Is TNFalpha really a good therapeutic target in motoneuronal degeneration? A case of amyotrophic lateral sclerosis in a patient with RA receiving infliximab.
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Aged↗
Biomedical subjects
V Reddy
Publications and source records attributed to V Reddy.
A recurring outbreak of Shigella sonnei among traditionally observant Jewish children in New York City: the risks of daycare and household transmission.
Dispersed community outbreaks of Shigella sonnei have occurred cyclically among traditionally observant Jews in the United States. In February 2000, we investigated a S. sonnei outbreak in one Jewish community in New York City. To determine risk factors for introduction of infection into households, we conducted a cohort study of households to compare risk factors for illness among primary subjects within households and age-matched well siblings. Isolates were subtyped by pulsed-field gel electrophoresis (PFGE). We used a random effects model to assess extra-household vs. intra-household transmission in households with multiple ill household members. Daycare or pre-school attendance [matched odds ratio (mOR) 16.1, P<0.001] and age <60 months (mOR 6.3, P<0.001) were independently associated with index subject illness. Outbreak isolates were closely related by PFGE analysis to the strain previously observed in Jewish community outbreaks. The random effects model strongly indicated that multiple illnesses in a single household are due to secondary transmission. Disease containment efforts should focus on reducing Shigella transmission in childcare settings and within homes.
Case-Control Studies↗
High incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (RSV) bronchiolitis.
BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of viral lower respiratory tract infections (LRTI). Viral LRTI is a risk factor for bacterial superinfection, having an escalating incidence with increasing severity of respiratory illness. A study was undertaken to determine the incidence of pulmonary bacterial co-infection in infants and children with severe RSV bronchiolitis, using paediatric intensive care unit (PICU) admission as a surrogate marker of severity, and to study the impact of the co-infection on morbidity and mortality. METHODS: A prospective microbiological analysis was made of lower airways secretions on all RSV positive bronchiolitis patients on admission to the PICU during three consecutive RSV seasons. RESULTS: One hundred and sixty five children (median age 1.6 months, IQR 0.5-4.6) admitted to the PICU with RSV bronchiolitis were enrolled in the study. Seventy (42.4%) had lower airway secretions positive for bacteria: 36 (21.8%) were co-infected and 34 (20.6%) had low bacterial growth/possible co-infection. All were mechanically ventilated (median 5.0 days, IQR 3.0-7.3). Those with bacterial co-infection required ventilatory support for longer than those with only RSV (p<0.01). White cell count, neutrophil count, and C-reactive protein did not differentiate between the groups. Seventy four children (45%) received antibiotics prior to intubation. Sex, co-morbidity, origin, prior antibiotics, time on preceding antibiotics, admission oxygen, and ventilation index were not predictive of positive bacterial cultures. There were 12 deaths (6.6%), five of which were related to RSV. CONCLUSIONS: Up to 40% of children with severe RSV bronchiolitis requiring admission to the PICU were infected with bacteria in their lower airways and were at increased risk for bacterial pneumonia.
Anti-Bacterial Agents↗
Preliminary x-ray characterization of authentic providence virus and attempts to express its coat protein gene in recombinant baculovirus.
Providence Virus (PrV) is a non-envoloped, T = 4 icosahedral beta-tetravirus that undergoes autocatalytic cleavage of its coat protein precursor after capsid assembly. This is also a well characterized function of Nudaurelia capensis omega virus (NomegaV), a member of the related omegatetraviruses, whose x-ray structure has been determined. Virus-like particle (VLP) production of PrV in a recombinant baculovirus expression system was attempted to obtain high VLP yields for comparison of structural and autocatalytic active site properties between these virus groups. This resulted in insoluble aggregates of PrV coat protein even though NomegaV VLPs have been successfully produced in the same system. Betatetraviruses may be more dependent on compartmentalization and availability of their full-length genome for proper folding and assembly. However, crystals were grown of limited quantities of authentic PrV produced in cell culture and a partial X-ray data set collected to 3.8 A resolution. The virus particle position and orientation in the unit cell was determined by space group consideration and rotation function analysis. A phasing model, based on NomegaV, was developed to initiate the structure solution of PrV.
Baculoviridae↗
Three years of emergency department gastrointestinal syndromic surveillance in New York City: what have we found?
BACKGROUND: Use of syndromic surveillance as a tool to detect outbreaks and potential biologic or chemical terrorist attacks is increasing. Evaluating health departments' use of syndromic surveillance is necessary to determine the value of this methodology. METHODS: Syndromic surveillance signals detected by the New York City Department of Health and Mental Hygiene (DOHMH) during November 2001-August 2004 were reviewed for diarrhea and vomiting syndromes, the methods used to investigate such signals, and results of these investigations to determine if any unreported outbreaks were detected. Gastrointestinal (GI) outbreaks reported to DOHMH also were reviewed to understand why they were not detected by DOHMH's Emergency Department (ED) syndromic surveillance system. RESULTS: During the study period, ED surveillance generated 98 citywide and 138 spatial GI signals. Multiple outbreaks suspected to be caused by norovirus and rotavirus were identified, as well as a citywide increase in diarrheal illness. Of 98 citywide signals detected, 73 (75%) occurred during seasonal outbreaks. During the same period, 49 GI outbreaks were reported to DOHMH; none was detected simultaneously by ED surveillance. CONCLUSION: Only substantial, citywide syndromic signals were identified as outbreaks and routinely reported. GI outbreaks did not generate syndromic signals. Syndromic surveillance signals occur frequently, are difficult to investigate satisfactorily, and should be viewed as a supplement to, rather than a replacement for, well-maintained traditional surveillance systems that rely on strong ties between clinicians and public health authorities.
Disease Outbreaks↗
Chronic vulval ulceration--another immune reconstitution inflammatory syndrome?
We describe a patient who developed intractable chronic vulval ulceration that we believe was related to immune reconstitution following treatment of HIV infection with highly active antiretroviral treatment (HAART). Immune reconstitution inflammatory syndrome should be considered in the differential diagnosis of unexplained vulval ulceration that arises after starting HAART.
Adult↗
Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia.
Intensive therapy and autologous blood and marrow transplantation (ABMT) is an established post-remission treatment for acute myeloid leukemia (AML), although its exact role remains controversial and few data are available regarding longer-term outcomes. We examined the long-term outcome of patients with AML transplanted at a single center using uniform intensive therapy consisting of etoposide, melphalan and TBI. In all, 145 patients with AML underwent ABMT: 117 in first remission, 21 in second remission and seven beyond second remission. EFS and OS were significantly predicted by remission status (P<0.0001). For transplantation in first remission, 8 year EFS and OS were 55% (95% CI, 44-64%) and 62% (95% CI, 50-72%), respectively. By multivariate analysis, only age (P=0.04) and cytogenetic risk group (P=0.006) influenced OS. For patients transplanted in second remission, 8 year EFS and OS were 30% (95% CI, 9-55%) and 36% (95% CI, 13-60%), respectively. No pre-transplant variables significantly predicted outcome. None of the seven patients who underwent ABMT beyond second remission or in early relapse were long-term survivors. ABMT can provide long-term antileukemic control for patients with AML in first remission. For patients in second remission approximately 30% can achieve cure with ABMT, and this option may be preferable to alternate donor allogeneic stem cell transplantation.
Acute Disease↗
A multistate outbreak of Salmonella enterica Serotype Newport infection linked to mango consumption: impact of water-dip disinfestation technology.
Fresh produce increasingly is recognized as an important source of salmonellosis in the United States. In December 1999, the Centers for Disease Control and Prevention detected a nationwide increase in Salmonella serotype Newport (SN) infections that had occurred during the previous month. SN isolates recovered from patients in this cluster had indistinguishable pulsed-field gel electrophoresis (PFGE) patterns (which identified the outbreak strain), suggesting a common source. Seventy-eight patients from 13 states were infected with the outbreak strain. Fifteen patients were hospitalized; 2 died. Among 28 patients enrolled in the matched case-control study, 14 (50%) reported they ate mangoes in the 5 days before illness onset, compared with 4 (10%) of the control subjects during the same period (matched odds ratio, 21.6; 95% confidence interval, 3.53- infinity; P=.0001). Traceback of the implicated mangoes led to a single Brazilian farm, where we identified hot water treatment as a possible point of contamination; this is a relatively new process to prevent importation of an agricultural pest, the Mediterranean fruit fly. This is the first reported outbreak of salmonellosis implicating mangoes. PFGE was critical to the timely recognition of this nationwide outbreak. This outbreak highlights the potential global health impact of foodborne diseases and newly implemented food processes.
Adolescent↗
Busulfan and cyclophosphamide as a preparative regimen for allogeneic blood and marrow transplantation in patients with non-Hodgkin's lymphoma.
This study reports on overall and recurrence-free survival (OS and RFS) of 37 consecutive patients with low- and intermediate-grade NHL receiving a related donor allogeneic BMT using a nonradiation-containing preparative regimen. In addition, transplant-related toxicity and factors influencing outcome are discussed. The preparative regimen consisted of busulfan and cyclophosphamide. Median patient age was 44 years (range 20-55). In all, 18 were female. Median follow-up of surviving patients from BMT was 4.2 years. A total of 25 patients had low-grade, and 12 intermediate grade NHL. Most patients (89%) were treated with at least two different chemotherapy regimens prior to BMT. In all, 22 patients (59%) were transplanted in partial remission, 15 (41%) in complete remission. OS at 12 months was 89% (95% confidence interval (CI) of 79-99%) and 79% (64-93%) at 60 months. RFS at 12 months was 86% (75-97%) and at 5 years 70% (54-86%). Four patients (11%) relapsed. Seven patients (19%) died, six because of treatment-related toxicity and one with relapse. Univariate analysis showed improved OS for younger patients and patients of female gender, suggesting that allogeneic BMT using busulfan-cyclophosphamide as a preparative regimen can achieve disease control and possibly cure patients with NHL particularly younger ones.
Adult↗
Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital.
Despite new antifungal treatment strategies, invasive aspergillosis (IA) remains a principal cause of infectious mortality after bone marrow transplantation (BMT). We reviewed the medical records of 93 allogeneic and 149 autologous transplant recipients during a 20 month period, with attention to cases of proven or probable IA. No autologous transplant recipient developed IA, whereas IA was seen in 15.1% of allogeneic recipients (including two of five patients with a prior history of IA despite prophylaxis), for an overall incidence of 5.8%. The median time to occurrence was 92 days post transplant, with no de novo cases developing prior to engraftment. Survival 100 days from diagnosis was 29%. Risk factors for the development of IA included > or = 21 days of corticosteroid therapy of >or= 1mg/kg/day and post-transplant cytomegalovirus (CMV) infection. These two risk factors were statistically linked. Our data illustrate a shift toward a later occurrence of post-transplant IA, suggesting a need for close, prolonged surveillance in the outpatient environment. The contributory role of protracted corticosteroid use is also highlighted. These data have important implications in an era of alternate donor transplants and more intense immunosuppression. Established strategies implementing newer, less toxic antifungal agents as prophylaxis in high-risk patients are needed.
Adolescent↗
Treatment of refractory acute leukemia with timed sequential chemotherapy using topotecan followed by etoposide + mitoxantrone (T-EM) and correlation with topoisomerase II levels.
A phase I/II clinical study evaluated 17 patients with refractory/recurrent acute leukemia treated with 1.5 mg/m2/day topotecan on days 1-3 followed by etoposide (100 mg/m2/day)+mitoxantrone (10 mg/m2/day) on days 4, 5 and 9, 10. Timed sequential chemotherapy using the topoisomerase I-inhibitor topotecan before the topoisomerase II-inhibitors, etoposide+mitoxantrone (T-EM) treatment is proposed to induce topoisomerase II protein levels and potentiate the cytotoxic activity of the topoisomerase II-directed drugs. Fourteen patients had refractory and three had recurrent acute leukemia. The majority of patients were heavily pre-treated with greater than three re-induction chemotherapy regimens. Ten patients responded to T-EM treatment (59%). Four of seventeen (24%) had a complete remission and one had a partial remission. Four additional patients (24%) who scored complete leukemia clearance had no evidence of disease with complete white and red blood cell recovery but with platelet counts less than 100,000. The lack of platelet recovery in one patient having a partial response was scored as a partial leukemia clearance. The toxicity profile included major non-hematological toxicity including grade 3 mucositis (29%) and neutropenic fever (65%). Paired measurements of intracellular levels of topoisomerase II isoforms alpha and beta in leukemia blast cells (bone marrow) collected before (day 0) and after topotecan treatment (day 4) showed that a relative increase of topoisomerase IIalpha (Topo IIalpha) > or = 40% strongly correlated with response after T-EM treatment. Increased Topo IIalpha levels also corresponded to increased DNA fragmentation. Two patients who had an increase of Topo IIalpha of 20-25% had either a PR or PLC while patients with a < 10% increase showed no response to T-EM treatment. We conclude that timed sequential chemotherapy using topotecan followed by etoposide+mitoxantrone is an effective regimen for patients with refractory acute leukemia, and demonstrate Topo IIalpha protein level increases after topotecan treatment.
Acute Disease↗
Postpartum thyroiditis or hypopituitarism?
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Adult↗
Three-color flow cytometric assay for the study of the mechanisms of cell-mediated cytotoxicity.
Cytotoxic lymphocytes kill tumor or virus-infected target cells utilizing two mechanisms (1) release of lytic granules (containing perforin and granzymes) and (2) Fas ligand (FasL)/Fas or TNF initiated apoptosis. We have examined mechanisms of target cell lysis using a new Flow Cytometric Cytotoxicity Assay (FC Assay). Target cells were labeled with PKH 67 dye. Cell death was estimated by 7-amino-actinomycin (7-AAD) inclusion and annexin V-PE binding. A strong direct correlation has been found between the percentage of dead target cells in the FC Assay and the results of 51Cr release assay when human LAK and CTL were used as a model system. We have shown that both NK and CTL kill tumor cells mostly by granule-mediated mechanisms, as lysis was blocked by a perforin inhibitor Concanamycin A (Folimycin) but was significantly less sensitive to zVAD-FMK caspase inhibition. The FC assay allows accurate measurement of cell-mediated cytotoxicity as individual target cell death is detected directly.
Annexin A5↗
Correlation of human CD56+ cell cytotoxicity and IFN-gamma production.
The use of an IFN-gamma ELISPOT assay to evaluate cellular immune responses has gained increasing popularity, especially as a surrogate measure for cytotoxic T lymphocyte (CTL) responses. We have compared the IFN-gamma ELISPOT assay and the traditional(51)Cr release assay for detection of human natural killer (NK) cell activity. The cell populations used for evaluation of these assays included freshly isolated and IL-2-activated peripheral blood mononuclear cells (PBMC). CD56-positive cells were demonstrated to be the primary source of the IFN-gamma signal when PBMC were evaluated with NK-sensitive targets in the IFN-gamma ELISPOT assay. IFN-gamma ELISPOT and(51)Cr release assays showed excellent correlation suggesting that NK activity can be reliably evaluated with methods other than the traditional(51)Cr release assays.
CD3 Complex↗
Status of HER-2 in male and female breast carcinoma.
BACKGROUND: HER-2 overexpression is seen in 20% to 30% of invasive female breast carcinomas. Besides being prognostic, HER-2 may also be predictive of response to therapy. Similar studies in male breast carcinoma are lacking. We compared the overexpression and amplification of HER-2 in female and male breast carcinoma. DESIGN: Formalin-fixed, paraffin embedded archival material from 58 invasive male breast carcinomas and 202 invasive female breast carcinomas were immunostained for HER-2. Scoring was performed according to established guidelines. Each case was also assessed for HER-2 gene amplification by fluorescence in-situ hybridization (FISH) utilizing the PathVysion assay (Vysis corporation, Downers Grove, Illinois). RESULTS: There were 58 male patients who ranged in age from 38 to 92 years (mean 63). Thirty-five (60%) were T1 lesions and 23 (40%) were T2 lesions. Twenty-five patients (43%) had positive lymph nodes. One (1.7%) of the 58 cases showed 3+ staining of HER-2. The remaining 57 cases did not show overexpression. There was no amplification of the HER-2 gene in any of the cases. There were 202 female patients who ranged in age from 26 to 96 years (mean 52). In all, 129 (64%) were T1 lesions, 61 (30%) were T2 lesions, and 13 (6%) were T3 lesions. Fifty-two (26%) showed positive staining with HER-2 (44 cases 3+, 8 cases 2+). The remaining 150 (74%) did not show overexpression. There was amplification of HER-2 gene in 55 (27%) of the cases. Two of the cases negative by FISH were 3+ positive by IHC. CONCLUSIONS: HER-2 is overexpressed in approximately 27% of female breast carcinomas. A high level of correlation is demonstrated between IHC and FISH techniques. Gene amplification of HER-2 does not play a role in male breast carcinoma. The rate of single-copy overexpression of HER-2 appears identical in male and female breast carcinoma.
Adult↗
Engraftment syndrome in breast cancer patients after stem cell transplantation is associated with poor long-term survival.
An autoaggression graft-versus-host (GVHD)-like syndrome or engraftment syndrome (ES) presenting with skin rash, fever, and other clinical findings can accompany the early phase of engraftment after autologous peripheral blood stem cell (PBSC)/bone marrow (BM) transplantation. Because ES was suggested to be analogous to GVHD, we have investigated whether ES was associated with any graft-versus-tumor effect that would affect disease progression and survival in breast cancer patients. Eighty-five consecutive patients who received BM/PBSC transplantation for breast cancer (stages II-IV) between July 1991 and July 1997 with minimum 2-year follow-up were studied. Median follow-up time was 892 days (range, 106-2913 days). Thirty-three patients (39%) developed ES. The incidence of relapse/progressive disease for the whole cohort was 61% and was similar in patients who developed ES compared with those who did not. However, there was an increased rate of mortality observed among the patients who had developed ES versus those who had not, although it was statistically not significant, (52% versus 31%, respectively; log rank, P = .08). Increased mortality rates due to disease progression were seen in all patients with ES regardless of their disease stage. In relapsed patients, median survival time after transplantation was 586 days for those with ES versus 847 days for those without ES, and the mortality rate was 85% (17/20) versus 51% (16/31) (P = .008) for those with or without ES, respectively. Visceral (lung, liver, brain, adrenal) or multiple-site relapses were observed in 85% of patients with ES versus 52% without ES (P = .01). In conclusion, whereas there was no effect of ES on relapse rate, a surprisingly significant increase in disease-related mortality rates among relapsed breast cancer patients with ES was found. Thus, patients with ES should be considered for close follow-up and further therapy posttransplantation.
Adult↗
Taking a closer look at functional play in children with autism.
Research evidence indicates that children with autism may experience problems with functional play, in addition to their well-documented deficits in symbolic play. However, as a result of the tendency of previous studies to group all functional play into a single category, the precise nature and extent of this deficit remains unclear. The present study undertook a more refined analysis of such play, subtyping the functional acts into various categories, in terms of the developmental progression suggested by research with typical infants. The functional play of children with autism was compared to that of developmentally matched children with Down syndrome and typical infants. Although there were no group differences in overall measures of the proportion of total play time spent in functional play and in the number of functional acts performed, a closer analysis of the composition of this play did reveal striking, qualitative differences. The functional play of the autism group was less elaborated, less varied, and less integrated than that of the controls. The implications of these findings are explored in relation to current theoretical models of autism and in relation to the role of other people in mediating the appropriate use of objects.
Activities of Daily Living↗
Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease.
Some patients diagnosed with cryptogenic cirrhosis may have "burned-out" nonalcoholic fatty liver disease (NAFL). To test this hypothesis, we used our liver transplant database (November 1984 to November 1998) to assess the incidence of NAFL in patients with cryptogenic cirrhosis after orthotopic liver transplantation (OLT). We also examined the clinicodemographic features associated with post-OLT NAFL, obtained by chart review and telephone interviews. When available, post-OLT liver biopsy specimens were reviewed blindly by a hepatopathologist according to the NAFL pathology protocol. We identified 51 patients with cryptogenic cirrhosis (mean age, 51 +/- 12 years); 60% were women, 94% were white, and 34% had type 2 diabetes mellitus (DM). Mean pre-OLT body mass index (BMI) was 27.33 +/- 5.54 kg/m(2). Twenty-five patients underwent at least 1 post-OLT liver biopsy. Post-OLT NAFL was identified in 13 patients (25.4%), whereas post-OLT nonalcoholic steatohepatitis (NASH) was seen in 8 patients (15.7%). Features associated with post-OLT NASH were pre- and post-OLT type 2 DM (P < or =.05) and an elevated fasting triglyceride level (P <.05). BMI tended to be greater in patients with post-OLT NAFL or NASH. Those who did not develop post-OLT NAFL showed a decrease in BMI. Patients with cryptogenic cirrhosis undergoing OLT resemble patients with NAFL. Post-OLT NAFL and NASH can be seen in a number of patients with cryptogenic cirrhosis. This supports the notion that some cases of cryptogenic cirrhosis represent burned-out NAFL.
Adult↗