Unoperated severe aortic stenosis: decision making in an adult UK-based population.

INTRODUCTION: Severe symptomatic aortic stenosis is associated with a poor prognosis, with most patients dying 2-3 years after diagnosis. We analysed the proportion of patients with severe aortic stenosis not referred for aortic valve replacement (AVR) in a UK-based population and the clinical factors contributing to this. METHODS: Retrospective analysis of patients with echocardiographic evidence of severe aortic stenosis was performed at a university teaching hospital. RESULTS: A total of 178 consecutive patients with severe aortic stenosis (AVA: <1 cm(2), mean pressure gradient: ≥40 mmHg, or visually severe on echocardiography) were included in the study. Eighty-three patients did not have AVR (95% confidence interval: 39-54%). The cohort included 146 symptomatic patients (82%) and 32 (18%) who were asymptomatic. The most common reason for non-referral in symptomatic patients was 'high operative risk' and in asymptomatic patients 'no symptoms'. Of the patients who did not have AVR, only 19% (n=16) were referred for a surgical opinion. None of the patients in the asymptomatic group underwent echocardiographic stress imaging. The thirty-day operative mortality rate in the AVR group was 2.3%. Symptomatic patients who underwent AVR had superior survival, even after adjusting for co-morbidities (p<0.001). CONCLUSIONS: A considerable proportion of patients with severe aortic stenosis are not referred for surgery although they have a clear indication for AVR. Patients are often estimated as being too high risk or having prohibitive co-morbidities. Among asymptomatic patients, stress imaging was rarely used despite its useful role prognostically and in deciding the best time for intervention.

Virulence potential of Group A streptococci isolated from throat cultures of children from north India.

BACKGROUND & OBJECTIVES: Rheumatic fever (RF)/rheumatic heart disease (RHD) caused by Group A streptococcus (GAS) are more prevalent in north India as compared to the western world, where invasive diseases are common. This could be due to variation in the virulence of GAS in different geographic locations. Hence, we studied the virulence potential of GAS isolated from the throat of children from north India. METHODS: Fifty GAS isolated consecutively, from children with mild pharyngitis (20), severe pharyngitis (24) and asymptomatic pharyngeal carriers (6), were characterized by emm typing and opacity factor (OF). Adherence and internalization of GAS in HEp-2 cells and opsonophagocytosis in convalescent serum samples were studied. RESULTS: Twenty emm types, six sequence types, and one non-typeable GAS were circulating in the community. emm type 74, 11, 68, StI129 and NS292 were most prevalent. Twenty seven (54%) GAS isolates were OF negative. Sixty five per cent of the most prevalent emm types were OF negative indicating their rheumatogenic potential. Adhesion of GAS ranged from 0.1 to 100 per cent. Forty eight per cent of GAS were highly adherent. Invasion of GAS in HEp-2 cells ranged between 0 to 30 per cent. Only 20 per cent isolates exhibited highest invasion. GAS were opsonophagocytosed with highly divergent efficiency ranging from 0 to 91.7 per cent. Nineteen GAS were not opsonophagocytosed and 15 multiplied during the assay. Isolates of the same emm type also varied in their virulence potential. INTERPRETATION & CONCLUSIONS: GAS isolates from the throat of children from north India belonged to several emm types, majority were OF negative, excellent adherents but poor invaders. This explains why throat infections in these children tend to lead to ARF/RHD rather than invasive diseases. A few isolates exhibiting high invasion efficiency indicate that GAS throat cultures can also lead to invasive diseases.

Group A Streptococcus virulence factors genes in north India & their association with emm type in pharyngitis.

BACKGROUND & OBJECTIVES: Group A streptococcal (GAS) pharyngitis, especially among children, leads to high prevalence of rheumatic fever (RF)/rheumatic heart disease (RHD) in India, as compared to the western world where invasive diseases are common. GAS encodes numerous virulence factors that cause diseases by exhibiting extraordinary biological diversity. Hence, we studied the virulence factors genes of GAS isolated from the throat of children with pharyngitis and also asymptomatic carriers. METHODS: Fifty GAS isolates cultured from throats of north Indian children aged 5-15 yr with mild pharyngitis (20), severe pharyngitis (24) and asymptomatic pharyngeal carriers (6), during 2000-2003 along with reference M1 strain were emm typed and characterized for virulence factors genes by PCR. The presence of virulence factors was also checked for their association with emm type in pharyngitis. RESULTS: Twenty emm types, six sequence types, and one non-typeable strain were found circulating in north India. The five most prevalent types were emm 74 (12%), 11 & StI129 (8% each) and emm 68 and NS292 (6% each). The spe B gene was found to be significantly higher (P=0.0007) in opacity factor (OF) negative isolates. emm 3, 11, 77, 86, 87, 109 and StI129 showed maximum virulence factors genes. INTERPRETATION & CONCLUSIONS: GAS isolates collected from throats of children from north India possess highly virulent antigens. This study also supports concept of isolate-associated virulence rather than type relatedness.

Use of Contegra conduit reinforced with Goretex as a modified left Blalock-Taussig shunt.

This is the first report of the construction of a modified Blalock-Taussig shunt using a Contegra conduit reinforced with Goretex in a 4-year-old boy. The patient had a complex cardiac history with a primary diagnosis of pulmonary atresia, hypoplastic right ventricle (RV) and RV-coronary artery fistula.

Unidentified retained inferior vena cava myxoma detected by intra-operative trans-oesophageal echocardiography.

We report a unilateral right atrial familial myxoma with a multicentric nature discovered during cardiac surgery. After the patient was weaned off cardiopulmonary bypass, an inferior vena cava myxoma was discovered with intra-operative trans-oesophageal echocardiogram (TOE) which had been missed preoperatively and during surgery.

Induced sputum nitrites correlate with FEV1 in children with cystic fibrosis.

AIM: To determine the difference in the levels of nitrites in induced sputum of children with cystic fibrosis (CF) and controls. Furthermore, to evaluate the association between induced sputum nitrites and lung function in children with CF. METHODS: Nitrites, cell differentials, white blood cell count, were estimated in induced sputum of 20 children with CF and 10 age-matched healthy controls. Nitrites in induced sputum samples were measured using the Greiss assay. Lung function was ascertained by spirometry. RESULTS: We observed high levels of nitrites in CF (184.8 +/- 11.07 microM/L) versus controls (56.4 +/- 5.7 microM/L) (p < 0.01). A positive correlation between neturophil percent and nitrites, white blood cell count and nitrites (p < 0.05) in children with CF was observed. Sputum nitrites correlated negatively with FEV(1) (p < 0.05) in children with CF. CONCLUSION: Induced sputum nitrite could serve as a useful non invasive marker for assessing the degree of inflammation in the airways of children with CF.

Epidemiology of group A streptococcal pharyngitis & impetigo: a cross-sectional & follow up study in a rural community of northern India.

BACKGROUND & OBJECTIVE: Group A streptococcus (GAS) causes a wide array of human diseases. Epidemiological picture of streptococcal infection in India is not complete. Hence, disease burden due to GAS in 5-15 yr old school children in northern India was studied and emm typing of GAS isolates was carried out to help in designing prevention strategies. METHODS: A cross-sectional survey was carried out among 4249 school children (5-15 yr) from Raipur Rani Block of Panchkula district in Haryana during 2000-2002; 334 children were followed up fortnightly for one year. Standard clinical and microbiological procedures were used for collection of swabs from throat and skin and confirmation of GAS and its emm types. RESULTS: Of the 4249 children studied, 658 (15.5%) had pharyngitis; 579 of them could be swabbed, of which 2.8 per cent had GAS. From 3591 children without pharyngitis, 3385 who could be swabbed, GAS was found in 1.3 per cent of them. Impetigo was rare (0.7%), but 7.1 per cent (2/28) children had GAS. In the followup study, 17.4 per cent (776/4447 child-contacts) had pharyngitis, 761 could be swabbed and 2.4 per cent had GAS; among those without pharyngitis, 2016 swabs could be taken and GAS was found in 1.3 per cent; whereas only 2.6 per cent (2/75) of skin sores had GAS. Three children had GAS pharyngitis twice during follow up. Fourteen different GAS emm types were found. emm 71, 77 and 81 constituted 69 per cent of the pharyngeal isolates. GAS pharyngitis and impetigo were more common in winters and summers respectively. INTERPRETATION & CONCLUSION: In north India, pharyngitis was more common than impetigo. Most prevalent emm types of GAS in this region differ from those included in M protein-based vaccines.

Axillary and tympanic membrane temperature measurements are unreliable early after cardiopulmonary bypass.

BACKGROUND AND OBJECTIVE: Inaccurate measurements of body temperature following cardiopulmonary bypass may be associated with serious complications. The purpose of this study was to determine whether axillary and tympanic temperature measurements correlate with the urinary bladder temperature in the early postcardiac surgery period. METHODS: Forty-nine adult patients who underwent cardiac surgery under cardiopulmonary bypass at our institution were prospectively studied. Urinary bladder, right axillary, right tympanic and left tympanic temperature measurements were simultaneously recorded at 0, 6, 12 and 18 h following cardiopulmonary bypass. Patients had one to four sets of recordings and a total of 629 temperature measurements were recorded. The mean difference (bias) between the bladder and each of the other methods and limits of agreement were calculated using Bland and Altman method. RESULTS: The mean core body temperature recorded from the bladder on admission to the intensive care unit was 36.4 degrees C. After 6, 12 and 18 h the mean core body temperature was 37.4 degrees C (range: 35.2-39.0), 37.5 degrees C and 37.45 degrees C, respectively. The mean differences (bias) between the bladder temperature and the other three methods were: left tympanic, 0.65 degrees C (95% CI: -0.24 to 1.58); right tympanic, 0.57 degrees C (95% CI: -0.48 to 1.63) and right axillary, 0.55 degrees C (95% CI: -0.27 to 1.36). CONCLUSIONS: The axilla and tympanic membrane are unreliable sites for core body temperature measurement early after cardiopulmonary bypass in adult patients and clinical decisions should be based on more reliable methods.

Enhanced pro-inflammatory chemokine/cytokine response triggered by pathogenic Entamoeba histolytica : basis of invasive disease.

The virulence of Entamoeba histolytica is governed by adhesion/colonization in the gut which is mediated by a galactose specific lectin. Two morphologically identical but distinct species i.e. pathogenic E. histolytica and non-pathogenic E. dispar, can be differentiated by distinct epitopes in the lectin. Both species bind to colonic epithelial cells, but only E. histolytica infection induces an inflammatory response and subsequent pathogenesis. Thus, comparing the responses of the intestinal cells to pathogenic and non-pathogenic lectins is a point of interest. The pathogenic lectin causes cytolysis of epithelial and immune-competent cells. Our data (both qualitative and mRNA quantitation) indicate that the epithelial cells responded to E. histolytica lectin with an increased expression of pro-inflammatory IL-2, IL-6, IL-8, MIP-1alpha, MCP-1, RANTES, GROalpha and GMCSF as compared to E. dispar lectin. The pathogenic LCM induced a significant increase in intracellular calcium concentration, proliferative response and chemotaxis of lymphocytes from ALA patients as compared to non-pathogenic LCM. High RANTES and IL-6 were induced in patients' lymphocytes by pathogenic LCM, along with their receptors CCR5 and CD126 as compared to NP-LCM. The local release of such a complex network of cytokines/chemokines could explain the histopathology of E. histolytica infection. The comparative low levels of these chemokines/pro-inflammatory cytokines and high levels of anti-inflammatory IL-10 in response to non-pathogenic E. dispar could explain the absence of an acute inflammatory response and the disease process. The cytokines and chemokines may provide a mechanism for initiation, amplification or containment of inflammation during disease state.

Flash pulmonary edema manifesting for the first time after cardiac surgery: case report.

Flash pulmonary edema secondary to renal artery stenosis is an unrecognized complication following cardiac surgery. We report a case and discuss issues surrounding its diagnosis and management.

Activation of MAPK kinase pathway by Gal/GalNAc adherence lectin of E. histolytica: gateway to host response.

Amoebiasis caused by the protozoan parasite Entamoeba histolytica is one of the leading parasitic causes of morbidity and mortality in the developing countries. Among the variety of virulence factors, an adherence lectin (Gal/GalNAc, 260 kDa) has been known to mediate colonization and subsequent host responses. It is a major cell surface antigen which is universally recognized by the immune sera of patients with amoebic liver abscess (ALA). The role of this lectin in cytolysis and phagocytosis of human colonic mucin glycoproteins has also been established. The objective of the present study was to elucidate the signal transduction events induced in response to Entamoeba histolytica derived Gal/GalNAc lectin in the target epithelial cells. We have attempted to define a pathway in target cells that could link this immunodominant antigen to a known biological pathway for target cell activation and triggering of subsequent disease pathology/parasite survival. Lectin stimulated cells showed immediate rise in (Ca2+)i concentration corresponding to 1517.31+/-16.3 nM (approximately) at 0-2 min. The intracellular calcium also extruded from the cells as was measured by increase in calcium green-1 fluorescence. Expression of several protein kinases was checked by western blotting to delineate the signaling pathway. Results showed that the expression of PLA2, PI3K, Ras p21, Ras GAP, ERK-MAPK, p38MAPK and PKC was significantly increased. Expression of Raf-1 and MEK-1 was also found to be significant, as determined by intensity analysis. Overall, it indicated activation of MAPKinase pathway which is implicated in a variety of cellular functions. On the basis of our observations it can be stated that there is a calcium mediated activation of PKC in target cells, by lectin, which inturn activates cyclic nucleotides and other protein kinases. These protein kinases further phosphorylated downstream signals in a sequential manner, thus leading to the activation of MAPKinase cascade. Activation of MAPK cascade, in our studies, is implicated in a variety of physiological cellular functions including apoptosis, proliferation, cytoskeleton rearrangements and permeability changes. However, future screening of the genes responsible for the transcription and translation of new proteins and their biological functions in response to lectin stimulation will prove useful in understanding this host-parasite relationship.

Primary synovial sarcoma of the pleura: beware of misdiagnosis.

Primary synovial sarcoma of the pleura is an uncommon entity in the present medical literature. However, the paucity of documented cases may be due to misdiagnoses as a malignant mesothelioma in the past. Early diagnosis with new molecular techniques may improve the outcome of this tumour, which is believed to have a grave prognosis at present.

Distribution of Entamoeba histolytica Gal/GalNAc lectin-specific antibody response in an endemic area.

To demonstrate the dynamics of specific antibody isotypes against Entamoeba histolytica Gal/GalNAc adhesin and its correlation, if any, with the development of immunity, we evaluated subjects suffering from a spectrum of amoebic infections ranging from amoebic liver abscess (ALA) to asymptomatic cyst passers. The quantitative analysis of antibody levels was done in the sera by enzyme-linked immunosorbent assay. Gal/GalNAc adhesin-specific immunoglobulin G (IgG) was higher in ALA (and their follow-ups) and intestinal amoebiasis cases as compared with asymptomatic cyst passers (P < 0.05). Among the isotypes of IgG, high levels of IgG1 (60% of the total IgG concentration), suggestive of T-helper 2-type response, was associated with ALA cases. Intestinal amoebiasis cases and cyst passers had high percentage of IgG1 and IgG4 antibodies as compared with per cent IgG2 and IgG3 (of the total IgG), whereas follow-up cases of ALA had predominantly IgG2 and IgG3 isotypes of antibodies. Gal/GalNAc lectin-specific IgM antibodies were maximum in cases of intestinal amoebiasis. ALA cases and their follow-ups had significantly lower levels of Gal/GalNAc-specific IgM levels as compared with cyst passers (P < 0.05). Gal/GalNAc adhesin-specific IgA antibodies were raised maximally in intestinal amoebic infection cases. ALA cases and their 3-month follow-ups had significantly higher concentrations of lectin-specific IgA (P < 0.05) as compared with the healthy subjects.

Entamoeba histolytica Gal/GalNAc lectin depletes antioxidant defences of target epithelial cells.

Among the variety of virulence factors of Entamoeba histolytica, an adherence lectin (Gal/GalNAc, 260 kDa) is known to mediate colonization and subsequent host responses. Gal/GalNAc lectin is universally recognized by the immune sera of patients with amoebic liver abscess. It plays a crucial role in cytolysis and phagocytosis of human and rat colonic mucin glycoproteins. The objective of the present study was to elucidate the role of antioxidants in E. histolytica Gal/GalNAc lectin-induced signals in the target epithelial cells. We have attempted to define a pathway in target cells, Henle-407 cells (human intestinal epithelial cell line), that could link this immunodominant antigen to a known biological pathway for target cell activation and triggering of subsequent disease pathology/parasite survival. Since several workers have demonstrated that cAMP and cGMP may act as important cellular signals for altering ion transport, so in the present study, cAMP and cGMP levels were measured in Henle-407 cells which showed significant increase at 15 min after stimulation. Elevated cAMP and cGMP levels are implicated in altered electrolyte transport and conductance. Results showed that there were increased levels of ROS and RNI which led to reduced activities of antioxidant enzymes--catalase, superoxide dismutase and glutathione peroxidase. Despite the increased glutathione (reduced) levels, the enzymes were not able to combat the damage caused by ROS and RNI. Thus, there was an increased local concentration of the free radicals and reduced activities of all the three enzymes which could damage the target cell in terms of cytoskeleton and permeability changes.

Can we rely on arterial line sampling in performing activated plasma thromboplastin time after cardiac surgery?

BACKGROUND AND OBJECTIVE: Arterial catheters are routinely used to sample blood for clotting studies in most cardiothoracic intensive care units. The clotting profile in surgical bleeding after cardiac surgery influences further management. Aspiration and discard of a certain amount of blood from the line, prior to sampling, are assumed to clear heparin contamination. We have investigated this assumption through analysis of the clotting profile by simultaneous arterial line and peripheral venous samples. METHODS: The morning following cardiac surgery, simultaneous arterial line and peripheral venous blood samples were taken for activated plasma thromboplastin time (APTT) ratio and international normalized ratio (INR) in 49 randomly selected patients. Also, a thromboelastogram analysis (TEG) (n = 7) was made. A survey of 22 UK cardiothoracic intensive care units was carried out to determine the practice for the withdrawal of blood for clotting studies. RESULTS: The median arterial APTT ratio value was 1.32 +/- 0.52 as compared to the median peripheral APTT ratio value which was 1.1 +/- 0.24 (P < 0.001). INR values were statistically similar by both routes. Heparin contamination was confirmed by TEG which revealed that the R-value for arterial catheter blood samples without heparinase in the cup was higher (406.00 +/- 64.44 s) compared with the value for arterial samples with heparinase in the cup (318.28 +/- 47.26s, P < 0.05). The survey of 22 UK cardiothoracic intensive care units showed that heparinized arterial lines were by far the commonest ports used for blood withdrawal for the measurement of APTT ratio results. CONCLUSIONS: Samples withdrawn from heparinized arterial lines cannot be relied upon for APTT ratio results.

Modulation of the expression of M150 on macrophages by Th1/Th2 cytokines and co-stimulatory molecules CD40, B7-1, B7-2 and ICAM-1.

M150 is an 150-kDa protein associated with the surface of macrophages and is responsible chiefly for the activation of Th1 cells. It is a unique subset of the lysosome-associated membrane protein-1 glycoprotein and its co-stimulatory activity depends on its post-translational modification, which has a distinct glycosylation pattern restricted to macrophages. In the present study, we have observed that M150 is expressed constitutively on peritoneal but not splenic macrophages isolated from mice of different genetic backgrounds: Balb/c, C57BL/6 and C3He. However, M150 was expressed not only on peritoneal but also on splenic macrophages of non-obese diabetic (NOD) mice. Expression on splenic macrophages was induced by culture with lipopolysaccharide (LPS). Expression could also be significantly up-regulated by interferon (IFN)-gamma and granulocyte-macrophage colony stimulating factor (GM-CSF) but was inhibited by interleukin (IL)-10; IL-4 exhibited no effect. Further, cross-linking of B7-2, CD40, ICAM-1 but not B7-1 enhanced the level of M150 significantly. IFN-gamma and GM-CSF acted synergistically with CD40. The significance of these findings is that cytokines IFN-gamma, GM-CSF and IL-10 and the co-stimulatory molecules B7-2, CD40 and ICAM-1 can regulate the expression of M150 on macrophages.

Delivery of antigen in allogeneic cells preferentially generates CD(4+) Th1 cells.

We have examined the possibility of evoking antigen-specific T cell immune response by using allogeneic cells as a source of adjuvant and also as a vehicle to deliver antigen. The mice were immunized with different preparations of antigen-pulsed allogeneic and syngeneic splenocytes. It was observed during the study that the animals immunized with antigen-pulsed mitomycin C treated allogeneic cells elicited antigen specific CD(4+) Th1 cell response. Predominant release of IL-2, interferon (IFN)-gamma and IgG2a-isotype also occurred. In contrast, mice immunized with antigen-pulsed syngeneic cells chiefly enhanced the production of interleukin (IL)-4 and IgG1-isotype. Further, allogeneic macrophages induced better T cell response than B cells or splenocytes and prominently induced the expression of B7-1 and B7-2. Immunization with antigen-pulsed macrophages provided better recall responses compared to B cells. This was manifested by the high LFA-1alpha and low CD45RB expression on T cells. Because it is already known that mitomycin C-treated cells undergo apoptosis and dendritic cells engulf apoptotic cells, we therefore propose that generation of T cell response using antigen-pulsed allogeneic cells may be due to the engulfment of these cells by dendritic cells, which may then process and present antigen entrapped in allogeneic cells to activate naive CD(4+) T cells and differentiate them to Th1 cells. This study therefore provides a rational basis for manipulating antigen-specific responses by immunizing with antigen-pulsed allogeneic cells.

Issues concerning consent in patients undergoing cardiac surgery-the need for patient-directed improvements: a UK perspective.

AIMS: To determine the extent to which informed patient consent for cardiac surgery corresponds with standard guidelines and to assess patient satisfaction with the consent process. METHODS: A questionnaire developed in accordance with consent guidelines published by the Medical Defence Union (MDU) and the Practicalities Of Producing Patient information (POPPi) Guide was administered to 82 patients after they were consented for cardiac surgery. RESULTS: Patients were informed about i) type of operation [n=80, 97.5%] ii) reason for surgery [n=78, 95%] iii) surgical procedure [n=77, 94%] iv) length of hospital stay [n=73, 89%] and v) post-surgical care [n=79, 96.3%]. However, a decreasing number of patients were notified about i) possible risks of surgery [n=64, 78%] and ii) consequences of no surgery [n=62, 75.6%]. Interestingly, patients received less adequate information about i) alternative methods of treatment (n=34, 41.4%], ii) future lifestyle (n=55, 67%] and iii) medications following surgery [n=40, 48.7%]. 81% (n=67) were overall 'satisfied' with the information provided. More than 95% (n=78) patients were invited to ask questions. The most commonly asked questions were about i) quality of life ii) length of operation and hospital stay iii) surgical procedure iv) consequences of no surgery. CONCLUSIONS: The study has highlighted areas of informed consent in cardiac surgical patients that need attention. Although, patients were generally satisfied and well informed about the procedure, less information was presented covering alternative treatments, future lifestyle and medications. This was reflected in the questions asked by patients and their suggested improvements for the consent procedure.

A thymic carcinoid mimicking acute aortic dissection.

Thymic carcinoids are extremely rare. We present an 80 year old hypertensive patient who presented as an emergency with sudden onset of severe chest and upper back pain raising the suspicion of acute aortic dissection or acute coronary syndrome. Further investigations revealed a carcinoid tumour of thymic origin.