to date; to assess the impact screening would have on other services (e.g. the cochlear implant programme); and to assess the longer term outcome for children identified by the screening programme. PATIENTS: All children identified by the Avon universal newborn hearing screening programme between April 2002 and July 2006. RESULTS: Fifty-four children with a bilateral hearing impairment of worse than 40 dBHL were identified from a screened population of approximately 44 000. Nine of these children were put forward for cochlear implantation, and seven had been implanted at the time of writing. Thirteen of these children were identified with possible auditory neuropathy or dys-synchrony. All the newborn hearing screening programme criteria assessed were met. CONCLUSIONS: The screening programme was effective. Some areas may need review in order to optimise patient care.

Long-term outcome of children undergoing surgery for suspected perilymph fistula.

UNLABELLED: A number of authors have suggested that surgery for suspected perilymph fistula is effective in preventing deterioration of hearing and in improving hearing in some cases in the short term. We present long-term hearing outcome data from 35 children who underwent exploration for presumed perilymph fistula at The Children's Hospital, Sydney, Australia, between 1985 and 1992. METHODS: The pre-operative audiological data (mean of 500, 1000, 2000 and 4000 Hz results) were compared with the most recently available data (range two to 15 years) and the six-month post-operative data. RESULTS: The short-term results showed no significant change in hearing at six months, with a subsequent, statistically significant progression of hearing loss in both operated and non-operated ears (Wilcoxon signed rank test: operated ear, p < 0.017; non-operated ear, p < 0.009). CONCLUSION: In this case series, exploratory surgery for correction of suspected perilymph fistula did not prevent progression of long-term hearing loss.

Resistance of the Echinococcus granulosus cyst wall to complement activation: analysis of the role of InsP6 deposits.

The larva of the cestode Echinococcus granulosus (hydatid cyst) is protected by the acellular laminated layer (LL). The mechanisms that make this thick coat a poor activator of host complement are incompletely understood. The structure binds, through unknown motifs, the host regulator of the alternative complement pathway (ACP), factor H. A second potential mechanism of ACP regulation, the inhibition of factor B activation, was detected in assays employing purified components (Immunopharmacology 42 : 91). The inhibitor was subsequently identified as myo-inositol hexakisphosphate (InsP(6)), which in the form of nano-deposits is a major component of the LL (Biochem J 362 : 297; J Cell Biochem 93 : 1272; FEBS J 273 : 3192). In this report we show that colloidal InsP(6 )solids inhibit factor B activation, through adsorption and associated impairment of C3b binding. However, this interaction is not relevant in the presence of serum proteins. In serum, InsP(6) deposits instead bind C1q, and initiate complement activation. This activation is curtailed through efficient C3b inactivation, previously shown to be entirely factor H-dependent, and now observed to be independent of the InsP(6) deposits. Therefore the complement resistance of the LL must be based on functional factor H binding sites present on the mucin-based meshwork that is its other major constituent.

Efficacy of Gyrus diego microdissector at varying oscillation speeds.

OBJECTIVE: To determine the efficacy of the Gyrus diego microdissector at increasing oscillation speeds, using an in vitro tissue model. BACKGROUND: It had not previously been established whether microdissectors were more efficient at higher or lower speeds. METHODS: We investigated the effect of varying microdissector oscillation speeds on the weight of material aspirated in a given time. A 4 mm straight blade was used with constant suction strength. Jelly and liver were used to simulate polyps and muscle plus connective tissue, respectively. Water was used as a control. Repeat readings were taken at speeds of 1000, 2000, 3000, 4000 and 5000 rpm. Data were analysed using linear bivariate regression. RESULTS: The results showed significant linear trends in the cases of liver and jelly, with faster cutter speeds being associated with higher aspiration rates. CONCLUSION: These results suggest that microdissector efficacy increases with speed, up to 5000 rpm.

Otolaryngological requirements for recreational self-contained underwater breathing apparatus (SCUBA) diving.

Recreational self-contained underwater breathing apparatus (SCUBA) diving continues to grow in popularity. Medical requirements to be 'fit to dive' vary throughout the world, from self-certification to a full medical examination prior to training. This review discusses the relative merits of the most commonly used guidelines for recreational SCUBA diving, with reference to common diving-related otorhinolaryngological conditions. Areas of controversy, such as fitness to dive after rhinological and otological surgery, are discussed. The authors suggest that a unified approach from the various recreational SCUBA diving organizations involved would aid in clarification for divers and physicians alike. The difficulties in achieving such a unified approach, however, should not be underestimated.

Severe fibrosis in hepatitis C virus-infected patients is associated with increased activity of the mannan-binding lectin (MBL)/MBL-associated serine protease 1 (MASP-1) complex.

Mannan-binding lectin (MBL) binds microorganisms via interactions with glycans on the target surface. Bound MBL subsequently activates MBL-associated serine protease proenzymes (MASPs). A role for MBL in hepatitis C virus (HCV) infection had been indicated by previous studies examining MBL levels and polymorphisms in relation to disease progression and response to treatment. We undertook this study to investigate a possible relationship between disease progression and functional MBL/MASP-1 complex activity. A functional assay for MBL/MASP-1 complex activity was employed to examine serum samples from patients with chronic HCV infection, non-HCV liver disease and healthy controls. Intrapatient consistency of MBL/MASP-1 complex activity levels was assessed in sequential samples from a subgroup of patients. Median values of MBL/MASP-1 complex activity were higher in sera from patients with liver disease compared with healthy controls. MBL/MASP-1 complex activity levels correlate with severity of fibrosis after adjusting for confounding factors (P = 0.003). MBL/MASP-1 complex activity was associated more significantly with fibrosis than was MBL concentration. The potential role of MBL/MASP-1 complex activity in disease progression is worthy of further study to investigate possible mechanistic links.

Prospective randomized, double-blind, placebo-controlled study of pre- and postoperative administration of a COX-2-specific inhibitor as opioid-sparing analgesia in major colorectal surgery.

PURPOSE: To demonstrate the opioid-sparing effect and reduction in postoperative ileus obtained with valdecoxib 40 mg administered pre- and postoperatively in patients undergoing colorectal resection. METHODS: Patients for elective colorectal resection from December 2002 to June 2004 were randomized to receive either valdecoxib or placebo with standard patient-controlled analgesia (PCA) morphine. In the study arm, the first dose of valdecoxib 40 mg was administered orally as close as possible to 1 h prior to the start of surgery. Each subsequent dose was administered at 24-h intervals up to 120 h. Patients in the control arm were served placebos at the same time-points. RESULTS: Forty patients were enrolled in the study arm and 39 (excluding one protocol violation) in the control arm. The groups were comparable in age, sex, American Society of Anesthesiology status, body mass index, incision length, and duration and types of operations. Mean PCA doses at 12 and 24 h were 18.6 and 28.3 mg in the study arm vs 26.2 and 41.2 mg in controls, representing a one-third opioid reduction. Bowel sound and movement first appeared at medians of 12 and 72 h in the study arm vs 24 and 84 h, respectively, in controls (P < 0.05). Tolerance of solid diet was at a median of 60 h and discharge at a median of 4 days in the study arm vs 72 h and 6 days in controls (P < 0.05 and P < 0.01, respectively). Seven (18%) morbidities occurred in the control vs six (15%) in the study arm. CONCLUSIONS: Patients treated with a cyclo-oxygenase 2-specific inhibitor have a shorter recovery time when compared with patients on a standard postoperative PCA morphine-only regimen after colorectal resection.

[Circulating immune complexes in families with positive history of ischemic stroke].

The concentrations and protein composition of immune complexes circulating in the blood of patients with residuals of ischemic stroke and their healthy relatives from families with positive history of stroke have been determined. The data obtained have been compared with the results of our previous study on determination of concentration and protein composition of immune complexes circulating in the blood of patients with acute ischemic stroke and healthy subjects. Basing on the results obtained we conclude that the elevated level of immune complexes in the blood of patients with residuals of stroke is not genetically determined but rather reflects alterations developing as the result of previous stroke. However, the protein composition of the immune complexes, particularly the presence of C-reactive protein, may, to a certain degree, reflect genetic predisposition to stroke.

Discrete MBL-MASP complexes show wide inter-individual variability in concentration: data from UK vs Armenian populations.

Mannan-binding lectin (MBL) circulates in plasma in complex with MBL-associated serine proteases (MASP) -1, -2 and -3 and a smaller component, MAp19. When MBL binds to the surface of foreign material (microorganisms), MASP-1, -2, -3 are activated. MASP-2 then activates the complement system. MASP-1 and -3 may activate other (unidentified) systems. MBL levels, MBL-bound MASP-1 and MBL-bound MASP-2 activities have been evaluated in healthy individuals from UK and Armenian populations. MBL-bound MASP-2 activity declines in aging (P<0.04). MBL correlates with smoking (P<0.02). There were significant differences between the two populations in MBL-bound MASP-1 activity and in MBL, but no difference in MBL-bound MASP-2 activity. When MASP activities were normalised to MBL (i.e. MASP-1 activity/MBL, MASP-2 activity/MBL), normalised MASP-2 activity in UK individuals was more than 2 fold higher than in Armenians. The difference in normalised MASP-2 activity level between these two Caucasoid populations, suggests that concentration of the MBL-(MASP-2) complex, and therefore the function of activating complement, depends not only on the quantity of MBL in serum and its oligomeric state, but also on the quantity of MASP-2 in serum. It is likely that in individuals with high MBL concentration there is excess free MBL not occupied by MASPs, particularly not by MASP-2.

Primary retroperitoneal mucinous cystadenocarcinoma in a male patient.

Primary retroperitoneal mucinous cystadenocarcinomas (PRMCs) are rare. This is the first reported case in the literature in English of PRMC in a man. The 64-year-old man presented with a large retroperitoneal cystic tumour measuring 24 x 20 x 16 cm3, which was removed intact. Areas ranging from a benign mucinous cyst to borderline mucinous tumour to mucinous cystadenocarcinoma were observed on microscopy. Strong patchy staining for cytokeratins 7 and 20 and strong diffuse staining for MUC2 and MUC5AC core peptides, similar to staining patterns in ovarian mucinous tumours, were shown in the benign and atypical epithelium. Staining for CA19.9 and carcinoembryonic antigen was also shown by both components. The theory of its origin from the mucinous metaplasia of peritoneal (mesothelial) inclusion cysts, rather than from ectopic ovarian tissue or ovarian teratomas, is supported by the occurrence of such a tumour in a male patient.

Collectins and host defence.

The collectins are a small family of soluble oligomeric proteins containing collagenous regions and C-type lectin domains. They are related in structure and function to complement protein C1q, and to H-, L- and M-ficolins. In humans, the collectins mannose-binding lectin (MBL) and surfactant proteins A and D (SP-A, SP-D) have important roles in innate immunity. MBL occurs mainly in blood plasma and in the upper respiratory tract. It binds to neutral sugar arrays on microorganisms and acts as an opsonin either directly (by binding to cell-surface calreticulin) or indirectly by activating complement. MBL circulates in complex with any of three proteases, named MBL-associated serine proteases (MASPs)-1, -2 and -3. MBL-MASP-2 complexes activate complement, but the role of MBL-MASP-1 and MBL-MASP-3 complexes is not yet known. MBL deficiency occurs at high frequency, and is associated with susceptibility to infection, particularly in infants. SP-A and SP-D are most abundant in the lungs, and also bind to microorganisms and inhaled particulates, mainly by lectin-sugar interactions. They do not activate complement, but act as opsonins and agglutinators, and have additional effects on cellular regulation. Mice deficient in SP-A or SP-D are susceptible to lung infections, and SP-D-deficient mice develop an emphysema-like condition.

Use of a ProSeal laryngeal mask airway and a Ravussin cricothyroidotomy needle in the management of laryngeal and subglottic stenosis causing upper airway obstruction.

We report the successful use of a ProSeal laryngeal mask airway (PLMA) as a dedicated airway to allow fibre-optic inspection and passage through a tightly stenosed glottic and subglottic lesion, before fibre-optic-guided transtracheal placement of a Ravussin needle and jet ventilation. The described technique avoided both tracheostomy and the potential of 'seeding' the tumour by passage of the needle through the mass. The PLMA may be a useful 'dedicated airway' and has several advantages over the classic LMA(double dagger) and intubating LMA when used for this purpose. These include improved airway seal and reduced risk of aspiration. Four other cases of use of the PLMA as a dedicated airway during management of difficult airways are discussed. double daggerLMA is the property of Intavent Ltd.

[Concentration and protein composition of circulating immune complexes in the blood of patients with schizophrenia and subjects with positive familial history of disease].

A comparative study of blood serum concentrations and pathogenic properties of circulating immune complexes (CIC), along with identification of their protein composition, was conducted in 45 patients with schizophrenia, 15 their healthy relatives and 39 normal controls. In patients and their relatives, mean concentration of small CIC was within the normal range, while concentrations of giant, large and middle CIC were higher than those of the controls (p<0.001). Over 80% of schizophrenic patients and their relatives had pathogenic immune complexes in the circulation. Clinical and immunologic analysis of patients with schizophrenia revealed a correlation between the illness duration and CIC concentration for all sizes. Smokers had significantly lower levels of small CIC comparing to non-smokers. Determination of CIC composition in patients and relatives revealed a presence of specific proteins in the immune complexes with molecular weights of 36 and 25 kDa. The results suggest genetic determination of autoimmune processes in schizophrenia.