Effect of nonpermissive HLA-DPB1 mismatches after unrelated allogeneic transplantation with in vivo T-cell depletion.

We investigated the impact of donor-recipient HLA-DPB1 matching on outcomes of allogeneic hematopoietic stem cell transplantation with in vivo T-cell depletion using antithymocyte globulin (ATG) for patients with hematological malignancies. All donor-recipient pairs had high-resolution typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DRB3/4/5 and were matched at HLA-A, HLA-B, HLA-C, and HLA-DRB1. HLA-DPB1 mismatches were categorized by immunogenicity of the DPB1 matching using the DPB T-cell epitope tool. Of 1004 donor-recipient pairs, 210 (21%) were DPB1 matched, 443 (44%) had permissive mismatches, 184 (18%) had nonpermissive mismatches, in graft-versus-host (GVH) direction, and 167 (17%) had nonpermissive mismatches in host-versus-graft (HVG) direction. Compared with HLA-DPB1 permissive mismatched pairs, nonpermissive GVH mismatched pairs had the highest risk for grade II to IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 1.4; P = .01) whereas matched pairs had the lowest risk (HR, 0.5; P < .001). Grade III to IV aGVHD was only increased with HLA-DPB1 nonpermissive GVH mismatched pairs (HR, 2.3; P = .005). The risk for disease progression was lower with any HLA-DPB1 mismatches, permissive or nonpermissive. However, the favorable prognosis of HLA-DPB1 mismatches on disease progression was observed only in peripheral blood stem cell recipients who were in the intermediate-risk group by the Disease Risk Index (HR, 0.4; P = .001) but no other risk groups. Our results suggest avoidance of nonpermissive GVH HLA-DPB1 mismatches for lowering the risk for grade II to IV and III to IV aGVHD. Permissive or nonpermissive HVG HLA-DPB1 mismatches may be preferred over HLA-DPB1 matches in the intermediate-risk patients to decrease the risk for disease progression.

Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation.

A single mismatch in highly expressed HLA-A, -B, -C, and -DRB1 loci (HEL) is associated with worse outcomes in hematopoietic stem cell transplantation, while less is known about the cumulative impact of mismatches in the lesser expressed HLA loci DRB3/4/5, DQ, and DP (LEL). We studied whether accumulation of LEL mismatches is associated with deleterious effects in 3853 unrelated donor transplants stratified according to number of matches in the HEL. In the 8/8 matched HEL group, LEL mismatches were not associated with any adverse outcome. Mismatches at HLA-DRB1 were associated with occurrence of multiple LEL mismatches. In the 7/8 HEL group, patients with 3 or more LEL mismatches scored in the graft-versus-host vector had a significantly higher risk of mortality (1.45 and 1.43) and transplant-related mortality (1.68 and 1.54) than the subgroups with 0 or 1 LEL mismatches. No single LEL locus had a more pronounced effect on clinical outcome. Three or more LEL mismatches are associated with lower survival after 7/8 HEL matched transplantation. Prospective evaluation of matching for HLA-DRB3/4/5, -DQ, and -DP loci is warranted to reduce posttransplant risks in donor-recipient pairs matched for 7/8 HEL.

In Vitro Studies of Chromone-Tetrazoles against Pathogenic Protozoa, Bacteria, and Fungi.

In vitro studies to fourteen previously synthesized chromone-tetrazoles and four novel fluorine-containing analogs were conducted against pathogenic protozoan (Entamoeba histolytica), pathogenic bacteria (Pseudomonas aeruginosa, and Staphylococcus aureus), and human fungal pathogens (Sporothrix schenckii, Candida albicans, and Candida tropicalis), which have become in a serious health problem, mainly in tropical countries.

Synthesis of 3-tetrazolylmethyl-4H-chromen-4-ones via Ugi-azide and biological evaluation against Entamoeba histolytica, Giardia lamblia and Trichomona vaginalis.

The synthesis of novel 3-tetrazolylmethyl-4H-chromen-4-ones via an Ugi-azide multicomponent reaction and their biological evaluation against Entamoeba histolytica, Giardia lamblia and Trichomona vaginalis are described. Reported yields are moderate to good and biological results show that these compounds could be considered as candidates to anti-parasitic drugs, especially against G. lamblia.

RET splice site variants in medullary thyroid carcinoma.

Introduction: Medullary thyroid carcinoma (MTC) is an aggressive cancer that is often caused by driver mutations in RET. Splice site variants (SSV) reflect changes in mRNA processing, which may alter protein function. RET SSVs have been described in thyroid tumors in general but have not been extensively studied in MTC. Methods: The prevalence of RET SSVs was evaluated in 3,624 cases with next generation sequence reports, including 25 MTCs. Fisher exact analysis was performed to compare RET SSV frequency in cancers with/without a diagnosis of MTC. Results: All 25 MTCs had at least one of the two most common RET SSVs versus 0.3% of 3,599 cancers with other diagnoses (p < 0.00001). The 11 cancers with non-MTC diagnoses that had the common RET SSVs were 4 neuroendocrine cancers, 4 non-small cell lung carcinomas, 2 non-MTC thyroid cancers, and 1 melanoma. All 25 MTCs analyzed had at least one of the two most common RET SSVs, including 4 with no identified mutational driver. Discussion: The identification of RET SSVs in all MTCs, but rarely in other cancer types, demonstrates that these RET SSVs distinguish MTCs from other cancer types. Future studies are needed to investigate whether these RET SSVs play a pathogenic role in MTC.

Implementation of a High-Accuracy Targeted Gene Expression Panel for Clinical Care.

This study describes the validation of a clinical RNA expression panel with evaluation of concordance between gene copy gain by a next-generation sequencing (NGS) assay and high gene expression by an RNA expression panel. The RNA Salah Targeted Expression Panel (RNA STEP) was designed with input from oncologists to include 204 genes with utility for clinical trial prescreening and therapy selection. RNA STEP was validated with the nanoString platform using remnant formalin-fixed, paraffin-embedded-derived RNA from 102 patients previously tested with a validated clinical NGS panel. The repeatability, reproducibility, and concordance of RNA STEP results with NGS results were evaluated. RNA STEP demonstrated high repeatability and reproducibility, with excellent correlation (r > 0.97, P < 0.0001) for all comparisons. Comparison of RNA STEP high gene expression (log2 ratio ≥ 2) versus NGS DNA-based gene copy number gain (copies ≥ 5) for 38 mutually covered genes revealed an accuracy of 93.0% with a positive percentage agreement of 69.4% and negative percentage agreement of 93.8%. Moderate correlation was observed between platforms (r = 0.53, P < 0.0001). Concordance between high gene expression and gene copy number gain varied by specific gene, and some genes had higher accuracy between assays. Clinical implementation of RNA STEP provides gene expression data complementary to NGS and offers a tool for prescreening patients for clinical trials.

Characteristics of culprit atheromatous plaques obtained in vivo by intravascular ultrasound radiofrequency analysis: results from the CULPLAC study.

OBJECTIVES: We used virtual histology-intravascular ultrasound (VH-IVUS) to investigate the characteristics of culprit lesions in acute coronary syndromes (ACS). BACKGROUND: Autopsy studies of patients who died of ACS have shown that culprit atheromatous plaques almost always contain a large lipid-necrotic core covered by a ruptured thin fibrous cap. There are no studies of sufficient size that have assessed the in vivo characterization of plaques responsible for ACS. METHODS: Patients undergoing angiography for stable ischemic heart disease and ACS (with and without ST-segment elevation) were enrolled in a prospective study. Lesions in patients with stable angina were classified as stable and those in patients with ACS as culprit or nonculprit. RESULTS: The study included 189 patients: VH-IVUS was used to assess 253 lesions (73 stable, 82 nonculprit, and 98 culprit lesions). The thin-cap fibroatheroma phenotype (VH-TCFA) was more frequent among lesions in patients with ACS (55.1% in culprit lesions, 36.6% in nonculprit lesions and 14.4% in stable lesions; P = .007). The arc of the VH-TCFA exposed to the vessel lumen was significantly greater in culprit lesions than in nonculprit lesions (122.28° ± 58 vs 89.46° ± 52; respectively; P = .007). Multivariate analysis showed that VH-TCFA (OR 2.1; P = .033), calcified nodules (OR 2.1; P = .046), positive remodeling (OR 3.5; P < .001) and necrotic core volume (OR 1.02;P = .009) were independently associated with a clinically identified culprit lesion. CONCLUSIONS: Plaque phenotype, rather than the proportion of each tissue, appears to be associated with plaque instability. VH-TCFA, particularly subtype IV, is associated with lesions responsible for ACS.

Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation.

Anti-HLA donor-specific Abs (DSAs) have been reported to be associated with graft failure in mismatched hematopoietic stem cell transplantation; however, their role in the development of graft failure in matched unrelated donor (MUD) transplantation remains unclear. We hypothesize that DSAs against a mismatched HLA-DPB1 locus is associated with graft failure in this setting. The presence of anti-HLA Abs before transplantation was determined prospectively in 592 MUD transplantation recipients using mixed-screen beads in a solid-phase fluorescent assay. DSA identification was performed using single-Ag beads containing the corresponding donor's HLA-mismatched Ags. Anti-HLA Abs were detected in 116 patients (19.6%), including 20 patients (3.4%) with anti-DPB1 Abs. Overall, graft failure occurred in 19 of 592 patients (3.2%), including 16 of 584 (2.7%) patients without anti-HLA Abs compared with 3 of 8 (37.5%) patients with DSA (P = .0014). In multivariate analysis, DSAs were the only factor highly associated with graft failure (P = .0001; odds ratio = 21.3). Anti-HLA allosensitization was higher overall in women than in men (30.8% vs 12.1%; P < .0001) and higher in women with 1 (P = .008) and 2 or more pregnancies (P = .0003) than in men. We conclude that the presence of anti-DPB1 DSAs is associated with graft failure in MUD hematopoietic stem cell transplantation.

Exploiting antitumor immunity to overcome relapse and improve remission duration.

Cancer survivors often relapse due to evolving drug-resistant clones and repopulating tumor stem cells. Our preclinical study demonstrated that terminal cancer patient's lymphocytes can be converted from tolerant bystanders in vivo into effective cytotoxic T-lymphocytes in vitro killing patient's own tumor cells containing drug-resistant clones and tumor stem cells. We designed a clinical trial combining peginterferon α-2b with imatinib for treatment of stage III/IV gastrointestinal stromal tumor (GIST) with the rational that peginterferon α-2b serves as danger signals to promote antitumor immunity while imatinib's effective tumor killing undermines tumor-induced tolerance and supply tumor-specific antigens in vivo without leukopenia, thus allowing for proper dendritic cell and cytotoxic T-lymphocyte differentiation toward Th1 response. Interim analysis of eight patients demonstrated significant induction of IFN-γ-producing-CD8(+), -CD4(+), -NK cell, and IFN-γ-producing-tumor-infiltrating-lymphocytes, signifying significant Th1 response and NK cell activation. After a median follow-up of 3.6 years, complete response (CR) + partial response (PR) = 100%, overall survival = 100%, one patient died of unrelated illness while in remission, six of seven evaluable patients are either in continuing PR/CR (5 patients) or have progression-free survival (PFS, 1 patient) exceeding the upper limit of the 95% confidence level of the genotype-specific-PFS of the phase III imatinib-monotherapy (CALGB150105/SWOGS0033), demonstrating highly promising clinical outcomes. The current trial is closed in preparation for a larger future trial. We conclude that combination of targeted therapy and immunotherapy is safe and induced significant Th1 response and NK cell activation and demonstrated highly promising clinical efficacy in GIST, thus warranting development in other tumor types.

HLA population genetics: a Lebanese population.

Human leukocyte antigen (HLA) typing was done in 426 Lebanese subjects of 88 families, in which 347 haplotypes were identified. The A, B, C, DRB1, DRB3/4/5, DQB1 and DPB1 loci were typed at high resolution. This study shows that information theory, as originally developed by Claude Shannon in 1948, provides a promising theoretical foundation to study the population genetics of a genetic system like HLA. Although Lebanese carry HLA alleles found in other populations, the association of these alleles into haplotypes is quite unique. Comparisons are made with the main ethnic groups. Two haplotypes well represented in the Lebanese population are not identified in any global population: L1 = {A*26:01:01 - B*35:01:01:01- C*04:01:01:01- DRB1*16:01:01 - DRB5*02:02 - DQB1*05:02:01} and L2 = {A*02:02 - B*41:01- C*17:01:01:01 -DRB1*11:04:01 - DRB3*02:02:01:01- DQB1*03:01:01:01}. By studying linkage disequilibrium in two blocks at a time, with the division of the blocks at different levels in consecutive cycles, conserved haplotypes in full linkage disequilibrium come to light, such as {A*26:01:01- B*35:01:01:01 - C*04:01:01:01 - DRB1*16:01:01 - DRB5*02:02 - DQB1*05:02:01- DPB1*03:01:01} and {A*33:01:01 - B*14:02:01 - C*08:02:01 - DRB1*01:02:01- DQB1*05:01:01:01 - DPB1*04:01:01:01}.

Cytokine gene polymorphisms affect reactivation of cytomegalovirus in patients with cancer.

Reactivation of cytomegalovirus (CMV) in the bloodstream may occur upon severe immune defect or suppression during lifetime. We performed a case controlled study to probe the effects of the host cytokine gene single nucleotide polymorphisms (SNPs) on CMV reactivation. The study subjects were patients with cancer but without stem cell transplantation. The cases were patients tested positive for CMV pp65 antigenemia and the controls were those tested negative. Each case was matched to two controls for similar underlying disease, sex, age, and CMV antibody test status. Ninety cases and 182 controls were chosen and typed for 48 SNPs within 13 cytokines. Alleles of three cytokines were found to be significantly associated with CMV reactivation. Associated with risk of CMV reactivation were the TGFß1-2 allele (10C and 25G) with a hazard ratio (HR) of 1.97% and 95% confidence interval (CI) of 1.14-3.41 and the IL-4-3 allele (-1098T, -590T, and -33T) (HR, 2.08) (95% CI, 1.19-3.63); associated with protection was the IL-2-2 allele (-330T and +166G) (HR, 0.58) (95% CI, 0.35-0.97). Gene dosage, synergism, and antagonism among these alleles were also observed. Our results suggest roles of immunogenetic variations on the immunity against CMV, which may allow clinical CMV risk stratification. Further studies of these alleles are warranted.

Outcomes of patients with myeloid malignancies treated with allogeneic hematopoietic stem cell transplantation from matched unrelated donors compared with one human leukocyte antigen mismatched related donors using HLA typing at 10 loci.

Most candidates for hematopoietic stem cell transplantation (HSCT) lack a human leukocyte antigen (HLA)-identical sibling donor. Some patients may have a related donor with whom they are mismatched at 1 antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We evaluated the outcomes (survival, relapse, nonrelapse mortality [NRM]) of all 28 patients with a single HLA antigen/allele mismatch identified through high-resolution HLA typing at HLA-A, -B, -C, -DRB1, and -DQB1, and all 318 patients with myeloid malignancies who received transplants from a 10/10 MUD treated during the same period of time at a single institution. Overall, outcomes for patients treated from a 1-antigen/allele mismatch related donor were significantly worse than from a MUD, primarily because of increased NRM. Overall survival (OS) rates at 3 years for 1-antigen/allele mismatched related donor and MUD transplant recipients were 19% and 45% (P = .007), and NRM rates were 40% and 26% (P = .05), respectively. Patients with class I mismatches appeared to have poorer OS than did patients with class II mismatches. A higher incidence of graft rejection was identified in the mismatched related donor group (P = .02). These results indicate that transplant outcomes are better with a MUD than with a 1 antigen/allele-mismatched related donor.

Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease.

The polymorphic products of major histocompatibility complex class I-related chain A (MICA) genes are important in solid organ transplantation rejection. MICA expression is limited to gut epithelium and may play a role in triggering acute graft-versus-host disease (aGVHD). A total of 236 recipients of unrelated donor transplantation were studied. Donor-recipient human leukocyte antigen (HLA) match was 10/10 human leukocyte antigen (HLA-A, -B, -C, -DRB1, -DQB1) in 73% and MICA mismatch in 8.4%. Because of physical vicinity of the loci, MICA mismatch was significantly associated with mismatch at HLA-B and HLA-C. A higher rate of grade II-IV aGVHD was seen in MICA-mismatched patients (80% vs 40%, P = .003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P = .02) and HLA any mismatch (83% vs 46%, P = .003). The rate of grade II-IV gastrointestinal aGVHD was also higher in MICA-mismatched patients (35% vs 17%, P = .05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. This study was registered at ClinicalTrials.gov (Identifier NCT00506922).

Comparing Three Methods for Reducing Psychotropic Use in Older Demented Spanish Care Home Residents.

BACKGROUND/OBJECTIVE: In nursing homes across the world, and particularly in Spain, there are concerns that psychotropic medications are being overused. For older Spanish nursing home residents who had dementia, we sought to evaluate the association between applying interventions designed to reduce inappropriate psychotropic medication use and subsequent psychotropic use. DESIGN: Retrospective, propensity score-matched, controlled, patient-level observational analysis. SETTING: A total of 45 nursing homes in Spain. PARTICIPANTS: A total of 1653 nursing home residents, aged 70 to 99 years, who had dementia and were prescribed an antipsychotic, anxiolytic, or antidepressant medication, 606 of whom received an intervention; the remainder served as propensity score-matched controls. INTERVENTION: Team Rounds, Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert Doctors to Right Treatment (START) criteria, or a Patient Decision Aid. MEASUREMENTS: At 2 and 4 weeks following intervention: change from baseline drug class-specific milligram-equivalent daily dose (MEDD); at 2 weeks: patient falls and restraint use. RESULTS: Within each intervention/drug-class cohort, intervention patients and matched controls had similar baseline demographic characteristics, Charlson scores, lengths of admission, and drug class-specific MEDDs. Compared to controls, patients exposed to Team Rounds experienced a 23.3% (95% confidence interval [CI] = 13.9%-32.8%) reduction in antipsychotic and a 23.1% (95% CI = 18.3%-28.0%) reduction in anxiolytic MEDDs; those exposed to Patient Decision Aids had a 24.8% (95% CI = 15.6%-33.9%) reduction in antipsychotic and a 31.8% (95% CI = 25.5%-38.2%) reduction in anxiolytic MEDDs; and those exposed to STOPP/START application had a 27.7% (95% CI = 22.4%-33.0%) reduction in antipsychotic and a 39.5% (95% CI = 35.5%-43.5%) reduction in anxiolytic MEDDs. Intervention-associated antidepressant MEDD reductions were statistically significant but less dramatic. Interventions were associated with higher rates of medication discontinuation, but not higher rates of deaths, patient falls, or physical restraints. CONCLUSION: We found strong evidence that the interventions we studied were associated with reduced psychotropic use without commensurate harms, suggesting that such interventions should be incorporated into Spanish nursing home care models. Public reporting of psychotropic medication use in Spanish care homes may encourage care homes to regularly monitor psychotropic medication use and implement such instruments. J Am Geriatr Soc, 2019.

DP reactive antibody in a zero mismatch renal transplant pair.

This study describes molecular basis for positive B-cell flow crossmatch in a zero mismatch (0MM) transplant pair. Our end-stage renal disease patient was B-cell flow crossmatch positive with a 0MM deceased donor. DNA from the donor and patient were further typed by a high-resolution method. The patient's sera were tested for anti-HLA reactivity by single antigen bead using a Luminex platform. The patient and donor were found to be HLA identical except for a single DP allele MM (DPB1*0601). As there was no single antigen bead coated with DPB*0601, analysis of the amino acid residues of reactive and nonreactive DPB1 alleles was conducted. The results showed that all reactive alleles carried the amino acid D-E at residue 55 and 56 of DPB1. The MM allele DPB1*0601 also carries the DE 55-56 epitope. We conclude that positive B-cell flow crossmatch was likely the result of single MM in the DP locus.

Common and well-documented HLA alleles: report of the Ad-Hoc committee of the american society for histocompatiblity and immunogenetics.

In histocompatibility testing some genotype ambiguities are almost always resolved into the genotype with the most common alleles. To achieve unambiguous assignments additional unwieldy tests are performed. The American Society for Histocompatibility and Immunogenetics formed a committee to define what human leukocyte antigen (HLA) genotypes do not need to be resolved in external proficiency testing. The tasks included detailed analysis of large datasets of high-resolution typing and thorough review of the pertinent scientific literature. Strict criteria were used to create a catalogue of common and well-documented (CWD) alleles. In total, 130, 245, 81, and 143 of the highly polymorphic HLA-A, -B, -C, and DRB1 loci fell into the CWD category; these represent 27%-30% of all alleles recognized. For the loci DRB3/4/5, DQA1, DQB1, and DPB1, a total of 29, 16, 26, and 52 CWD alleles were identified. A recommendation indicated that an acceptable report should only include one possible genotype; multiple genotypes can only be reported if only one of these includes two alleles of the CWD group. Exceptions in which resolution is not necessary are ambiguities involving functional alleles with identical sequences in the antigen recognition site. The criteria were established for proficiency testing, which could be a valuable tool when making clinical histocompatibility decisions.

Association of HLA Class I and Class II genes with bcr-abl transcripts in leukemia patients with t(9;22) (q34;q11).

BACKGROUND: Based on the site of breakpoint in t(9;22) (q34;q11), bcr-abl fusion in leukemia patients is associated with different types of transcript proteins. In this study we have seen the association of HLA genes with different types of bcr-abl transcripts. The association could predict the bcr-abl peptide presentation by particular HLA molecules. METHODS: The study included a total of 189 patients of mixed ethnicity with chronic myelogenous leukemia and acute lymphocytic leukemia who were being considered for bone marrow transplantation. Typing of bcr-abl transcripts was done by reverse transcriptase PCR method. HLA typing was performed by molecular methods. The bcr-abl and HLA association was studied by calculating the relative risks and chi-square test. RESULTS: Significant negative associations (p < 0.05) were observed with HLA-A*02 (b2a2, e1a2), -A*68 (b2a2, b3a2, e1a2), -B*14 (b2a2, b3a2, e1a2), -B*15 (b2a2, b3a2), -B*40 (b2a2), -DQB1*0303 (b2a2, b3a2), -DQB1*0603 (b2a2), -DRB1*0401 (e1a2), -DRB1*0701 (b3a2), and -DRB1*1101 (b2a2). CONCLUSIONS: The negative associations of a particular bcr-abl transcript with specific HLA alleles suggests that these alleles play a critical role in presenting peptides derived from the chimeric proteins and eliciting a successful T-cell cytotoxic response. Knowledge of differential associations between HLA phenotypes and bcr-abl fusion transcript types would help in developing better strategies for immunization with the bcr-abl peptides against t(9;22) (q34;q11)-positive leukemia.

Effect of polymeric diets in patients on continuous ambulatory peritoneal dialysis.

OBJECTIVE: To determine if a diet complemented with calcium caseinate is better than a natural high protein diet for increasing serum albumin levels in patients on continuous ambulatory peritoneal dialysis (CAPD). PATIENTS AND METHODS: A 4-month clinical trial involving 100 patients older than 18 years was performed. Patients were randomized into two groups: group A, high protein diet (1.4 g natural protein/kg target weight/day and 35 kcal/kg target weight/day); and group B, calcium caseinate (0.7 g calcium caseinate plus 0.7 g natural protein diet/kg target weight/day and 35 kcal/kg target weight/day). Serum levels of albumin, total proteins (TP), BUN, creatinine, glucose, urea, sodium, and potassium, and hematocrit, leukocytes, erythrocytes, and hemoglobin were analyzed at baseline and every 30 days. RESULTS: The final mean albumin value was, for group A, 3.04 +/- 0.39 g/dL, and for group B, 3.12 +/- 0.41 g/dL (p < 0.05); TP for group A, 6.29 +/- 0.47 g/dL, and for group B, 6.49 +/- 0.51 g/dL (p < 0.05); leukocytes for group A, 6888 +/- 1282/mm3, for group B, 7288 +/- 1878/mm3 (p = 0.05); BUN for group A, 47 +/- 11 mg/dL, for group B, 50 +/- 16 mg/dL (p = 0.05). Regression analysis showed a treatment effect in serum albumin and TP levels from the third month in both groups. In group B, a constant elevation of serum albumin of 0.19 mg/dL and TP of 0.27 mg/dL was observed in every month of treatment with calcium caseinate. In the regression analysis of group A we observed a smaller increase in serum albumin, 0.06 mg/dL, and in TP, 0.11 mg/dL, in each month of treatment with the high protein diet. Both differences are significant (p < 0.05). CONCLUSION: Calcium caseinate used in CAPD patients suffering from malnutrition increases serum albumin levels.

[Relevance of CYP2C19 2 regarding platelet reactivity in patients with acute coronary syndrome treated with clopidogrel]. / Impacto de CYP2C19 2 en la reactividad plaquetar en pacientes con síndrome coronario agudo tratados con clopidogrel.

BACKGROUND AND OBJECTIVE: Previous studies have shown that the metabolism of P2Y12 receptor blockers is influenced not only by CYP2C19 2 but also by PON1-Q192R alelles. We aimed to evaluate the impact of CYP2C19 2 and PON1-Q192R polymorphisms carriage in platelet reactivity and clinical outcome in patients with ischemic heart disease undergoing cardiac catheterization. PATIENTS AND METHOD: We recruited prospectively patients with acute coronary syndrome undergoing cardiac catheterization (n=247). We evaluated the genotype (CYP2C19 2, CYP2C19 17, PON1-Q192R) with TaqMan(®) assay and platelet aggregometry in all patients. We assessed both in and out-of-hospital events (unstable angina, periprocedural and spontaneous myocardial infarction, myocardial infarction, all-cause death, stent thrombosis and stroke) during follow-up. RESULTS: Carriers of CYP2C19 2 alleles showed a significant higher residual platelet reactivity (PRU, mean [SD], 252 [76] vs. 287 [74], P=.002). Carriers of PON1-Q192R CT(RQ) and TT(QQ) alleles and CYP2C19 17 did not present a different response to clopidogrel. In a multivariable setting for the prediction of platelet reactivity, the contribution of CYP2C19 2 was modest (Wald=7.5; odds ratio [OR] for ≥ 1 alelle 2=2,786, 95% confidence interval [95% CI] 1,337-5,808). Independent predictors were baseline hemoglobin levels (g/dL, OR .666, 95% CI .555-.801) and the use of statins (OR .376, 95% CI .162-.873). Body mass index was a risk factor (OR 1,074, CI 95% 1,005-1,148). Studied polymorphisms did not predict an adverse outcome. CONCLUSIONS: CYP2C19 2 polymorphism influenced moderately platelet reactivity but did not show an impact on clinical outcome in patients with acute coronary syndrome. Neither CYP2C19 17 nor PON1-Q192R polymorphisms showed an impact upon platelet reactivity or outcome.