Evaluation of utility of immunohistochemistry markers as a tool for objective diagnosis of low-grade myelodysplastic syndrome in routine reporting: Prospective observational study

Purpose: Diagnosis of myelodysplastic syndrome (MDS) primarily relies on the detection of morphological dysplasia in bone marrow. It is subjective and many studies have reported lack of interobserver agreement in reporting. Biopsy is preferred specimen for megakaryocyte assessment. We studied 43 bone marrow biopsies from 40 suspected MDS patient having persistent undiagnosed cytopenia. Utility of immunohistochemistry (IHC) with CD61 and p53 in detecting low-grade MDS was analyzed over routine morphology. Method and Results: Total number of megakaryocytes and number of dysplastic megakaryocytes seen on CD61 IHC was significantly higher than that on H and E stain (P value < 0.05) Out of total 43 biopsies, 13 [30.2%] cases showed dysplastic megakaryocytes that were confirmed by interobserver agreement after IHC. From 30 cases with no significant dysplasia on morphology, 21/43 [48.8%] cases showed >10% dysplastic megakaryocytes on CD61 (P value 0.0001). Nine cases showed no significant dysmegakaryopoiesis with either H and E or CD61 IHC. Fourteen cases could meet higher cut off (30%) of dysmegakaryopoiesis with CD 61 IHC. Out of total 34 cases showing significant dysplasia 7 cases (20.6%) showed positivity for p53 on IHC, which is little less than that reported in low-grade MDS. Conclusion: CD61 IHC is helpful in making correct diagnosis of MDS in cases with minimal dysplasia and should be performed before excluding possibility of MDS on morphology in a patient with undiagnosed cytopenia. IHC is cost effective tool for MDS diagnosis in developing world where access to extensive flow cytometery and molecular testing is limited.

Correlation of optical coherence tomography angiography and microperimetry (MP3) features in wet age-related macular degeneration

Purpose: To evaluate and correlate the functional treatment response using microperimetry (MP3) with the morphological findings on optical coherence tomography angiography (OCTA) in wet AMD pre- and post-treatment with anti-vascular endothelial growth factor (VEGF). This was a single-centre prospective, interventional study. Methods: Patients with wet AMD were treated with 3 injections of intravitreal anti-VEGF at monthly intervals for 3 months and followed at 1, 2, 3, and 6 months postinjection. Using “overlay” features, morphologic characteristics of OCTA at the site of choroidal neovascular membrane (CNVM) lesion were analyzed and correlated functionally with MP3. Data were collected including visual acuity at presentation and follow-up with multimodal imaging features, treatment details, complications (if any), and treatment given for that complication. Descriptive observational analysis and paired t-test was used to compare the appearance of the neovascular network on OCTA imaging with retinal sensitivity on MP3. Results: OCTA in the pretreatment phase revealed CNVM as an abnormal vascular network arising from the choroid and invading the subretinal space. On MP3, decreased retinal sensitivity was observed corresponding to the area of CNVM. Post-treatment, OCTA revealed reduction in abnormal vascular network in 51 (91.07%) eyes that correlated with increased retinal sensitivity at the corresponding area on MP3. Statistical analysis showed baseline mean retinal sensitivity at the site of CNVM as 320.07 dB, which improved to 521.53 and 730.20 dB at 1 and 3 months postinjection follow-up, respectively. Conclusion: Combining the findings of OCTA and MP3 using “overlay” features gives us precise information of structure–function correlation at presentation and also in response to treatment. It also helps to improve patient's compliance, confidence to treatment, and their understanding of the disease process as well.

Hepatopulmonary syndrome, an unusual cause of hypoxemia.

A six-year-old boy presented with cough, cyanosis and clubbing. Investigations revealed hypoxia (PaO2 53 mm Hg on room air) which was only partially correctable (PaO2 73 mm Hg) with 100% oxygen administered through a non re breathing face mask. Liver function tests showed elevated total bilirubin, and transaminases, liver biopsy confirmed chronic hepatitis and endoscopy showed grade three varices. A contrast enhanced echocardiography (bubble study) revealed pulmonary arterio-venous communication. A diagnosis of hepatopulmonary syndrome was made based on the triad of hypoxemia, liver disease and intra pulmonary vascular communications.

Ten-year experience with the arterial switch operation.

BACKGROUND: Arterial level repair is considered the most appropriate procedure for transposition of the great arteries. This report describes our experience with the arterial switch operation over the past decade. METHODS AND RESULTS: From January 1991 to January 2001, a total of 299 patients underwent an arterial switch operation for transposition of the great arteries or double-outlet right ventricle. Group I (n=169, 56.5%) comprised patients with transposition of the great arteries in whom the ventricular septum was essentially intact. Group II patients (n=130, 43.5%) had transposition of the great arteries with an additional significant ventricular septal defect or had double-outlet right ventricle with a subpulmonic ventricular septal defect. Of the total, 245 (82%) were males and 54 (18%) were females. In group I, the ages ranged from 2 days to 18 years (median 19 days) and weight ranged from 1.7 to 68 kg (median 2.5 kg). In group II, the ages ranged from 4 days to 4 years (median 90 days) and weight ranged from 2.5 to 17 kg (median 4 kg). Fifteen percent of the patients (25/169) in group I and 30% of the patients (39/130) in group II had features of bacteriologic infection. Arterial switch operation was performed on standard lines. In group I, 141 patients (83.4%) had a primary arterial switch operation while 28 (16.6%) underwent a rapid two-stage repair. Twenty-three patients required concomitant relief of associated anatomic left ventricular outflow tract obstruction. Operative mortality was 8.8% (15/169) in group I and 33% (44/130) in group II with an overall mortality of 19% (59/299). The major causes of operative mortality included pulmonary arterial hypertensive crisis (n=21), sepsis and related complications (n=16), and left ventricular failure (n=8). Coexisting arch anomalies, longer cross-clamp time, late presentation, and preoperative bacteriologic infections were incremental risk factors. Follow-up ranged from 1 to 10 years and was 87% complete. On follow-up, 91% of the patients were asymptomatic and off all medications. There were 3 late deaths and 5 patients required reoperation. CONCLUSIONS: Excellent long-term results are obtained in operative survivors following the arterial switch operation. However. operative mortality remains a concern in our set-up.

Graded balloon atrial septostomy in severe pulmonary hypertension.

BACKGROUND: The prognosis of patients with severe primary pulmonary hypertension is poor. The role of balloon atrial septostomy as a palliative procedure in these patients is not well defined. We retrospectively analyzed our data regarding the safety, clinical outcome and survival benefit of graded balloon atrial septostomy in patients with severe pulmonary hypertension. METHODS AND RESULTS: Eleven patients (7 males), aged 6 to 30 years (mean age 16.2+/-8.9 years), with severe pulmonary artery hypertension (mean pulmonary artery pressure of 76+/-16.9 mmHg) and refractory congestive heart failure and/or recurrent syncope underwent balloon atrial septostomy. Graded balloon dilatation under echocardiographic guidance and arterial oxygen saturation monitoring was done in all the patients. Procedure-related mortality was 18.2%. Significant acute hemodynamic improvement was seen in the survivors (pre-balloon atrial septostomy cardiac index 1.88+/-0.48 L/min/m2; post-balloon atrial septostomy cardiac index 2.18+/-0.37 L/min/m2, p<0.009). Patients were followed up for a mean period of 20.3 months after the procedure (range: 3 months-5 years). There was functional improvement and increased exercise tolerance in all the patients for a mean follow-up period of 14.6 months (NYHA functional class 3.62+/-0.69 to 2+/-0.50). The estimated probability of survival in this cohort at 1 year was only 48%; but 7 of 8 patients (87%) who survived the procedure were alive at 1 year. CONCLUSION: We conclude that balloon atrial septostomy improves clinical status, hemodynamic variables and possibly also improves survival in selected patients with severe pulmonary artery hypertension. It remains a definite palliative option for refractory primary pulmonary hypertension. However, the procedure-related risks are high in very sick patients and, therefore, balloon atrial septostomy may be advocated early in the course of the disease.

Management of cardiomyopathy resulting from incessant supraventricular tachycardia in infants and children.

BACKGROUND: Radiofrequency ablation is considered to be the treatment of choice in patients with ventricular dysfunction related to incessant supraventricular tachycardia. However, reservations regarding its use in infants and children prompted us to try alternative strategies for this group. METHODS AND RESULTS: Eight children (age range: 1 day to 10 years) were diagnosed to have tachycardia-related ventricular dysfunction in the past 6 years. They presented with symptoms of palpitation, dyspnea and/or generalized swelling over the body of 3 months to 2 years'duration. The cardiothoracic ratio at presentation was 64% (52%-70%) and ejection fraction was 22.2% (15%-45%). In 7 patients tachycardia was diagnosed to be ectopic atrial and in 1 it was permanent junctional reciprocating tachycardia. Six of these children were managed with intravenous/oral amiodarone in combination with digoxin (3) and/or propranolol (2). In one child addition of amiodarone to digoxin and propranolol led to polymorphic ventricular tachycardia, and amiodarone was withdrawn. Only one child underwent radiofrequency ablation as the first choice because regular follow-up was not possible due to logistic reasons. Sinus rhythm with normalization of ventricular function was achieved in 6 of the 7 children treated medically. One child continued to have frequent episodes of tachycardia and underwent successful radiofrequency ablation of a high right atrial ectopic focus. Two out of the 6 patients on amiodarone could be managed with only digoxin and propranolol after their ventricular function had returned to normal. A third patient relapsed on stopping amiodarone and underwent successful radiofrequency ablation of a left atrial ectopic tachycardia. CONCLUSIONS: Short-term amiodarone in combination with digoxin/propranolol is a safe and effective treatment strategy for infants/children with tachycardiomyopathy. Control of tachycardia is achieved in the majority, leading to recovery of ventricular function. This approach may avoid unnecessary ablations in children or at least postpone it till the procedure would be safer.

Aneurysm of the vein of galen in neonates: report of four cases.

In neonates, aneurysm of the vein of Galen often masquerades as cyanotic congenital heart disease. We report 4 cases of neonates presenting with malformation of the vein of Galen at our insititution. An increased awareness of this entity seems warranted.

Characterization of antibody response to human cytomegalovirus in Indian renal transplant patients.

BACKGROUND & OBJECTIVES: Cytomegalovirus (CMV) disease in seroendemic transplant populations is due to reactivation of the virus, or reinfection. In this context, the antibody response is likely to influence presentation, clinical severity and outcome of the disease, and may provide a diagnostic and prognostic marker. This study was carried out in Indian renal transplant patients and healthy adults to characterize the antibody response to cytomegalovirus. METHODS: Thirty three transplant recipients with CMV illness (symptomatology with IgM and/or nPCR positive status), 20 recipients who were asymptomatic in the 6 months of follow up after transplantation and 62 healthy controls were investigated for markers of CMV infection. These individuals were tested for IgG avidity and neutralizing antibody by ELISA techniques. RESULTS: All 53 transplant recipients were found to have an IgG avidity index of > 50 per cent. Antibody to a CMV envelope glycoprotein gB/AD-1 (putative neutralizing antibody) was expressed as S/N ratio and was > or = 5 in asymptomatic (65%) and symptomatic (27%) immunosuppressed renal transplant recipients. However, none of the 53 CMV IgG positive healthy controls were positive for neutralizing antibodies S/N ratio > or = 5 (S/N ratio = sample mean OD/mean OD of 3 negative controls in each run). We observed the simultaneous presence of CMV PCR signal in leukocytes and neutralizing antibody (S/N ratio > or = 5) in the plasma in 22 (41.5%) of the 53 renal transplant recipients. INTERPRETATION & CONCLUSIONS: In this study among the immunosuppressed transplant patients we observed an association between symptomatic disease and the relative absence of neutralizing antibodies. The neutralizing antibodies are less frequently demonstrable among controls; while appearance in a higher proportion of asymptomatic recipients especially in association with high IgG avidity (> 90%) is suggestive of its role in control of CMV disease despite reactivation as evidenced by DNAemia while on immunosuppressive therapy.

Mitochondrial myopathy presenting as ataxia with dilated cardiomyopathy.

Mitochondrial disorders are multisystem diseases with very heterogeneous clinical manifestations. Common cardiac features include cardiomyopathy and conduction defects. We report a five-year-old boy who presented with signs of congestive cardiac failure and was diagnosed to have dilated cardiomyopathy. Six months later, he developed progressively worsening ataxia, hypotonia, other cerebellar signs, hearing loss, severe sensory peripheral neuropathy and lactic acidosis. Electronmicroscopy of skeletal muscle biopsy was consistent with mitochondrial myopathy.

Hypocalcemic heart failure masquerading as dilated cardiomyopathy.

Hypocalcemia is a rare, but reversible, cause of congestive heart failure. We report a 4-month-old boy diagnosed as dilated cardiomyopathy who had prolonged QoTc with low blood levels of calcium, normal phosphate, elevated alkaline phosphatase and findings suggestive of rickets. In view of non response to calcium and vitamin D3, a possible diagnosis of VDDR I (Vitamin D-dependent rickets) was made and he was treated with calcium and calcitriol. The serum calcium levels normalised within 10 days, along with resolution of the signs and symptoms of heart failure, near normal left ventricular function and normalisation of QoTc. Pediatricians should be aware of the association of hypocalcemia with cardiac dysfunction and should keep it as a possible reversible cause of heart failure in children.

Immunosuppression in live-related donor renal transplantation.

BACKGROUND: Triple immunosuppression with cyclosporine, azathioprine and prednisolone is the most common regimen employed following renal transplantation. No information is available regarding its impact on the results of renal transplantation in India. The present study is an audit of a fixed-dose cyclosporine-based immunosuppressive regimen in an exclusively live-related donor transplant programme, with specific regard to graft and patient outcomes. METHODS: Patients transplanted over a 3-year period and receiving cyclosporine-based immunosuppression were studied. The relationship between immunosuppression and graft outcomes [rejection episodes (RE), graft function, graft survival], and patient outcomes (patient survival) was analysed in those receiving triple immunosuppression. Dosage schedules were audited. Cyclosporine trough level monitoring was employed at graft dysfunction episodes, or at dose reduction points. RESULTS: The median follow up was 14 months. Triple drug immunosuppression was used in 191 patients and double drug therapy in 26. The overall one-year patient survival rate was 91% and the corresponding graft survival rate was 90%. An audit of dosing schedules showed that over the first 6 months post-transplant, cumulatively, 20%-50% of patients received azathioprine, and 55%-60% received cyclosporine in doses below the protocol. The immunosuppressive doses (both of cyclosporine and azathioprine) in the first month were significantly related to the RE (p < 0.01) in the first month and the total number of RE in the first 6 months (p < 0.01). The other predictors were younger recipient age and older donor age. The sixth-month serum creatinine level was predicted by the donor age, the level of serum creatinine in the first month and the total number of RE in the first 6 months post-transplant. While no specific predictors of graft loss were identified in this cohort, diabetic nephropathy (p = 0.000) as the native renal disease, and the total number of RE were strongly related to patient mortality. The occurrence of > or = 2 RE in the first 6 months was an independent predictor, increasing the risk of death in the first 2 years post-transplant by 2.3 (p = 0.0001, 95% CI: 1.5-3.4). CONCLUSIONS: Sub-therapeutic baseline immunosuppression in the early post-transplant period predisposes to acute RE. This has an impact not only on graft function but also forms an important proximate marker of mortality, as seen in this cohort. Thus, immunosuppressive drug dosage should be optimized and therapeutic drug level monitoring strategies should be preemptive rather than event related, especially in the early post-transplant period. While fixed-dose immunosuppressive drug schedules are widely followed, it is possible to fall short of the target unless a specific effort is made to meet and sustain schedules.

Carotid endarterectomy under regional analgesia:a retrospective study (1988-1999).

The procedure of carotid endarterectomy is more or less standardized. Controversies persist on many technical issues, one of which is general versus regional anaesthesia. We retrospectively evaluated the influence of regional analgesia on perioperative complications, the hospital stay and the perioperative mortality after carotid endarterectomy in 53 patients. All the patients in the study received deep cervical block regional anaesthesia (Winne's technique) for carotid endarterectomy. Indications for surgery included transient ischaemic haemodynamically significant stenosis. Shunt was used in 7 cases (13.2%). General anaesthesia was supplemented in 2 patients (3.8%). There was no perioperative mortality. Permanent non-fatal neurologic deficit occurred in 1 patient (1.9%) and temporary neurologic Deficit occurred in 1 patient (1.9%). The mean ICU stay was 1.85 (+/-0.82) days and the hospital stay was 5.2 (+/-1.14) days. On the basis of our data we believe that under regional anaesthesia carotid endarterectomy can be performed with acceptable complications and that regional anaesthetic technique is safe and well tolerated by the patients.

Does inhaled nitric oxide improve survival in operated congenital disease with severe pulmonary hypertension?

BACKGROUND: The present study aimed to assess the impact of inhaled nitric oxide on survival following correction of congenital heart defects with residual pulmonary arterial hypertension. METHODS AND RESULTS: Inhaled nitric oxide was utilized for the management of residual pulmonary hypertension in 24 children following surgical correction of their underlying heart defects. Their ages ranged from 15 days to 14 months (median 5 months). Pulmonary artery hypertension was diagnosed either by direct pulmonary artery pressure monitoring or by echocardiography. Inhaled nitric oxide was used electively in 22 patients when the ratio of the mean pulmonary arterial pressure and mean systemic arterial pressure exceeded 0.5. In the remaining 2 patients, nitric oxide was used only to manage a pulmonary hypertensive crisis. Inhaled nitric oxide was also used a second time in 2 patients who developed delayed pulmonary hypertensive crisis. Twenty-two patients showed an initial response to therapy and the pulmonary artery pressures dropped significantly. Of the patients on direct pulmonary artery pressure monitoring, a pulmonary artery to systemic artery pressure ratio below 0.3 on prolonged therapy was associated with a survival ratio of 4/6 (including 1 neurological death and one reoperation); that between 0.3 and 0.5 with a survival ratio of 3/4. Three out of four patients with sustained echocardiographic and clinical response also survived and were discharged from the hospital. All the patients who showed a lack of response to (n=2), tolerance to (n=1), or dependence on (n=6) the use of inhaled nitric oxide died. In addition, all 5 patients who had a pulmonary hypertensive crisis died, 3 in spite of successful resuscitation with nitric oxide. Thus, excluding one neurological death and one re-operation, only 9 (41%) out of 22 patients survived. CONCLUSIONS: Though inhaled nitric oxide is effective in lowering pulmonary pressure, it does not appear to improve the survival rate following repair of congenital heart disease in those with associated severe pulmonary hypertension. A randomized trial between the use and non-use of inhaled nitric oxide is warranted to determine its exact role in influencing survival in patients with residual pulmonary hypertension following surgical repair.

Changes in transfusion therapy guided by thromboelastograph in cardiac surgery.

This study was conducted to determine the use of thromboelastograph in predicting excessive postoperative bleeding, detecting coagulopathy related bleeding, reducing usage of blood and blood products and aiding reexploration decisions. One hundred fifty patients undergoing coronary artery bypass graft surgery under cardiopulmonary bypass were randomized and studied prospectively in two equal groups. In the study group, celite activated heparinase pretreated blood samples, 30 minutes after protamine administration were subjected to thromboelastographic analysis and blood and blood component therapy was administered based on thromboelastograph values, if they had significant bleeding. In the control group transfusion therapy was based on routine coagulation tests and clinical judgement of the surgeon. Patients who bled 100ml / hour in the first three hours or 300 ml in the first three hours and 75 ml/hour in the next three hours were considered significant bleeders. Haematocrit at 0,6,12,18,24,30 and 36 hours of shifting to intensive care unit were noted. Accuracy of thromboelastograph in predicting excess postoperative bleeding was found to be 92%. Consumption of whole blood, packed red blood cells and fresh frozen plasma (p values 0.03, 0.05, 0.001 respectively) was significantly less in the study group. There was poor correlation between postoperative bleeding and platelet count but those who did not bleed had a significantly higher platelet count as compared to those who did. Except at 30 hours, haematocrit was significantly higher in the study group up to 36 hours. Thromboelastograph is a useful diagnostic tool to detect coagulopathies following cardiopulmonary bypass. It helps in instituting appropriate blood and blood component therapy thereby avoiding unnecessary transfusion and associated risks. Accurate detection of coagulopathy is possible with heparinase pretreatment of the blood sample.