Body mass index in Bengali adolescents

We describe a mixed longitudinal analysis of body mass index (BMI) in a group of Bengali adolescents (age 11-17 years) from a middle income family background and compare this against existing national and international data. Healthy school children, comprising of 416 boys and 343 girls were consented for annual repeat measurements of weight, height and pubertal staging between the years 1998 and 2001. The LMS method was used to construct smoothed BMI mean and standard deviation (SD) curves. Bengali adolescents have lower BMI than affluent Indian children and are -1 to -2 SD below US children. BMI increases in adolescence (boys: r = 0.49, p < 0.001, girls: r = 0.54, P < 0.001) with age but SMR does not have an independent effect on BMI.     

Gene expression profiling identifies BAX-delta as a novel tumor antigen in acute lymphoblastic leukemia

The identification of new tumor-associated antigens (TAA) is critical for the development of effective immunotherapeutic strategies, particularly in diseases like B-cell acute lymphoblastic leukemia (B-ALL), where few target epitopes are known. To accelerate the identification of novel TAA in B-ALL, we used a combination of expression profiling and reverse immunology. We compared gene expression profiles of primary B-ALL cells with their normal counterparts, B-cell precursors. Genes differentially expressed by B-ALL cells included many previously identified as TAA in other malignancies. Within this set of overexpressed genes, we focused on those that may be functionally important to the cancer cell. The apoptosis-related molecule, BAX, was highly correlated with the ALL class distinction. Therefore, we evaluated BAX and its isoforms as potential TAA. Peptides from the isoform BAX-delta bound with high affinity to HLA-A*0201 and HLA-DR1. CD8+ CTLs specific for BAX-delta epitopes or their heteroclitic peptides could be expanded from normal donors. BAX-delta-specific T cells lysed peptide-pulsed targets and BAX-delta-expressing leukemia cells in a MHC-restricted fashion. Moreover, primary B-ALL cells were recognized by BAX-delta-specific CTL, indicating that this antigen is naturally processed and presented by tumor cells. This study suggests that (a) BAX-delta may serve as a widely expressed TAA in B-ALL and (b) gene expression profiling can be a generalizable tool to identify immunologic targets for cancer immunotherapy.     

Splenic marginal zone lymphomas in acquired C1-inhibitor deficiency: clinical and molecular characterization

Angioedema due to acquired deficiency of the inhibitor of the first component of complement (C1-INH) is a rare disease known as acquired angioedema (AAE). About 70% of patients with AEE display autoantibodies to C1-INH, the remaining patients have no antibodies to C1-INH. The clinical features of C1-INH deficiency include recurrent, self-limiting local swellings involving the skin, the gastrointestinal tract, and the upper respiratory tract. Swelling is due to accumulation of bradykinin released from high molecular weight kininogen. Patients with angioedema due to acquired C1 inhibitor deficiency (AEE) often have an associated lymphoproliferative disease including Non-Hodgkin Lymphomas (NHL). Among AAE patients with NHL, splenic marginal zone lymphoma (SMZL) has a higher prevalence (66%) compared to general population (2%) In the present study, we focused on patients with SMZL in AAE. We found 24 AAE patients with NHL and, among them 15 SMZL (62.5% of all NHL). We found NOTCH 2 activation in 4 /15 patients (26.6%) with SMZL, while no patients carried MYD 88 or BIRC3 mutations. Restricted immunoglobulin gene repertoire analysis showed that the IGHV1-2*04 allele was found to be over-represented in the group of patients with or without lymphoproliferative disease presenting with autoantibodies to C1-INH (41 of 55 (75%) of patients; p value 0.011) when compared to the control group of patients with AEE without antibodies to C1-INH, (7 of 27 (26%) of patients). Immunophenotyping failed to demonstrate the presence of autoreactive clones against C1-inhibitor. Taken together, these findings suggest a role for antigenic stimulation in the pathogenesis of lymphomas associated with AEE.     

IMRT planning parameter optimization for spine stereotactic radiosurgery

Spine stereotactic radiosurgery (SSRS) is a noninvasive treatment for metastatic spine lesions. MD Anderson Cancer Center reports a quality assurance (QA) failure rate approaching 15% for SSRS cases, which we hypothesized is due to difficulties in accurately calculating dose resulting from a large number of small-area segments. Clinical plans typically use 9 beams with an average of 10 segments per beam and minimum segment area of 2-3 cm². The purpose of this study was to identify a set of intensity-modulated radiation therapy (IMRT) planning parameters that attempts to optimize the balance among QA passing rate, plan quality, dose calculation accuracy, and delivery time for SSRS plans. Using Pinnacle version 9.10, we evaluated the effects of 2 IMRT parameters: maximum number of segments and minimum segment area. Initial evaluation of the data revealed that 5 segments per beam along with minimum segment area of 4 cm² and 4 monitor units (MU) per segment (5-4-4 plans) was the most promising. IMRT QA was performed using a PTW OCTAVIUS 4D phantom with a 2D detector array. Our data showed no significant plan quality change with decreased number of segments and increased minimum segment area. The average coverage of GTV and CTV was 82.5 ± 13% (clinical) vs 82.5 ± 13% (5-4-4) and 92.3 ± 8% (clinical) vs 91.5 ± 8% (5-4-4). Maximum point dose to cord was 11.4 ± 3.5 Gy (clinical) vs 11.0 ± 4.0 Gy (5-4-4). Total plan delivery time was decreased by an average of 11.3% for the 5-4-4 plans. For IMRT QA, the gamma index passing rate (distance to agreement: 2.5 mm, local dose difference: 4%) for the original plans vs the 5-4-4 plans averaged 90.3% and 91.9%, respectively. In conclusion, IMRT parameters of 5 segments per beam and 4 cm² minimum segment areas provided a better balance of plan quality, delivery efficiency, and plan dose calculation accuracy for SSRS.     

Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia

Nucleophosmin (NPM) exon-12 mutations occur in 50% to 60% of adult acute myeloid leukemia (AML) with normal karyotype and are predictors of favorable prognosis. We evaluated bone marrow or peripheral blood samples from 450 adult patients with AML of the GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto)/AML12 EORTC (European Organization for Research and Treatment of Cancer) trial to (1) search for new exon-12 NPM mutations; (2) determine whether NPM immunostaining on paraffin-embedded biopsies predicts NPM mutations; and (3) investigate altered nucleocytoplasmic NPM traffic in primary AML cells. Fourteen NPM mutations, including 8 new variants, were identified. All 200 AML cases expressing cytoplasmic NPM (NPMc(+) AML) carried NPM mutations. None of the 250 cases with nucleus-restricted NPM (NPMc(-) AML) was mutated. At the C-terminus, NPM leukemic mutants carried mutations of only tryptophan 290 or of both tryptophans 288 and 290 and a new nuclear export signal (NES) motif, which appear to underlie their nuclear export. The specific Crm1/exportin-1 inhibitor leptomycin-B relocated NPM mutants from cytoplasm to nucleus of primary NPMc(+) AML cells, demonstrating that nuclear export is NES dependent. NPM mutants bound and recruited wild-type NPM into leukemic cell cytoplasm. Because alterations at C-terminus of leukemic NPM mutants are similar, immunohistochemistry detects all exon-12 NPM mutations and is a valuable, inexpensive tool in the diagnostic-prognostic work-up of patients with AML with normal karyotype.     

Complex regional pain syndrome secondary to leprosy

Introduction. Leprosy is a chronic infectious disease caused by Mycobacterium leprae affecting the skin and the nerves. Complex regional pain syndrome (CRPS/Sudeck's dystrophy) is a painful and disabling condition-a triad of autonomic, sensory, and motor symptoms disproportionate to the inciting event (inflammatory, infective, or traumatic nerve damage). Case. A 20-year-old male presented with continuous pain, aggravated by cold and emotions, loss of fine touch and temperature sensation, redness, swelling, along lateral aspect of left hand and forearm with weakness in the grip of 6 months' duration. There was a 5-year history of sensory loss only over left index finger that he ignored. Examination revealed abnormal sensory and autonomic functions along left radial and median nerve distribution that were confirmed by nerve conduction studies suggestive of mononeuritis multiplex. Radial cutaneous nerve biopsy was suggestive of leprosy. Magnetic resonance imaging and ultrasonography showed no compressive etiology; however, MRI showed involvement of brachial plexus. Antileprosy, anti-inflammatory drugs, and steroids were given in view of neuritis because of lepra reaction with supportive measures of physiotherapy, transcutaneous electrical nerve stimulation, to no avail. A surgical median nerve decompression also failed to relieve the pain. Temporary stellate ganglion block improved the pain scale. Thus, excluding all other causes, the final diagnosis was CRPS secondary to leprosy. There is only one reported case of CRPS with leprosy. Conclusion: Leprous neuropathy caused the nerve damage that lead to CRPS type 2. Very rarely leprosy can lead to CRPS. CRPS is a diagnosis of exclusion.     

Cheilitis granulomatosa (Miescher granulomatous macrocheilitis) with trisomy 21

A 30-year-old male with Down syndrome presented to us with diffuse swelling of the lower lip of seven years duration. On examination, there was gross enlargement of his lower-lip with fissuring at places. A histopathological specimen from the lower lip showed non-caseating granulomas. We treated our patient with intralesional triamcinolone acetonide and oral clofazimine. We report this case because of the rare association of cheilitis granulomatosa with Down syndrome.     

Human Cytomegalovirus UL144 Is Associated with Viremia and Infant Development Sequelae in Congenital Infection

Human cytomegalovirus (HCMV) strains may be genotyped based on polymorphisms that exist within the UL144 gene, which is one of 19 viral genes lost in attenuated laboratory strains. In the present study, UL144 genotypes in congenitally infected babies (congenital cytomegalovirus [cCMV]) were determined, and the relationship between the genotype, viral load, cytokine profile, and patient developmental outcome was investigated. All cCMV infections identified during 2006 and 2007 were included (n = 29). A portion of the infants were clinically assessed at birth and at 12 to 18 months postinfection for cCMV clinical sequelae (n = 18/29). The plasma viral load (PVL) was requested for 23/29 patients, and the UL144 genotype was determined (n = 27/29). The cytokine profile in patient plasma or serum was assessed (n = 20/29). UL144 genotypes A, B, and C were detected within the cCMV population at 33.3%, 29.6%, and 25.9%, respectively. UL144 A and C were associated with a high PVL (P < 0.04). Furthermore, a significant association between the developmental outcome and UL144 A and C was observed (P < 0.04). Only patients infected with UL144 B and A/B were described as having a normal clinical outcome. In addition, a significant correlation between interleukin 10 (IL-10) levels and the PVL was observed (P < 0.04); however, there was no association between the genotype and the cytokine profile. The present study determined that the specific detection of UL144 genotypes A and C was indicative of serious cCMV infection and more likely to lead to long-term cCMV-associated clinical manifestations. The inclusion of HCMV UL144 genotyping along with the recommended PVL monitoring following cCMV diagnosis may aid prediction of the clinical outcome.Congenital cytomegalovirus (cCMV) infection is the most common congenital infection in the developed world, affecting approximately 1% of live-born neonates. It is a frequent cause of mental retardation and the leading nongenetic cause of sensorineural hearing loss (SNHL) (7, 11). cCMV disease can result from either primary maternal infection or reactivation from latency during pregnancy, although generally, the most severe clinical syndromes follow primary infection. However, at present there is no way of definitively identifying at birth those infants who will develop sequelae and those who will not.The clinical significance of human cytomegalovirus (HCMV) molecular epidemiology is unclear and controversial, as the 236-kb viral genome suggests that a large number of polymorphic strains may potentially exist (10). HCMV infects many different cell types, resulting in a diverse range of clinical manifestations and suggesting that the clinical outcome may be related to both genetic variation among HCMV strains and the host immune response(s). Previous studies have investigated genetic polymorphisms that exist within the envelope glycoprotein genes, as their encoded proteins are targets for neutralizing antibodies. However, the glycoprotein B (gB) gene, which encodes a putative target for HCMV vaccination, has shown no consistent relationship with disease outcome (3, 16, 25).HCMV strains may be genotyped based on polymorphisms that exist within the UL144 gene, which is one of 19 viral genes lost in attenuated laboratory strains (4). The majority of these deleted genes are nonessential for viral replication; however, expression in vivo may contribute to disease pathogenesis (8). Three main HCMV genotypes, based on the ectodomain of the UL144 protein, have been described: UL144 A, UL144 B, and UL144 C (1, 2, 16, 24). Conflicting reports on the association between the UL144 genotypes and the viral load, clinical presentation, and clinical outcome have been published. Arav-Boger and colleagues concluded that infection with the UL144 A and C strains was associated with unfavorable clinical outcome in neonates (2). In addition, genotype UL144 C was linked to termination of pregnancy following detection of HCMV in the amniotic fluid (1). In direct contrast, UL144 genetic polymorphisms were associated with neither clinical presentation nor viral-load levels in the amniotic fluid in a French population (18, 19). Furthermore, Bale and colleagues found no relationship between the UL144 genotype and the congenital clinical outcome (3).The present study addresses these inconsistent findings. The UL144 genotypes, detected in a well-defined, geographically distinct group of congenitally infected infants, were analyzed with respect to the viral loads, immunological cytokine profiles, and developmental outcomes of affected infants. Our findings show that the HCMV genotypes UL144 A and C are significantly associated with high plasma viral loads (PVLs) and long-term cCMV clinical sequelae.(Part of this work was presented in a 15-minute oral presentation [abstract number O-12] at the 2008 Congenital Cytomegalovirus Conference, Centers for Disease Control and Prevention, Atlanta, GA, 5 November 2008.)     

Bone marrow microenvironment and the progression of multiple myeloma.

The BM microenvironment in MM, in terms of adhesive features, is well organized to entrap circulating precursors with BM-seeking properties and is able to produce cytokines that offer them the optimal conditions for local growth and final differentiation. Likewise, the malignant B cell clone is equipped with adhesion molecules which enable the cell to establish close contacts with BM stromal cells. Furthermore a number of cytokines are released including IL-1 beta and M-CSF activating BM stromal cells to produce other cytokines, such as IL-6, that stimulate the proliferation of plasma cells. Finally, most cytokines produced locally, including IL-1 beta, TNF-beta, M-CSF, IL-3 and IL-6, also have OAF properties, explaining why the expansion of the B cell clone parallels the activation and numerical increase of the osteoclast population.