Recurrent Takotsubo cardiomyopathy in a postmenopausal Indian lady: Is there a pattern?

Takotsubo cardiomyopathy (TTC) is a syndrome of acute left ventricular dysfunction with a clinical presentation often mimicking acute coronary syndrome. Without a high index of suspicion, this clinical entity often goes unrecognized. Although initially categorized as a benign completely reversible condition, it is no longer considered to be so. Recurrence of this condition, though rare, has been reported in a non-Indian population. We present a case of recurrent TTC in a postmenopausal Indian lady who had a similar clinical presentation both at the index event and at recurrence.

Postoperative euglycaemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors (gliflozins): a report of two cases and review of the literature.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i)-associated euglycaemic diabetic ketoacidosis (euDKA) is a serious and increasingly recognised complication of treatment with this class of oral hypoglycaemic agents and can present a diagnostic challenge, resulting in delayed recognition, inappropriate treatment and potentially life-threatening acidosis. We present two cases of patients developing SGLT2i-associated euDKA in the early postoperative period. We support ceasing SGLT2i for 72 hours preoperatively and would suggest continuing to withhold the medication until oral intake is restored, and recommend a wider awareness of SGLT2i-associated diabetic ketoacidosis (DKA) amongst patients and their healthcare providers with an emphasis on checking ketone levels irrespective of blood glucose levels in the postoperative setting.

Stabilization of the third fibronectin type III domain of human tenascin-C through minimal mutation and rational design.

Non-antibody scaffolds are increasingly used to generate novel binding proteins for both research and therapeutic applications. Our group has developed the tenth fibronectin type III domain of human tenascin-C (TNfn3) as one such scaffold. As a scaffold, TNfn3 must tolerate extensive mutation to introduce novel binding sites. However, TNfn3's marginal stability (T(m) ∼ 59°C, ΔG(unfolding) = 5.7 kcal/mol) stands as a potential obstacle to this process. To address this issue, we sought to engineer highly stable TNfn3 variants. We used two parallel strategies. Using insights gained from structural analysis of other FN3 family members, we (1) rationally designed stabilizing point mutations or (2) introduced novel stabilizing disulfide bonds. Both strategies yielded highly stable TNfn3 variants with T(m) values as high as 83°C and ΔG(unfolding) values as high as 9.4 kcal/mol. Notably, only three or four mutations were required to achieve this level of stability with either approach. These results validate our rational design strategies and illustrate that substantial stability increases can be achieved with minimal mutation. One TNfn3 variant reported here has now been successfully used as a scaffold to develop two promising therapeutic molecules. We anticipate that other variants described will exhibit similar utility.

Impact of delirium and suture-less securement on accidental vascular catheter removal in the ICU.

The objectives were to describe the incidence of accidental vascular catheter removal (AVCR) in an Australian Intensive Care Unit (ICU) and evaluate whether the fixation method or patient delirium increased the risk of AVCR. This prospective observational study was based in a tertiary level ICU between April 2011 and October 2012. All vascular catheters were secured either by sutures or by a suture-less securement device (STATLOCK(™), Bard Medical, Covington, GA, USA) as per the treating clinician. Data were obtained from bedside nursing staff, with daily screening for delirium completed by the ICU medical team using the Confusion Assessment Method-ICU. 2361 patients were admitted during this period with 1032 patients screened and data available for 322 patients (452 vascular catheters). AVCR occurred in 15 patients (16 vascular catheters) (5.0%) with an incidence of AVCR of 2.77 per 100 catheter-days. Delirious patients were 13-fold more likely to have an AVCR event (odds ratio=13.3; 95% confidence interval 4.36, 40.52; P <0.0001). There was a non-significant trend to an increase in AVCR when using the suture-less securement device (odds ratio=2.6; 95% confidence interval 0.87, 7.8; P=0.09) but delirious patients were no more likely to have an AVCR episode when a suture-less securement device was used (P=0.95). In this study the use of suture-less securement did not seem to increase the risk of AVCR. However, there was a non-significant trend towards increased AVCR when using suture-less securement devices, which may reflect a ß error.

Dual specificity of human plasma lactose-binding immunoglobulin to anomers of terminal galactose enables recognition of desialylated lipoprotein(a) and xenoantigens.

Human plasma lactose-binding immunoglobulin (LIg) isolated by affinity chromatography on lactose-Sepharose was largely IgG with significant IgA and IgM contents. LIg-mediated agglutination of desialylated human RBC was inhibited equally by the α- and ß-anomers of methyl galactoside. Recognition of either the terminal α-galactose (TAG)-containing glycans of bovine thyroglobulin or the N-acetyl lactosamine (LacNAc)-terminating glycans of asialofetuin by LIg was inhibitable nearly as much by the α-galactoside melibiose as by the ß-galactoside lactose. Melibiose covalently conjugated to protein and coated on polystyrene wells captured several times more LIg molecules than its lactose analogue. LIg binding to bovine thyroglobulin or rabbit RBC membrane proteins, both bearing TAG was substantially reduced by prior treatment of the proteins with α-galactosidase to remove TAG though enzyme-treated glycans contained newly exposed LacNAc moieties. Desialylated O-linked oligosaccharides, however, were no ligand for LIg. Unlike LDL, plasma lipoprotein(a) [Lp(a)] coated on polystyrene well and desialylated by neuraminidase was recognized by LIg through terminal LacNAc moieties exposed by the enzyme on its apo(a) subunit. Further, same amount of added fluorescence-labelled LIg formed significantly more immune complex with Lp(a) in high Lp(a) plasma than in low Lp(a) plasma. Results suggest (1) possibility of a role for LIg in combating non-primate molecules and cells bearing TAG moiety and (2) a mechanism for Lp(a)-mediated vascular injury as diabetes, infections and inflammations induce greater release of neuraminidase into circulation.

Leflunomide for cytomegalovirus: bench to bedside.

Cytomegalovirus (CMV) remains a major cause of morbidity and mortality among transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide has been shown to have immunosuppressive activity in experimental allograft models together with antiviral activity inhibiting CMV both in vitro and in vivo. Data are emerging about its potential role in ganciclovir-sensitive and -resistant CMV, primarily by virtue of a unique mechanism inhibiting virion assembly, as opposed to inhibition of viral DNA synthesis by current agents. This review aims to put in perspective, the knowledge acquired in the last decade or so on leflunomide for CMV. Evidence suggests that it might have activity against human CMV with good oral bioavailability and, more importantly in the resource-poor setting, is economical. Although the data presented here are not from randomized trials, several relevant observations have been made that could influence future, more structured assessments of the drug. An immune suppressive compound with antiviral features and experimental activity in chronic rejection is an attractive combination for organ transplantation, and it appears that leflunomide may just fit that niche.

An unusual case of abdominal wall bleeding after renal allograft biopsy.

We report an unusual case of a enlarging anterior abdominal wall hematoma after percutaneous biopsy of a renal allograft. Angiography-directed embolization of the vessels filling the pseudoaneurysm was done and followed up with surgical exploration of the hematoma. In order to avoid this complication, Color Doppler evaluation of the overlying abdominal wall is suggested to look for significant vessels before the biopsy procedure.

Influenza A (H1N1) 2009 pandemic: was there a difference in the two waves in patients requiring admission to the intensive-care unit?

Influenza virus is prone to mutations that may alter the intensity of subsequent waves of infection. In this study, we evaluated whether outcomes were different in the two waves of the influenza A (H1N1) 2009 pandemic in patients admitted to the intensive-care unit. Age, gender, lag-time to presentation and APACHE-II scores were similar in both waves. Although ventilatory requirements were similar (36/37 vs. 36/39), non-significant reductions in the durations (days) of ventilation (10.3 ± 8.0 vs. 7.8 ± 9.4, p 0.11) and hospitalization (14.9 ± 10.5 vs. 12.3 ± 14.1, p 0.20) were observed in the second wave. The clinical profile and outcomes were not significantly different between the two waves among severely ill patients.

Adjuncts and alternatives to oxime therapy in organophosphate poisoning--is there evidence of benefit in human poisoning? A review.

Organophosphate poisoning is common in developing countries. The morbidity and mortality with organophosphate poisoning is relatively high despite the use of atropine as specific antidotal therapy and oximes to reactivate acetylcholinesterase. Several adjunct and alternative therapies have been explored in animal and human studies. We reviewed the literature to ascertain if there was evidence of benefit of such therapies. Adjunct and alternative therapies included treatments to reduce poison absorption by topical application of creams, enhance toxin elimination by haemoperfusion or bioremediation and neutralise the poison by scavenging free organophosphate with cholinesterase-rich human plasma. In addition, magnesium, clonidine, diazepam, N-acetyl cysteine and adenosine receptor agonists have also been used to counteract poison effects. Detailed assessment was limited by the paucity of trials on adjunct/alternative therapies. The limited evidence from the review process suggested potential benefit from the use of human plasma infusion, early initiation of haemoperfusion and intravenous magnesium, in addition to standard therapy with atropine and pralidoxime. There appeared to be no additional benefit with alkalinisation or use of glycopyrrolate instead of atropine in human trials. Diazepam administration has been advocated by military authorities if symptoms developed following exposure to organophosphate. Bioremediation, clonidine, N-acetyl cysteine and adenosine receptor agonists have been evaluated only in animal models. The impact of adjunct and alternate therapies on outcomes in human poisoning needs to be further explored before implementation as standard treatment.

Pulmonary lymphomatoid granulomatosis in a renal allograft recipient.

Lymphomatoid granulomatosis (LYG) is a rare multisystemic angiocentric lymphoproliferative disease, which can masquerade as necrotic tissue. There is a paucity of reports of LYG in renal transplant recipients. Herein, we describe LYG in a 56-year-old renal allograft recipient 11 years after transplantation, on azathioprine and prednisolone maintenance immunosuppression, presenting to us with fever, weight loss, and nodular and patchy opacities in both lung fields. Initial percutaneous samples showed necrotic tissue while open biopsy revealed characteristic histopathology with evidence of Epstein-Barr virus. We have reviewed the radiological and pathological findings, and discussed clinical features, differential diagnosis, and treatment of LYG.

Outcomes of renal transplantation in patients with immunoglobulin A nephropathy in India.

BACKGROUND: There is a paucity of data on the course of renal transplant in patients with immunoglobulin A (IgA) nephropathy (IgAN) from India. While the natural history of IgAN in the Indian context is rapidly progressive, the post-transplant course remains speculative. AIM: To study the graft survival in renal transplant recipients whose native kidney disease was IgAN and the incidence and correlates of recurrent disease. SETTINGS AND DESIGNS: Retrospective case control study from a Nephrology unit of a large tertiary care center. MATERIALS AND METHODS: The outcomes of 56 transplant patients (58 grafts) with biopsy-proven IgAN and of 116 patients without IgAN or diabetic nephropathy, transplanted during the same period were analyzed. Correlates of biopsy-confirmed recurrent disease were determined. STATISTICAL ANALYSIS: Means were analyzed by Student's t test and Mann-Whitney test; proportions were determined by Chi-square analysis and graft survival curves were generated using the Kaplan-Meier. RESULTS: Five-year graft survival for IgA patients was not significantly different from that in the reference group (90% and 79%, P = 0.6). During a mean follow-up of 42 months (range, 1-144), 28 event graft biopsies were required in 20 grafts of IgAN. Histological recurrence was diagnosed in five of the 20 available biopsies (25%) after a mean duration of 28 months. Recurrence did not correlate with donor status, HLA B35 and A2, recipient age, gender or immunosuppression. CONCLUSIONS: Renal transplantation is an appropriate treatment modality for IgA nephropathy patients with end-stage renal disease in India, despite the potential for recurrent disease. The posttransplant course is an indolent one when compared to the malignant pretransplant phase.

Mucormycosis isolated from perilymphatic tissue: an unusual presentation.

We present a rare case of a patient who presented with atypical cranial nerve palsies, with subsequent isolation of mucormycosis from an upper neck subcutaneous swelling. This is an unusual initial site of isolation of mucormycosis. We believe that this should be considered among the differentials when a diabetic or immunosupressed patient presents with cervical lymphadenopathy and cranial nerve palsies.

Cardiovascular response in anemia.

OBJECTIVE: To study the functional consequences of nutritional anemia by evaluating the exercise performance in these children. METHODS: The study was conducted on 30 each of anemic and normal children of both sexes aged between 7 and 14 years. Relevant history was taken, and detailed examination was done. These children were classified according to severity of anemia based on hemoglobin estimation as mild (10-11.9 g/dl), moderate (7-9.9 g/dl) and normal (>12 g/dl). Children with severe anemia (Hb < 7g/dl), heart disease, non-nutritional anemia, acute febrile or respiratory illness were excluded. The subjects were tested on Mortara X Scribe colour stress treadmill using the modified Bruce protocol. Continuous computerised electrocardiographic analysis was done. The parameters studied included heart rate, systolic blood pressure, double product (DP = HRxSBP), ECG changes, metabolic equivalents (METS) and exercise duration. The end point of the test was a HR of 170/min (non-fatigue group) or inability to perform further (fatigue group). Statistical analysis was done by appropriate tests. RESULTS: Fifteen children each with mild and moderate anemia and 30 age-matched controls were enrolled in the study. There was no significant difference in the resting HR, exercise duration or DP between the cases and controls. Thirty-one children reached the target HR (non-fatigue group). The end-point HR was significantly lesser among the anemic children in the fatigue group (P 0.04). The percent gain of SBP, at peak exercise (P 0.0007) and recovery SBP as percent of resting SBP (p 0.006) were significantly more in the anemic children, more so in the mildly anemic ones. Lesser METS was achieved by anemics as compared to controls (P 0.04). ECG changes occurred significantly more often in anemic children, 53.8% of those with changes being moderately anemic, the main abnormality being ST depression. None developed arrhythmia during exercise testing. CONCLUSION: The cardiovascular response to physical exercise is compromised in children with nutritional anemia and hence these children may never attain their full potential in various school activities. Prevention of anemia should be a priority in school going children.

Dextran-binding human plasma antibody recognizes bacterial and yeast antigens and is inhibited by glucose concentrations reached in diabetic sera.

Dextran-binding antibody was isolated in high yield from plasma of all 40 blood donors screened in a South Indian population. The antibody was purified by a single step affinity chromatography on Sephadex G100 using 1-O-methyl alpha-D-glucoside as eluant. Analysis of protein peaks obtained in size exclusion high pressure liquid chromatography (HPLC) revealed dominance of IgG and suggested the presence of polymeric IgA in this antibody. Methyl and para-nitrophenyl alpha-D-glucosides, in contrast to their beta-anomers, were very efficient inhibitors of binding of this antibody to dextran. Galactose and glucose were equally good inhibitors. Among disaccharide inhibitors sucrose was more efficient than maltose or melibiose. Hemoglobin artificially glycosylated to contain covalently-linked glucose or alpha-anomeric galactose was sugar-specifically recognized by this antibody. Galactose moieties in glycoproteins or polysaccharides were, however, not recognized. The dextran-binding antibody bound sugar-specifically to glycoconjugates from yeast (Saccharomyces cerevisiae) and to lipopolysaccharides from Klebsiella and group A Streptococci, but not to lipopolysaccharides from E. coli. Inhibition studies suggested glucose moiety with unsubstituted C2 and C4 and alpha-anomeric C1 as ideal for recognition by the dextran-binding antibody. Concentration of glucose required for 50% inhibition of binding of the purified antibody to polystyrene-coated dextran in phosphate buffered saline was above the glucose concentrations in normal sera, but well below those reached in diabetic sera. Binding of the antibody from dialysed plasma to immobilized dextran was lowered only marginally in presence of glucose at 4.5mM (which nears normal serum glucose concentrations), but substantially in presence of the sugar at 20mM and above which are reached in diabetic sera. If verified in vivo, inhibition of this antibody by high serum glucose may possibly be among reasons for the increased susceptibility of diabetics to infection.