Persistent reversed end diastolic flow in the fetal middle cerebral artery: an ominous finding

Fetal persistent middle cerebral artery reversed end diastolic flow is a rare and ominous finding. Previous cases have been associated with intracranial hemorrhage, growth restriction, anaemia, and hepatic anomaly. Intrauterine demise or early neonatal death is a common outcome. We report the case of persistent middle cerebral artery reversed end diastolic flow in a well-grown fetus at 32 weeks’ gestation resulting from acute, severe anaemia due to a large feto-maternal hemorrhage. An emergency cesarean section was performed and the neonate required advanced resuscitation and immediate blood transfusion. Postnatal magnetic resonance imaging confirmed a hemorrhagic parietal infarct and bilateral ischaemic changes in the basal ganglia. This provides further evidence that persistent middle cerebral artery reversed end diastolic flow in any fetus is an ominous finding warranting urgent diagnostic evaluation and/or delivery.     

Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen

We have studied the use of a new preparative regimen for the treatment of patients in remission of acute myeloid leukemia (AML) with autologous bone marrow transplantation. Chemotherapy consisted of busulfan 1 mg/kg every 6 hours for 4 days (total dose, 16 mg/kg) on days -7 through -4 followed by an intravenous infusion over 6 to 10 hours of etoposide 60 mg/kg on day -3. Autologous bone marrow, treated in vitro with 100 micrograms/mL of 4-hydroperoxycyclophosphamide, was infused on day 0. We have treated 58 patients up to the age of 60 years, 32 in first remission, 21 in second or third remission, and 5 with primary refractory AML unresponsive to high-dose Ara-C, but achieving remission with aggressive salvage regimens. Of the first remission patients, there has been 1 treatment related death and 5 relapses. With median follow-up of 22 months, the actuarial relapse rate is 22% +/- 9% and disease-free survival is 76% +/- 9% at 3 years. Patients with favorable French-American-British (FAB) subtypes (M3 or M4 EO) did especially well, with no relapses seen in 15 patients observed for a median of 30 months. Actuarial relapse rate at 3 years was 48% for first remission patients with less favorable FAB subtypes. Of patients in second or third remission, there were 5 treatment related deaths and 4 relapses. With median follow-up of 22 months, the actuarial relapse rate is 25% +/- 11% and disease-free survival is 56% +/- 11% at 3 years. Four of five primary refractory patients died during treatment and 1 remains in remission with short follow-up. These preliminary data are very encouraging and, if confirmed, support the use of autologous purged bone marrow transplantation using aggressive preparative regimens as one approach to improve the outcome of adults with AML.     

Beneficial effects of insulin-like growth factor I on epithelial structure and function in parenterally fed rat jejunum

BACKGROUND & AIMS: The functional significance of intestinal hyperplasia stimulated by insulin-like growth factor (IGF)-I is unclear and has not been studied in a model of mucosal atrophy induced by total parenteral nutrition (TPN). The aim of this study was to determine how IGF-I affects intestinal structure and epithelial function in the absence of luminal nutrition caused by TPN. METHODS: Rats were maintained with TPN with or without IGF-I (800 micrograms/day), and jejunal histology and epithelial ion transport were measured after 5 days. In a third TPN group without IGF-I, a short-term dose of IGF-I was added during in vitro flux chamber experiments. RESULTS: Rats given TPN with IGF-I had greater jejunal mucosal weight, greater protein and DNA content, and increased villus height and crypt depth compared with rats given TPN only. TPN increased ionic permeability and ion transport responses to secretory and absorptive agents. IGF-I in vivo reversed most of these changes; IGF-I in vitro enhanced sodium-dependent glucose absorption but had no other effects. CONCLUSIONS: Coinfusion of recombinant human IGF-I with TPN solution stimulates intestinal hyperplasia and attenuates transport changes induced by TPN. The latter effect seems to be primarily associated with the growth state of the epithelium. (Gastroenterology 1996 Dec;111(6):1501-8)     

The major histocompatibility complex region marked by HSP70-1 and HSP70- 2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat- shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.     

Analysis of ASPM in an ethnically diverse cohort of 400 patient samples: perspectives of the molecular diagnostic laboratory

Primary Autosomal Recessive Microcephaly (MCPH) is characterized by congenital microcephaly usually without additional clinical findings. The most common gene implicated in MCPH is ASPM and a large percentage of mutations described have been homozygous and in consanguineous families primarily of East Asian and Middle Eastern origin. ASPM sequencing was performed on 400 patients between the years 2009 and 2012. Seventy of the patient samples were also analyzed for copy number changes in the ASPM gene. Forty protein truncating mutations, including 29 novel mutations, were identified in 39 patients with MCPH. Approximately one third of patients were compound heterozygotes, indicative of non‐consanguinity in these patients. In addition, 46 non‐synonymous variants were identified and interpreted as variants of uncertain significance. No deletion/duplication in ASPM was identified in the patients analyzed. A wide ethnic distribution was observed, including the first reported patients with ASPM‐related MCPH of Hispanic descent. Clinical information was collected for 26 of the ASPM‐positive patients and 41 of the ASPM‐negative patients. As more individuals are identified with MCPH, we anticipate that we will continue to identify ASPM mutation‐positive patients from all ethnic origins supporting the occurrence of this genetic condition beyond that of consanguineous families of certain ethnic populations.     

Active tuberculosis in inflammatory bowel disease patients under treatment from an endemic area in Latin America

BACKGROUNDThere has been an increase in cases of inflammatory bowel disease (IBD) in recent years. There is also greater access and availability of immunosuppressive and biological agents, which increase the risk of opportunistic infection despite improving the quality of life and promoting mucosal healing. Tuberculosis (TB) remains a public health problem, and it has a high incidence in several countries. Therefore, knowledge of the risk of developing TB in patients with IBD is important.AIMTo evaluate the risk of active TB in patients with IBD under treatment from an endemic area in Latin America.METHODSA standard questionnaire included demographic variables, clinical aspects of IBD disease, history of active TB during treatment, active TB characteristics and evolution, initial screening and results and time from the start of anti-tumor necrosis factor alpha (TNFα) to TB development.RESULTSAzathioprine, anti-TNFα and the combination of these two drugs were associated with a higher risk of active TB incidence. The TNFα blockers increased the relative risk of developing active TB compared to other treatments. All four multivariable models showed that the use of TNFα blockers alone or in combination with azathioprine was an important risk factor for the incidence of active TB. After adjustment for sex, age, type of IBD and latent TB, anti-TNFα with azathioprine increased the relative risk to 17.8 times more than conventional treatment. Late TB, which was diagnosed 3 mo after the start of anti-TNFα, was the most frequent.CONCLUSIONTreatment with anti-TNFα increased the risk of active TB in IBD patients from an endemic area in Latin America. This risk was increased when anti-TNFα was combined with azathioprine. The time from the beginning of the treatment to the active TB diagnosis suggests a new TB infection.     

Temporal trends in the relative prevalence of dysphagia etiologies from 1999-2009

AIM: To examine the relative prevalence and temporal variation of dysphagia etiologies in patients undergoing upper endoscopy (EGD) over the past decade.METHODS: EGDs with the indication of dysphagia at an urban, university medical center in 1999, 2004 and 2009 were retrospectively identified from the electronic medical record. The entire patient chart, including EGD, pathology, manometry, radiographic and clinician reports, was reviewed for demographic and clinical data and to determine the etiology of dysphagia. The number of EGDs in which an esophageal biopsy was performed was also noted. Gastroesophageal reflux disease (GERD) as a cause of dysphagia independent of peptic stricture was defined by symptoms with erosive esophagitis or symptom response to proton pump inhibition (PPI). Cases of eosinophilic esophagitis (EoE) were defined by an appropriate clinical history and histological criteria of ≥ 15 eosinophils per high powered field. PPI-responsive esophageal eosinophilia was not routinely reported prior to 2008. Statistical analysis was performed using one-way analysis of variance to analyze for trends between 1999, 2004 and 2009 and a post-hoc Tukey analysis was performed following a significant main effect.RESULTS: A total of 1371 cases (mean age 54 years, 43% male) met pre-specified inclusion criteria with 191, 504 and 675 cases in 1999, 2004 and 2009, respectively. Patients were older in 2004 compared to 2009 (mean ± SD, 54.0 ± 15.7 years vs 52.3 ± 16.8 years, P = 0.02) and there were more males in 1999 compared to 2004 (57.5% vs 40.8%, P = 0.005). Overall, GERD (27.6%) and EoE (7.7%) were the most common identifiable causes of dysphagia. An unspecified diagnosis accounted for 21% of overall cases. There were no significant differences in the relative prevalence of achalasia or other motility disorders, peptic stricture, Schatzki’s ring, esophageal cancer or unspecified diagnoses over the 10-year time period. There was, however, a decrease in the relative prevalence of GERD (39.3% vs 24.1%, P < 0.001) and increases in the relative prevalence of EoE (1.6% vs 11.2%, P < 0.001) and oropharyngeal disorders (1.6% vs 4.2%, P = 0.02) from 1999 to 2009. Post-hoc analyses determined that the increase in relative prevalence of EoE was significant between 1999 and 2009 as well as 2004 and 2009 (5.4% vs 11.6%, P < 0.001), but not between 1999 and 2004 (1.6% P 5.4%, P = 0.21). On the other hand, the decrease in relative prevalence of GERD was significant between 1999 and 2009 and 1999 and 2004 (39.3% vs 27.7%, P = 0.006), but not between 2004 and 2009 (27.7% vs 24.1%, P = 0.36). There were also significantly more EGDs in which a biopsy was obtained in 1999 compared to 2009 (36.7% vs 68.7%, P < 0.001) as well as between 2004 and 2009 (37.5% vs 68.7%, P < 0.001). While total EGD volume did increase over the 10-year time period, the percentage of EGDs for the indication of dysphagia remained stable making increasing upper endoscopy an unlikely reason for the observed increased prevalence of EoE.CONCLUSION: EoE has emerged as a dominant cause of dysphagia in adults. Whether this was due to a rise in disease incidence or increased recognition is unclear.