Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura

High-dose intravenous gammaglobulin (IVIgG) was given to 12 children and adults with chronic idiopathic thrombocytopenic purpura (ITP) to avoid splenectomy or because they either failed to respond to or required maintenance with high doses of steroids and/or immunosuppressives. The average platelet count increase to initial therapy was 239,500/microliters (range 23,000-790,000). A concomitant IgG Fc receptor blockade, measured by IgG-sensitized 51Cr-labeled autologous erythrocytes, was seen in 11 of 11 patients tested, both splenectomized and not splenectomized, lasting 3-4 wk. Six or more months after treatment, 2 children are in remission, 2 children and 2 adults are stable requiring no therapy with platelet counts of approximately 50,000 and 30,000, respectively, 3 children require maintenance IVIgG therapy at 2-10-wk intervals, and 1 child and 2 adults have become refractory to further IVIgG. Splenectomy was not performed in 4 children. Two adults were able to discontinue daily prednisone. The 3 patients who became unresponsive to Swiss Red Cross gamma-globulin (IgSRK) therapy did so in conjunction with a markedly elevated platelet-associated IgG and IgM. Serum IgM increased an average of 103 mg/dl after the IVIgG infusions. No significant side effects were seen.     

A common mutation C677T in the 5,10-methyltetrahydrofolate reductase gene is associated to idiopathic deep venous thrombosis

PURPOSE: Moderate hyperhomocysteinemia is a risk factor for deep venous thrombosis. The homozygous C677T methylenetetrahydrofolate reductase (MTHFR) mutation is associated with increased level of total plasma homocysteine. The association between homozygous C677T mutation and deep venous thrombosis is still controversial. METHOD: In order to evaluate this association, we studied the prevalence of C677T mutation in 168 patients with confirmed deep venous thrombosis; 31 with an idiopathic deep venous thrombosis (group A) and 137 with thromboembolic event explained by one or more clinical and/or biological risk factors (group B). RESULTS: The distribution of genotypes was different between group A and B [++/+ -/- -(n(%))] : 9(29)/10(32)/12(39) vs 16(12)/57(42)/64(46) (chi(2) : 6.03; P: 0.049). The comparison between homozygotes and the two other genotypes showed significant statistical relationship between homozygous genotype and idiopathic character of deep venous thrombosis (chi(2) : 6.01; P : 0.014; OR : 3.09 [IC 95% : 1.06-8.53]). CONCLUSION: These results suggest that homozygous C677T methylenetetrahydrofolate reductase mutation could be considered as a genetic risk factor for venous thrombosis.     

The prognostic role of left ventricular hypertrophy in patients with or without coronary artery disease.

OBJECTIVE: To examine the association between echocardiographically determined left ventricular hypertrophy and mortality in patients with and without coronary artery disease. DESIGN: Cohort study with a mean follow-up period of 4 years. SETTING: An inner-city public hospital in Chicago. PATIENTS: A cohort of 785 patients, most of whom were black and had hypertension. INTERVENTIONS: Coronary arteriography for presumed coronary artery disease and echocardiography. MAIN OUTCOME MEASURE: All-cause and cardiac mortality. RESULTS: Left ventricular hypertrophy, based on left ventricular mass corrected for body surface area, was present in 194 of 381 patients (51%) with coronary artery disease and in 162 of 404 patients (40%) without coronary artery disease. Patients with left ventricular hypertrophy had worse survival than those without hypertrophy in both the group with coronary artery disease and the group without coronary artery disease. After adjustment was made for age at baseline, sex, and hypertension, the relative risk for death from any cause in patients with hypertrophy compared with patients without hypertrophy was 2.14 (95% CI, 1.24 to 3.68) among those with coronary artery disease and 4.14 (CI, 1.77 to 9.71) among those without coronary artery disease. CONCLUSIONS: Echocardiographically determined left ventricular hypertrophy is an important prognostic marker in patients with or without coronary artery disease. The effect of reversing ventricular hypertrophy in patients with and without coronary disease deserves further study.     

T-cell death by apoptosis in vertically human immunodeficiency virus- infected children coincides with expansion of CD8+/interleukin-2 receptor-/HLA-DR+ T cells: sign of a possible role for herpes viruses as cofactors?

One mechanism proposed to play a role in T-cell depletion in human immunodeficiency virus (HIV) infection is apoptosis (activation-induced cell death). We assessed whether apoptosis is related to activation of T cells in vivo and its possible triggers. DNA was extracted from peripheral blood mononuclear cells (PBMC) taken from 16 vertically HIV- infected children and 9 HIV-negative children born to HIV-positive mothers (controls) and tested by agarose gel electrophoresis for the presence of DNA fragments specific for apoptosis. Signs of apoptosis were found on in vitro culture of PBMC from 12 of 16 HIV-infected children, but not in PBMC from the nine controls. Eleven of the 12 HIV- infected children with apoptosis showed an elevated (> 15%) proportion of CD3+/HLA-DR+ cells. This was due to an increased proportion of CD8+/HLA-DR+ cells, as shown in 7 of 7 further tested patients. In none of the probands an increased (> 5%) proportion of IL-2 receptor expressing CD3+ cells was found. T cells undergoing apoptosis were preferentially of the CD8+ phenotype. Expansion of circulating CD8+/interleukin-2 receptor (IL-2R)-/HLA-DR+ T cells is known to occur during active infection with herpes viruses. To investigate the possible role of herpes viral coinfections for apoptosis in HIV infection, we focused on Epstein-Barr virus (EBV) as an example for a herpes virus usually acquired during childhood. In 10 of 12 patients with apoptosis, we found increased levels of EBV genome in PBMC and/or tissues, indicating active EBV replication. By contrast, no increased burden of EBV was found in the four HIV-infected patients without apoptosis or in the controls. Our data indicate that in children the occurrence of apoptosis in HIV infection is closely related to activation of CD8+ T cells. Furthermore, primoinfection with or reactivation of herpes viruses, such as EBV, may substantially contribute to such T-cell activation and the ensuing apoptosis. Additional studies are warranted to evaluate the contribution of herpes virus-triggered apoptosis to the T-cell loss leading to the acquired immunodeficiency syndrome.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

Denaturing interaction between sickle hemoglobin and phosphatidylserine liposomes

It is hypothesized that abnormal interaction between sickle hemoglobin (HbS) and erythrocyte membrane lipid might promote deposition of denatured hemoglobin (hemichrome) on the membrane. We compared the interaction of HbS and normal HbA with large unilamellar phosphatidylserine (PS) liposomes under low salt/pH conditions. Admixture of oxyHb and dioleoyl-PS resulted in loss of absorbance at 412 nm, the apparent first order rate constant for which was .25 +/- 0.02 hour-1 for HbA and .85 +/- 0.18 hour-1 for HbS. This was ascribable largely to formation of metHb and hemichromes and was accompanied by some actual transfer of heme from hemoglobin to lipid phase. By comparison, admixture of oxyHb with liposomes made from bovine brain PS having unsaturated acyl chains promoted even faster absorbance loss if the starting liposomal material contained detectable peroxidation by-product. In such cases, actual heme destruction developed with accompanying liberation of free iron and promotion of lipidperoxidation. Fluorescence quenching experiments indicate that hemoglobin/lipid interaction is characterized by very rapid initial electrostatic interaction, followed by development of irreversible changes. Similar changes still occur under conditions of physiologic salt/pH, but they develop much more slowly. The 3.4-fold faster oxidation of HbS versus HbA on lipid observed here represents an additional augmentation of the disparity in oxidation rates for hemoglobins in solution (1.7-fold faster for HbS than for HbA) observed previously. The accelerated promotion of Hb denaturation resulting from lipid contact may help explain deposits of hemichrome on sickle red blood cell membranes, particularly because these cells are in double jeopardy by virtue of having both the mutant HbS and abnormal amounts of peroxidized membrane lipid.     

Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss

Mohebbi N, Vargas‐Poussou R, Hegemann SCA, Schuknecht B, Kistler AD, Wüthrich RP, Wagner CA. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near‐normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non‐consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.     

Kaplan-Meier Survival Analysis Overestimates the Risk of Revision Arthroplasty: A Meta-analysis

Background

Although Kaplan-Meier survival analysis is commonly used to estimate the cumulative incidence of revision after joint arthroplasty, it theoretically overestimates the risk of revision in the presence of competing risks (such as death). Because the magnitude of overestimation is not well documented, the potential associated impact on clinical and policy decision-making remains unknown.

Questions/purposes

We performed a meta-analysis to answer the following questions: (1) To what extent does the Kaplan-Meier method overestimate the cumulative incidence of revision after joint replacement compared with alternative competing-risks methods? (2) Is the extent of overestimation influenced by followup time or rate of competing risks?

Methods

We searched Ovid MEDLINE, EMBASE, BIOSIS Previews, and Web of Science (1946, 1980, 1980, and 1899, respectively, to October 26, 2013) and included article bibliographies for studies comparing estimated cumulative incidence of revision after hip or knee arthroplasty obtained using both Kaplan-Meier and competing-risks methods. We excluded conference abstracts, unpublished studies, or studies using simulated data sets. Two reviewers independently extracted data and evaluated the quality of reporting of the included studies. Among 1160 abstracts identified, six studies were included in our meta-analysis. The principal reason for the steep attrition (1160 to six) was that the initial search was for studies in any clinical area that compared the cumulative incidence estimated using the Kaplan-Meier versus competing-risks methods for any event (not just the cumulative incidence of hip or knee revision); we did this to minimize the likelihood of missing any relevant studies. We calculated risk ratios (RRs) comparing the cumulative incidence estimated using the Kaplan-Meier method with the competing-risks method for each study and used DerSimonian and Laird random effects models to pool these RRs. Heterogeneity was explored using stratified meta-analyses and metaregression.

Results

The pooled cumulative incidence of revision after hip or knee arthroplasty obtained using the Kaplan-Meier method was 1.55 times higher (95% confidence interval, 1.43–1.68; p < 0.001) than that obtained using the competing-risks method. Longer followup times and higher proportions of competing risks were not associated with increases in the amount of overestimation of revision risk by the Kaplan-Meier method (all p > 0.10). This may be due to the small number of studies that met the inclusion criteria and conservative variance approximation.

Conclusions

The Kaplan-Meier method overestimates risk of revision after hip or knee arthroplasty in populations where competing risks (such as death) might preclude the occurrence of the event of interest (revision). Competing-risks methods should be used to more accurately estimate the cumulative incidence of revision when the goal is to plan healthcare services and resource allocation for revisions.     

Feasibility of determining myocardial infarction type from medical record review

BACKGROUND

Hospital discharge data are used extensively in health research. Given the clinical differences between ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI), it is important that these entities be distinguishable in a medical record. The authors sought to determine the extent to which the type of MI is recorded in medical records, as well as the consistency of this designation within individual records.

METHODS

Records of all MI patients admitted to a tertiary care centre in Canada from April 1, 2000, to March 31, 2001, were reviewed. Documentation and consistency of the use of the terms STEMI (Q wave, ST elevation or transmural MI) or NSTEMI (non-Q wave, subendocardial or nontransmural MI) were assessed in the admission history, progress notes, coronary care unit summary and discharge summary sections of each record.

RESULTS

Missing data were common; each chart section mentioned MI type in fewer than one-half of charts. When information was combined, it was possible to determine the type of MI in 81.1% of cases. MI type was consistently described as STEMI in 48.7% of cases, and as NSTEMI in 32.4%. Of concern, MI type was discrepant across sections in 10.5% of cases and missing entirely in 8.4% of cases.

CONCLUSIONS

The designation of MI cases as STEMI or NSTEMI is both incomplete and inconsistent in hospital records. This has implications for health services research conducted retrospectively using medical record data, because it is difficult to comprehensively study processes and outcomes of MI care if the type cannot be retrospectively determined.