BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia.

BACKGROUND: Fetal hemoglobin (HbF) levels in sickle cell anemia patients vary. We genotyped polymorphisms in the erythroid-specific enhancer of BCL11A to see if they might account for the very high HbF associated with the Arab-Indian (AI) haplotype and Benin haplotype of sickle cell anemia. METHODS AND RESULTS: Six BCL112A enhancer SNPs and their haplotypes were studied in Saudi Arabs from the Eastern Province and Indian patients with AI haplotype (HbF ~20%), African Americans (HbF ~7%), and Saudi Arabs from the Southwestern Province (HbF ~12%). Four SNPs (rs1427407, rs6706648, rs6738440, and rs7606173) and their haplotypes were consistently associated with HbF levels. The distributions of haplotypes differ in the 3 cohorts but not their genetic effects: the haplotype TCAG was associated with the lowest HbF level and the haplotype GTAC was associated with the highest HbF level and differences in HbF levels between carriers of these haplotypes in all cohorts were approximately 6%. CONCLUSIONS: Common HbF BCL11A enhancer haplotypes in patients with African origin and AI sickle cell anemia have similar effects on HbF but they do not explain their differences in HbF.

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704.

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²7Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²7Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²7Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²7Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

Human papillomavirus genotypes associated with cervical cytologic abnormalities and HIV infection in Ugandan women.

Human papillomavirus (HPV) infection is associated with almost all cases of cervical cancer, and cervical cancer is a common malignancy in women living in developing countries. A cross-sectional study was conducted to determine the prevalence of HPV infection, human immunodeficiency virus (HIV) infection, and cervical cytologic abnormalities in women presenting to a sexually transmitted infections clinic in Kampala, Uganda. In June and July, 2002, 135 women underwent complete physical exams including Papanicolaou (Pap) smears. HIV status was evaluated by serology. Cervical and vaginal swabs were obtained by clinicians and tested for HPV genotypes by PCR/reverse blot strip assay. Of the 106 women with cervical swabs adequate for HPV testing, the HPV prevalence was 46.2% (49/106). HIV prevalence was 34.9% (37/106). High risk genotypes 52, 58, and 16 were the genotypes detected most commonly. Eighteen percent (9/49) of women infected with HPV were found to have genotypes 16 and/or 18. Seventy-three percent (27/37) of HIV-positive women versus 16% (10/63) of HIV-negative women had abnormal Pap smears (P < 0.0001). Among HIV-positive women, abnormal Pap smears were associated with the presence of high risk HPV genotypes (P < 0.001). The majority of women infected with HPV attending this sexually transmitted infections clinic in Uganda were infected with high risk HPV genotypes other than 16 and 18. Future studies should focus on whether current HPV vaccine formulations, that are limited to high risk genotypes 16 and 18, would be effective at decreasing the burden of cervical cancer in this population.

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea.

The increase in fetal hemoglobin (HbF) in response to hydroxyurea (HU) varies among patients with sickle cell anemia. Twenty-nine candidate genes within loci previously reported to be linked to HbF level (6q22.3-q23.2, 8q11-q12 and Xp22.2-p22.3), involved in metabolism of HU and related to erythroid progenitor proliferation were studied in 137 sickle cell anemia patients treated with HU. Three-hundred and twenty tagging single nucleotide polymorphisms (SNPs) for genotyping were selected based on HapMap data. Multiple linear regression and the nonlinear regression Random Forest method were used to investigate the association between SNPs and the change in HbF level after 2 years of treatment with HU. Both methods revealed that SNPs in genes within the 6q22.3-23.2 and 8q11-q12 linkage peaks, and also the ARG2, FLT1, HAO2 and NOS1 genes were associated with the HbF response to HU. Polymorphisms in genes regulating HbF expression, HU metabolism and erythroid progenitor proliferation might modulate the patient response to HU.

Radiation modifiers: treatment overview and future investigations.

Many radiosensitizers are in current clinical use. In addition, a myriad of potential new targeted therapies, which may also interact with radiation, are in clinical development. The clinical utility of new targeted therapies, in combination with existing radiation sensitizers (chemotherapies) requires further evaluation, as does the understanding of their acute and late radiation effects. Free radical scavengers appear to show promise as radioprotectors, but data for mucoprotection are less convincing.

Review article: the management of lower gastrointestinal bleeding.

Several recent advances have been made in the evaluation and management of acute lower gastrointestinal bleeding. This review focuses on the management of lower gastrointestinal bleeding, especially acute severe bleeding. The aim of the study was to critically review the published literature on important management issues in lower gastrointestinal bleeding, including haemodynamic resuscitation, diagnostic evaluation, and endoscopic, radiologic, and surgical therapy, and to develop an algorithm for the management of lower gastrointestinal bleeding, based on this literature review. Publications pertaining to lower gastrointestinal bleeding were identified by searches of the MEDLINE database for the years 1966 to December 2004. Clinical trials and review articles were specifically identified, and their reference citation lists were searched for additional publications not identified in the database searches. Clinical trials and current clinical recommendations were assessed by using commonly applied criteria. Specific recommendations are made based on the evidence reviewed. Approximately, 200 original and review articles were reviewed and graded. There is a paucity of high-quality evidence to guide the management of lower gastrointestinal bleeding, and current endoscopic, radiologic, and surgical practices appear to reflect local expertise and availability of services. Endoscopic literature supports the role of urgent colonoscopy and therapy where possible. Radiology literature supports the role of angiography, especially after a positive bleeding scan has been obtained. Limited surgical data support the role of segmental resection in the management of persistent lower gastrointestinal bleeding after localization by either colonoscopy or angiography. There is limited high-quality research in the area of lower gastrointestinal bleeding. Recent advances have improved the endoscopic, radiologic and surgical management of this problem. However, treatment decisions are still often based on local expertise and preference. With increased access to urgent therapeutic endoscopy for the management of acute upper gastrointestinal bleeding, diagnostic and therapeutic colonoscopy can be expected to play an increasing role in the management of acute lower gastrointestinal bleeding.

Single-operator duodenoscope-assisted cholangioscopy is an effective alternative in the management of choledocholithiasis not removed by conventional methods, including mechanical lithotripsy.

BACKGROUND AND STUDY AIMS: The widespread use of cholangioscopy in the management of difficult choledocholithiasis has been limited by the need for two expert operators. This report describes the use of a technique of single-operator duodenoscope-assisted cholangioscopy (SODAC) in the successful management of 75 patients with choledocholithiasis. PATIENTS AND METHODS: The single-operator technique, allowing simultaneous control of both the duodenoscope and cholangioscope, was prospectively studied between June 1999 and June 2001 in the diagnosis and treatment of choledocholithiasis. RESULTS: A total of 109 SODAC procedures were conducted in 75 patients to manage choledocholithiasis. The indications were: firstly, SODAC-guided electrohydraulic lithotripsy (EHL) of stones in which conventional methods, including mechanical lithotripsy, had not been successful (52 SODAC procedures in 26 patients); and secondly, direct visualization of the biliary tree after cholangiography to assess the presence of stones (57 SODAC procedures in 49 patients). The locations and numbers of the stones, but not their size, were predictive of the number of SODAC-guided lithotripsy sessions required. All of the patients were free of stones at the end of the study period, and no complications were recorded. CONCLUSIONS: Single-operator SODAC-guided electrohydraulic lithotripsy was effective in the treatment of difficult cases of choledocholithiasis in which conventional methods had previously failed. The technique may allow increased use of cholangioscopy in the management of choledocholithiasis.

Polymorphisms near a chromosome 6q QTL area are associated with modulation of fetal hemoglobin levels in sickle cell anemia.

In patients with sickle cell anemia, fetal hemoglobin (HbF) concentrations vary by 2 orders of magnitude. This variance may be a result of heterogeneity in gene regulatory elements; accordingly, we searched for single nucleotide polymorphisms (SNPs) that might identify this variation. More than 180 SNPs were studied in 38 genes in 280 sickle cell anemia patients. The strongest association with HbF was found with SNPs near a QTL previously localized on chromosome 6q22.3-q23.2. Initially, two SNPs were identified in intergenic portions of this QTL and were associated with about a 20% difference in percent HbF. Subsequently, we genotyped 44 additional SNPs in the genomic region between 136.1 Mb and 137.5 Mb on chromosome 6q. Twelve SNPs, associated with a 20%-30% difference in HbF concentrations, were located in the introns of four genes, PDE7B, MAP7, MAP3K5 and PEX7. In K562 cells, the p38-MAPK pathway has been associated with the activation of gamma-globin gene expression by histone deacetylase inhibitors. Haplotypes C-T-T-T in MAP7 and T-C-C in PEX7 were significantly associated with increases in concentration of HbF, both showing strong dominance. Genetic elements abutting the 6q22.3-q23.2 QTL, may harbor trans-acting elements that help modulate baseline HbF level in sickle cell anemia.

Treatment of bleeding colonic diverticula by endoscopic band ligation: an in-vivo and ex-vivo pilot study.

BACKGROUND AND STUDY AIMS: Angiographic and surgical therapy are standards of care for persistent diverticular bleeding. Colonoscopic intervention using epinephrine injection, multipolar electrocautery, and placement of an Endoclip has not gained widespread acceptance due to concerns about complications,and the widespread management of severe lower gastrointestinal bleeding by surgeons and interventional radiologists. The utility of colonoscopic band ligation for control of diverticular bleeding was evaluated both in vivo and ex vivo. PATIENTS AND METHODS: Endoscopic band ligation of diverticula was performed on surgical resection specimens and in patients with actively bleeding colonic diverticula. RESULTS: In the in-vivo study, active diverticular bleeding was completely controlled in four patients by endoscopic band ligation. In two cases, a visible vessel was seen on the everted and banded diverticulum. Procedure time ranged from 45 to 140 min. The total lengths of hospital stays for the four patients were 2, 6, 14, and 35 days. The long hospital stays (> 7 days)were associated with non-gastrointestinal co-morbidity. There were no acute complications of band ligation. No rebleeding or need for surgery occurred during a follow-up period of 12 months in any of the patients. In the ex-vivo study, 11 diverticula were successfully everted and banded in five of nine surgical specimens (one right colon and four left colons). Mucosa was identified in all of the "banded" segments. Ten of 11 ligated diverticula revealed evidence of blood vessels or submucosal tissue. The presence of subserosal fat was suggested in three of the 11 "banded" segments, and none of the ex-vivo ligated diverticula contained muscularis propria or serosal involvement. There was no evidence of perforation. CONCLUSIONS: Both in-vivo and ex-vivo data suggest that endoscopic band ligation may be a safe and effective therapy for actively bleeding colonic diverticula.

Gastrointestinal bleeding in the elderly.

Among patients with acute gastrointestinal bleeding, older age is associated with an increased rate of comorbidity, greater medication use, and atypical clinical presentations. The aging of the population makes the evaluation and management of gastrointestinal bleeding in the elderly a special and increasingly common clinical challenge. The unique features and common causes of upper and lower gastrointestinal bleeding in the elderly are reviewed. Important management issues considered include hemodynamic resuscitation; anticoagulation; and medical, surgical, and endoscopic therapy.

Diverticular disease in the elderly.

Diverticular disease is common among the elderly. Because of the advanced age and muted symptoms and signs of many of those affected, diagnosis can be difficult. Consequently, great demands are placed on the physician to diagnose and treat clinically evident diverticular disease. Endoscopic, radiologic, and surgical advances have increased the availability of more definitive therapies for patients with complicated diverticular disease and diverticular hemorrhage.

Detection and tumor staging of malignancy in cystic, intraductal, and solid tumors of the pancreas by EUS.

BACKGROUND: EUS can provide detailed imaging of pancreatic malignancies and direct fine needle aspiration (FNA) of pancreatic masses. The ability of EUS to detect and stage malignancy in cystic and intraductal lesions has not been investigated. Our aim was to determine the sensitivity and specificity of EUS imaging and FNA in detecting and staging of malignancy in solid, cystic, and intraductal lesions of the pancreas. METHODS: The records of 96 patients (46 solid, 26 cystic, 24 intraductal lesions) who underwent EUS followed by surgical exploration over a 3-year period were reviewed. The accuracy of EUS for detecting and staging malignancy was calculated based on the results of surgery and histology. RESULTS: EUS-guided FNA provided evidence of malignancy in solid, cystic, and ductal lesions with sensitivities of 59.5%, 50%, and 60%, respectively. The accuracy of staging by EUS was significantly less for intraductal lesions (47%), compared with cystic (100%) and solid lesions (85%) (p < 0. 05). CONCLUSIONS: EUS can be used to detect malignancy in cystic and intraductal tumors of the pancreas.

Idiopathic giant esophageal ulcers in a renal transplant patient responsive to steroid therapy.

Idiopathic giant esophageal ulcers in immunocompromised patients have been described only in patients with acquired immunodeficiency syndrome. A solitary report of an idiopathic giant esophageal ulcer in an immunocompetent patient exists. We describe a case of idiopathic esophageal ulceration ultimately responsive to steroid therapy in a 31-year old immunosuppressed, human immunodeficiency virus-negative renal transplant patient. The case is described with particular reference to the evaluation, differential diagnosis, and therapeutic response to steroids. Similarities in presentation and treatment to giant esophageal ulcers in human immunodeficiency virus infection suggest an underlying immune defect as the likely cause. This is the first described case of giant esophageal ulceration responsive to steroids in an immunosuppressed human immunodeficiency virus-negative patient. This entity should be added to the differential diagnosis of esophageal ulceration in solid organ transplant recipients.

Gastrointestinal bleeding in older people.

Aging is associated with an increased rate of comorbidity, greater medication use, and atypical clinical presentations. The aging of the population makes the evaluation and management of gastrointestinal bleeding in older people a special and increasingly common clinical challenge. The unique features and common causes of upper and lower gastrointestinal bleeding in older people are reviewed. Important management issues considered include hemodynamic resuscitation, anticoagulation, and endoscopic and surgical therapy.

Brain SPECT with dipyridamole stress to evaluate cerebral blood flow reserve in carotid artery disease.

UNLABELLED: This is a preliminary study of SPECT brain scan using dipyridamole as a stress agent to assess cerebral blood flow reserve in six patients with severe carotid artery disease. METHODS: We performed SPECT scanning of the brain, with and without dipyridamole stress. Dipyridamole (0.57 mg/kg) was given intravenously 3 min before infusion of 99mTc-HMPAO. Patients were studied 30 min later using a rotating head gamma camera. The scans were analyzed qualitatively and semiquantitatively. An acetazolamide stress SPECT image was also obtained in two patients. RESULTS: All patients had at least 80% stenosis in one internal carotid artery, three of them also had contralateral carotid stenosis. The dipyridamole SPECT showed an increased region of hypoperfusion in the hemisphere ipsilateral to the severe carotid disease in four patients. That suggests poor perfusion reserve and the potential risk of regional ischemia. In four of six patients, side-to-side asymmetry increased from the baseline condition after injection of dipyridamole. The asymmetry index increased more after dipyridamole than after acetazolamide injection in two patients. CONCLUSION: This study suggests that dipyridamole stress SPECT is useful in assessing cerebral blood flow reserve. It demonstrates the region of poor vascular reserve in patients with severe carotid artery disease. Dipyridamole SPECT scans show more extensive hypoperfusion than acetazolamide in the two cases.

The diagnosis of an intramuscular metastasis aid from a finding on a computerized tomography scan.

A case of an intramuscular metastasis is reported in which a computerized tomography scan aided in the diagnosis. The clinical features of intramuscular metastases and the importance of performing a thorough review of the soft tissue structures displayed on computerized tomography scans is discussed.

A novel cancer therapy using a Mössbauer-isotope compound.

Cancer radiotherapy uses high doses of ionizing radiation (1-10(2) Gy; 10(2)-10(4) rad) because only a small fraction of the absorbed dose leads to lethal double-strand breaks in DNA. These breaks are more efficiently produced by Auger electrons (1-10 eV nm-1) generated in proximity to the DNA. The energy of these electrons (on average 21 electrons for the decay of 125I) is dissipated within 10-100 nm of the Auger event and produces multiple double-strand DNA breaks. A single Auger event can be lethal to a cell and is comparable to more than 10(5) photon absorption events in conventional radiotherapy. We now report that 57Fe(III).bleomycin, administered to malignant cells in vitro and in vivo and irradiated with resonant Mössbauer gamma rays (14.4 keV), causes ablation of the malignant cells, presumably by Auger cascade, with extremely small radiation doses--about 10(-5) Gy. As a basis for comparison, about 5 Gy is necessary to achieve a similar effect with conventional radiotherapy.

Ultrasound lumbar canal measurement in hospital employees with back pain.

The oblique parasagittal diameter of the lumbar spinal canal at the L5-S1 level was measured in 49 employees of the Wm Jennings Bryan Dorn Veterans' Hospital using real time ultrasound in a case-control study. Individuals with a canal diameter of less than 14 mm represented the lowest 10th percentile in this population and being in the narrowest 10th percentile constituted a risk factor for time missed from work because of low back pain (odds ratio 10.7). Whereas numbers in this pilot study are small, results are consistent with earlier ultrasound studies done in the United Kingdom and with other research showing increased morbidity from low back pain in individuals with small lumbar canals. Ultrasound has advantages over other modalities for measuring the size of the lumbar canal and may be useful as a preplacement screening examination in industry.

Resistance to antibiotics in clinical isolates of Klebsiella pneumoniae.

The antibiotic resistance of Klebsiella pneumoniae isolates from 12 medical centers worldwide, over a 1- to 6-year period, were tested. Clinical isolates of K. pneumoniae were resistant to ampicillin and carbenicillin. Resistance to other antibiotics was less frequent with isolates of K. pneumoniae from 5 of 6 US centers than with those from 6 centers outside the US. In nearly all of the centers, resistance to sulfamethoxazole-trimethoprim, gentamicin, tobramycin, or chloramphenicol was more frequent in isolates of K. pneumoniae than in those of Escherichia coli, while the reverse was true for resistance to tetracycline. Resistance to multiple antibiotics declined gradually in isolates of K. pneumoniae at one center, but rose abruptly again with dissemination of a new plasmid.