Biomedical subjects

N Elias

Publications and source records attributed to N Elias.

At least 19 recordsLinked to original sources

PubMed2006

Nonspecific dizziness: frequency of supine hypertension associated with hypotensive reactions on head-up tilt.

The clinical syndrome of supine hypertension associated with orthostatic hypotension (OH) in given individuals is recognized by specialists, but is underdiagnosed in the community. The objective of this study was to assess supine hypertension associated with hypotensive reactions on head-up tilt (SH-HRT) among patients evaluated for nonspecific dizziness. Consecutive patients with nonspecific dizziness were studied with a 10-min supine 30-min head-up tilt test. Supine hypertension (SH) was diagnosed when supine systolic blood pressure (SBP) was > or = 140 mmHg and/or supine diastolic blood pressure (DBP) was > or = 90 mmHg. Hypotensive reactions on tilt (HRT) were diagnosed when SBP decreased by > or = 30 mmHg on tilt and/or DBP decreased by > or = 15 mmHg. Of 430 patients tested, 42 (9.8%) had SH-HRT. The median age was 67 years; 37 had a pretest diagnosis of hypertension, with treatment. The median supine BP was 162/90 mmHg; the median nadir BP on tilt was 118/78 mmHg. Four SH-HRT patterns were recognized: (I) SH with typical neurogenic OH (n = 6), (II) SH with vasovagal reaction on tilt (n = 4), (III) SH with sustained HRT (n = 28), and (IV) SH with mixed orthostatic-vasovagal reaction on tilt (n = 4). Dizziness on tilt occurred in 25% of patients category III (SH with sustained HRT), while appearing universally in other SH-HRT patterns. In conclusion, nonspecific dizziness may be the chief complaint in patients with SH-HRT, a disorder often unrecognized by clinicians. Different patterns of SH-HRT on HUTT may reflect different aberrations in cardiovascular homeostasis and may require differentiated management strategies.

Aged↗

PubMed2006

The patient with supine hypertension and orthostatic hypotension: a clinical dilemma.

Coexistent supine hypertension and orthostatic hypotension (SH-OH) pose a particular therapeutic dilemma, as treatment of one aspect of the condition may worsen the other. Studies of SH-OH are to be found by and large on patients with autonomic nervous disorders as well as patients with chronic arterial hypertension. In medical practice, however, the aetiologies and clinical presentation of the syndrome seem to be more varied. In the most typical cases the diagnosis is straightforward and the responsible mechanism evident. In those patients with mild or non-specific symptoms, the diagnosis is more demanding and the investigation may benefit from results of the tilt test, bedside autonomic tests as well as haemodynamic assessment. Discrete patterns of SH-OH may be recognisable. This review focuses on the management of the patient with coexistent SH-OH.

Aged↗

PubMed2006

Amiodarone toxicity presenting as pulmonary mass and peripheral neuropathy: the continuing diagnostic challenge.

A 64 year old man receiving long term amiodarone treatment presented with dyspnea, cough, and weight loss. Radiographs and computed tomography showed a lung mass with associated multiple pulmonary nodules. Biopsies of the pulmonary mass showed foamy histiocytes without malignant cells. However, findings on FDG-PET scan were consistent with a malignant tumour. These findings on computed tomography and PET scan and the unusually late resolution of the pulmonary lesions after withdrawal of amiodarone treatment posed a challenging diagnostic problem.

Amiodarone↗

PubMed2005

Autoantibodies against bactericidal/permeability-increasing protein (BPI-ANCA) in cystic fibrosis patients treated with azithromycin.

Autoantibodies against bactericidal/permeability-increasing protein (BPI-ANCA) were found in patients with cystic fibrosis (CF). It is speculated that they represent a marker of the chronic endobronchial infection and sustained inflammatory response in CF. Our aim was to evaluate whether azithromycin (AZM), through its antiinflammatory effect, could affect the level of BPI-ANCA in CF patients. Eighteen patients with CF aged 5.5-36.3 years (median 15.1) were enrolled in a randomised, double-blind, placebo-controlled trial of AZM (250 mg twice a week to 10 patients) or placebo (8 patients) for 12 weeks. BPI-ANCA levels were recorded pre- and post-treatment and compared to a group of 18 matched healthy controls. Chi-square analysis, Kruskal-Wallis and Mann-Whitney tests were used to compare between the groups. Pre- and post-treatment values were compared using the Wilcoxon Signed-Ranked test. BPI-ANCA was found in 12 CF patients (67%) and four (22%) healthy subjects (P<0.001). The mean BPI-ANCA level was 3.94+/-6.15 U/ml (mean+/-SD) in healthy subjects and 38.11+/-42.34 U/ml in CF patients (P=0.023). The mean BPI-ANCA level was higher in patients with Pseudomonas aeruginosa compared to those without (64+/-35 U/ml and 25+/-41 U/ml respectively, P=0.032). No change in BPI-ANCA levels occurred in the AZM-treated patients [35 (0-127) U/ml (median (range) and 30 (0-120) U/ml, respectively] or in the placebo group [10 (0-66) U/ml and 13 (0-83) U/ml, respectively]. BPI-ANCA levels are significantly higher in patients with CF compared to healthy controls. BPIANCA levels are higher among patients colonised with P. aeruginosa. Twelve weeks of AZM therapy did not lower the BPI-ANCA level in patients with CF.

Adolescent↗

PubMed2005

Statin escape phenomenon: Does it really exist?

BACKGROUND: The normalization of blood lipid profile has become an accepted method of primary and secondary prevention of vascular disease, with statins being the most popular group of medicines prescribed to lower cholesterol and LDL cholesterol levels. The failure of statins, administered in an appropriate dose, to maintain the optimal level of LDL cholesterol is a rare phenomenon, and is still not well understood in patients compliant for both medication and diet. The entity of "statin escape phenomenon", proposed to explain the failure of statins in some of these patients, has not been studied or characterized extensively, and reports of its prevalence are scarce. METHODS: Patients with hyperlipidemia type 2a or 2b who had been treated with statins for at least 1 year and who were followed up in the lipid clinic on a regular basis every 3-4 months were included in this study. The charts of patients whose LDL cholesterol levels were elevated by 15% or more while receiving the same treatment were analyzed, and patients with putative statin escape phenomenon were included in the study and further characterized. RESULTS: Forty-five of 358 statin-treated patients demonstrated a 15% increase in LDL cholesterol levels, leading to suspicion of statin escape phenomenon. However, a strict exclusion analysis left only two patients without evident potential triggers for the observed elevation in LDL cholesterol. CONCLUSIONS: Whether a statin escape phenomenon really exists is still not certain, but if it does exist, it is probably an uncommon event with a low prevalence.

Journal Article↗

PubMed2005

Hyperventilation and amplified blood pressure response: is there a link?

Based on prior studies, the hypothesis that hyperventilation (HV) may have a pressor effect and play a causal role in hypertension has been suggested. The objective of this study was to correlate HV with blood pressure (BP)-change during a postural challenge. Consecutive subjects referred for evaluation of syncope, dizziness, chronic fatigue syndrome (CFS), fibromyalgia, or non-CFS fatigue were assessed with a 10-min supine 30-min head-up tilt test combined with capnography. We selected for analysis the records of patients aged 17-70 years, not taking vasoactive medications, having sitting systolic BP (SBP) < 140 mmHg, sitting diastolic BP (DBP) < 90 mmHg, and who completed 30 min of tilt. HV was diagnosed when end-tidal pressure of CO2 < 30 mmHg was recorded consecutively for > or = 10 min. Postural hypertension (PHT) was diagnosed when DBP on tilt > or = 90 mmHg was recorded consecutively for > or = 10 min. DBP-change was computed as (median DBP on tilt) -(median DBP supine). PHT and DBP-change were correlated with HV. A total of 320 patient charts were reviewed. PHT was present in 30 cases. The mean DBP-change in patients with PHT was +9.9 mmHg (s.d. 5.8), with three patients manifesting HV. Of the remaining 290 patients, 56 had HV, their mean DBP-change was -0.3 mmHg (s.d. 7.2). The other 234 patients without HV had a mean DBP-change +0.95 mmHg (s.d. 5.7), comparable to the DBP-change in patients with HV. In, conclusion, posturally induced HV was not associated with an increase in BP, nor was PHT associated with HV, except in a small minority of cases.

Adolescent↗

PubMed2004

Patterns of cardiovascular reactivity in disease diagnosis.

BACKGROUND: Aberrations of cardiovascular reactivity (CVR), an expression of autonomic function, occur in a number of clinical conditions, but lack specificity for a particular disorder. Recently, a CVR pattern particular to chronic fatigue syndrome was observed. AIM: To assess whether specific CVR patterns can be described for other clinical conditions. METHODS: Six groups of patients, matched for age and gender, were evaluated with a shortened head-up tilt test: patients with chronic fatigue syndrome (CFS) (n = 20), non-CFS fatigue (F) (n = 15), neurally-mediated syncope (SY) (n = 21), familial Mediterranean fever (FMF) (n = 17), psoriatic arthritis (PSOR) (n = 19) and healthy subjects (H) (n = 20). A 10-min supine phase was followed by recording 600 cardiac cycles on tilt (5-10 min). Beat-to-beat heart rate (HR) and pulse transit time (PTT) were measured. Results were analysed using conventional statistics, recurrence plot analysis and fractal analysis. RESULTS: Multivariate analysis evaluated independent predictors of the CVR in each patient group vs. all other groups. Based on these predictors, equations were determined for a linear discriminant score (DS) for each group. The best sensitivities and specificities of the DS, consistent with disease-related phenotypes of CVR, were noted in the following groups: CFS, 90.0% and 60%; SY, 93.3% and 62.5%; FMF, 90.1% and 75.4%, respectively. DISCUSSION: Pathological disturbances may alter cardiovascular reactivity. Our data support the existence of disease-related CVR phenotypes, with implications for pathogenesis and differential diagnosis.

Adult↗

PubMed2004

Life threatening hyperphosphataemia after administration of sodium phosphate in preparation for colonoscopy.

An elderly woman developed severe hyperphosphataemia, hypocalcaemia, and cardiac arrest after oral administration of sodium phosphate in preparation for colonoscopy. This is an unusual complication and is attributed to decreased phosphate excretion by the kidneys. At increased risk are patients with impaired renal function, age more than 65 years, and presenting with intestinal obstruction or decreased intestinal motility, increased intestinal permeability, liver cirrhosis, or congestive heart failure. Though there are no accepted guidelines for anticipation and prevention of this adverse effect, it may be desirable to check serum phosphate concentrations before choosing the method for colonic preparation and before giving the second oral dose of sodium phosphate in patients at risk. Hyperphosphataemia should be suspected if a patient develops hypotension or neuromuscular irritability after administration of sodium phosphate. Haemodialysis for direct removal of phosphate and intravenous calcium for treatment of symptomatic hypocalcaemia may be life saving.

Aged↗

PubMed2001

Mini-sternotomy for the treatment of aortic valve lesions.

OBJECTIVE: To compare inverted-L mini-sternotomy performed above the sternal furcula with conventional sternotomy in patients with aortic valve diseases who undergo surgical treatment. METHODS: We operated upon 30 patients who had aortic valve lesions that had clinical and hemodynamic findings. All patients underwent inverted-L sternotomy, which extended from above the manubrium of the sternum to the 3rd right intercostal space, without opening the pleural cavity. Their ages ranged from 32 to 76 years, and 18 were males and 12 were females. We used negative pressure in a venous 1/4-inch cannula, and the patients were maintained in Trendelemburg's position. Twenty-seven patients received bioprostheses with diameters ranging from 23 to 29mm. Three patients underwent only removal of the calcifications of the aortic valve leaflets and aortic commissurotomy. RESULTS: The mean duration of anoxic cardiac arrest was 63.11min. Access was considered good in all patients. One death was due to pulmonary and renal problems not related to the incision. All patients had a better recovery in the intensive care unit, got out of bed sooner, coughed more easily, and performed prophylactic physiotherapeutic maneuvers for respiratory problems more easily and with less pain in the incision. Early ambulation was more easily carried out by all patients. CONCLUSION: Mini-sternotomy proved to be better than the conventional sternotomy because it provided more comfort for the patients in the early postoperative period, with less pain and greater desire for early ambulation and all its inherent advantages.

Adult↗

PubMed2000

In vivo metabolism of ApoB, ApoA-I, and VLDL triglycerides in a form of hypobetalipoproteinemia not linked to the ApoB gene.

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder that may result from different mutations in the apolipoprotein B (apoB) gene or chromosome 2. However, linkage of FHBL to the apoB gene was ruled out in 2 kindreds reported to date, and the genetic and metabolic bases for FHBL remain unknown. One of the reported kindreds is our 40-member F kindred, in which we found linkage of FHBL to a novel susceptibility region on chromosome 3p21. 1-2. In addition to having low apoB levels, some, but not all, of the affected subjects in the F kindred also had low levels of high density lipoprotein (HDL) cholesterol and apoA-I. Our aim was to define the metabolic bases of the disorder in the F kindred. Therefore, we studied the in vivo kinetics of apoB and apoA-I and very low density lipoprotein (VLDL) triglycerides in 4 affected subjects and 5 normolipidemic relatives. Deuterated leucine and deuterated glycerol were used to label the apolipoproteins and triglycerides, respectively. Compartmental modeling was used to obtain the kinetic parameters. Affected subjects had (1) normal fractional catabolic rates (FCRs) for VLDL apoB, (2) increased FCRs for low density lipoprotein (LDL) apoB (0.050+/-0.009 versus 0. 030+/-0.006 pools per hour for normal subjects, P=0.005), and (3) decreased production rates of VLDL apoB (11.4+/-1.7 versus 25.6+/-4. 9 mg. kg(-1). d(-1), P=0.003), LDL apoB (7.8+/-1.3 versus 12.7+/-3.7 mg. kg(-1). d(-1), P=0.04), and VLDL triglycerides (8.2+/-4.5 versus 19.6+/-10.8 58 micromol. kg(-1). h(-1), P=0.09). These data differ from those obtained in previously studied FHBL heterozygotes bearing apoB-2 and apoB-9, 2 very short truncations of apoB. Low HDL cholesterol and apoA-I levels were caused by higher apoA-I FCRs (0. 035+/-0.005 versus 0.018+/-0.005 pools per hour in controls, P<0.01) without significant decrease in apoA-I production rates (18.7+/-2.7 versus 22.8+/-5.6 mg. kg(-1). d(-1)). In conclusion, decreased secretion of apoB-containing lipoproteins and hypercatabolism of LDL account for low apoB and cholesterol levels in this novel form of FHBL.

Adult↗

PubMed1999

Incidence of bacteraemia following fibreoptic bronchoscopy.

Guidelines for antibiotic prophylaxis of infective endocarditis prior to fibreoptic bronchoscopy, are based on only five studies, which showed a bacteraemia rate of <1% among 291 patients studied. T his study was designed to expand the current data regarding the frequency of bacteraemia following fibreoptic bronchoscopy. Aerobic and anaerobic cultures of venous blood and of lavage fluid were drawn from 200 consecutive patients undergoing fibreoptic bronchoscopy without respiratory infection or antibiotic treatment prior to the procedure. The true bacteraemia rate was calculated after excluding probable "contaminated" blood cultures. A possible correlation between type of procedure performed during the bronchoscopy and occurrence of bacteraemia was investigated. Positive blood cultures were noted following 26 bronchoscopy examinations. Coagulase negative Staphylococcus was found in the cultures of 18 patients, coagulase positive Staphylococcus in 3 patients, nonhaemolytic streptococci and a Klebsiella species in 2 patients each, and beta haemolytic streptococcus in one patient. After exclusion of 13 "contaminated" specimens the bacteraemia rate was 6.5% (13/200 patients). This study showed a bacteraemia rate of 6.5%, significantly higher than previously recognized in a cohort of patients undergoing fibreoptic bronchoscopy without either pulmonary infection or an unusually high rate of invasive procedures. These findings should be taken into account in future evaluations of recommendations for antibiotic prophylaxis of endocarditis.

Adolescent↗

PubMed1999

Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder characterized by low levels of apolipoprotein (apo) B and low-density lipoprotein (LDL) cholesterol. Decreased production rates of apoB have been demonstrated in vivo in FHBL heterozygotes. In the present study, we wished to investigate whether the transport of triglycerides was similarly affected in these subjects. Therefore, we studied the in vivo kinetics of very-low-density lipoprotein (VLDL) triglycerides and VLDL apoB-100 simultaneously in 7 FHBL heterozygotes from 2 well-characterized kindreds and 7 healthy normolipidemic subjects. In both kindreds, hypobetalipoproteinemia is caused by mutations in the 5' portion of the apoB gene specifying short truncations of apoB undetectable in plasma. A bolus injection of deuterated palmitate and a primed constant infusion of deuterated leucine were given simultaneously, and their incorporation into VLDL triglycerides and VLDL apoB, respectively, were determined by gas chromatography-mass spectrometry. Kinetic parameters were calculated by using compartmental modeling. VLDL apoB fractional catabolic rates (FCRs) in FHBL heterozygotes and controls were similar (11. 6+/-3.9 and 10.9+/-2.4 pools per day, respectively, P=0.72). On the other hand, FHBL heterozygotes had a 75% decrease in VLDL apoB production rates compared with normal subjects (5.8+/-1.8 versus 23.4+/-7.1 mg/kg per day, P<0.001). The decreased production rates of VLDL apoB accounts for the very low concentrations of plasma apoB found in heterozygotes from these kindreds (24% of normal). Mean VLDL triglyceride FCRs in FHBL subjects and controls were not significantly different (1.06+/-0.74 versus 0.89+/-0.50 pools per hour, respectively, P=0.61). There was a good correlation between VLDL apoB FCR and VLDL triglyceride FCR in the 2 groups (r=0.84, P<0. 001). VLDL triglyceride production rates were decreased by 60% in FHBL heterozygotes compared with controls (9.3+/-6.0 versus 23.0+/-9. 6 micromol/kg per hour, P=0.008). Thus, the hepatic secretion of VLDL triglycerides is reduced in FHBL heterozygotes but to a lesser extent than the decrease in apoB-100 secretion. This is probably achieved by the secretion of VLDL particles enriched with triglycerides.

Adolescent↗

PubMed1999

Validation of a new procedure to determine plasma fatty acid concentration and isotopic enrichment.

Assessment of free fatty acid (FFA) concentration and isotopic enrichment is useful for studies of FFA kinetics in vivo. A new procedure to recover the major FFA from plasma for concentration and isotopic enrichment measurements is described and validated. The procedure involves extraction of plasma lipids with hexane, methylation with iodomethane (CH(3)I) to form fatty acid methyl esters (FAME), and subsequent purification of FAME by solid phase extraction (SPE) chromatography. The new method was compared with a traditional method using thin-layer chromatography (TLC) to recover plasma FFA, with subsequent methylation by BF(3)/methanol. The TLC method was found to be less reliable than the new CH(3)I method because of contamination with extraneous fatty acids, chemical fractionation of FFA species, and incomplete recovery of FFA associated with TLC. In contrast, the CH(3)I/SPE method was free of contamination, did not exhibit chemical fractionation, and had higher recovery. The iodomethane reaction was specific for free fatty acids; no FAME were formed when esterified fatty acids (triglycerides, cholesteryl esters, phospholipids) were subjected to the methylation reaction. We conclude that the CH(3)I/SPE method provides rapid and convenient recovery of plasma fatty acids for quantification or GC/MS analysis as methyl esters, and is not subject to the problems of contamination, reduced recovery, and chemical fractionation associated with recovery of FFA by TLC.

Chromatography↗

PubMed1998

Role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a heterogeneous genetic disorder characterized by multiple lipoprotein phenotypes. The genetic defect is unknown, although linkage to the region of the apolipoprotein (apo) A-I-apoC-III-apo A-IV gene cluster on chromosome 11 has been suggested. The metabolic abnormality in many affected individuals is overproduction of apoB-containing lipoproteins causing elevated levels of plasma cholesterol, triglycerides, or both. Low levels of high-density lipoprotein (HDL) cholesterol and an abundance of dense low-density lipoprotein (LDL) particles are other features contributing to the high association of this disorder with premature coronary artery disease. Many affected individuals need drug therapy to lower their lipid levels. The hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins," offer a potent therapeutic option in patients with FCHL. These drugs significantly decrease levels of total cholesterol, LDL cholesterol, and apoB, although their effects on HDL cholesterol and triglycerides are limited. The mechanisms by which statins exert their beneficial effects in patients with FCHL remain controversial. We studied 7 patients with FCHL and 5 genetically uncharacterized patients with mixed lipemia during treatment with pravastatin 20 mg/day. Metabolic parameters of very-low-density lipoprotein (VLDL)-apoB and LDL-apoB were studied using endogenous labeling with stable isotopes. In all patients pravastatin caused an increase in fractional catabolic rates of LDL-apoB without a significant effect on the production rates of apoB-containing lipoproteins. We cannot exclude the possibility that higher doses of statins may decrease VLDL and LDL production.

Animals↗

PubMed1998

mRNA cytokine profile in peripheral blood cells from chronic hepatitis C virus (HCV)-infected patients: effects of interferon-alpha (IFN-alpha) treatment.

Natural immune responses, both cellular and humoral, are not capable of terminating HCV infection in most patients. A role has been suggested for peripheral blood leucocytes (PBL) in viral persistence and clinical implications, as these cells may serve as a viral reservoir and at the same time may be inadequate active participants in antiviral immune reactions. IFN-alpha administration, although only partially successful, is currently the main therapy available for chronic HCV patients. In addition to its antiviral effects, IFN-alpha regulates the function of cytokines, their receptors and other molecules of immune importance. The aim of this study was to determine cytokine mRNA expression in PBL derived from chronic HCV patients prior to and at termination of IFN-alpha treatment. HCV RNA was still observed in sera of most patients (10 out of 14 treated patients) at termination of treatment. In pretreated patients mRNA expression of Th2 (IL-4, IL-6 and IL-10) and Th3 (transforming growth factor-beta (TGF-beta)) was observed in only a low percentage of PBL samples from patients, similar to controls. IFN-alpha treatment led to an elevation in the number of samples expressing these cytokines (significant for IL-4, IL-6, IL-10, tumour necrosis factor-alpha (TNF-alpha) and TGF-beta), accompanied by reduction in liver enzymes but in serum viral load in only approximately 30% of patients. Expression of TNF-alpha and TNF-beta mRNA was observed in samples from patients but not controls, while no differences were observed for mRNA of classical Th1 cytokines (IL-2 and IFN-gamma) between patients before or during treatment as well as controls. The cytokine mRNA profile following IFN-alpha treatment points to an anti-inflammatory response which does not appear to be involved in termination of the viral infection. The PBL cytokine profile observed in this study may explain the failure of the immune system to eradicate HCV chronic infection and suggests that early treatment in the acute phase of disease with agents that stimulate cytotoxic immune type 1 responses may lead to eradication of HCV infection.

Antiviral Agents↗

PubMed1998

Colonic ulcers in a patient with hepatitis C virus-associated polyarteritis nodosa.

An elderly woman presented with abdominal discomfort, pulmonary infiltrates, acute renal failure, purpura, and massive hematochezia. Numerous colonic ulcers with underlying fibrinoid necrotizing arteritis were found in the colectomy specimen. Anti-hepatitis C virus (HCV) antibodies and HCV RNA were present in the serum. The diagnosis of HCV-associated polyarteritis nodosa was clear. This clinical presentation differs from the more commonly occurring vasculitis complicating HCV infection, which is of the leukocytoclastic type, and is associated with overt liver disease and cryoglobulinemia. In our patient, results of liver tests were normal, there was no cryoglobulinemia, and the vasculitis was of the fibrinoid necrotizing arteritis type. HCV-associated polyarteritis nodosa should be considered in the differential diagnosis of necrotizing fibrinoid arteritis even in a patient with normal liver function test results and in the absence of cryoglobulinemia.

Aged↗

PubMed1997

A hexameric phosphorothioate oligonucleotide telomerase inhibitor arrests growth of Burkitt's lymphoma cells in vitro and in vivo.

A phosphorothioate oligonucleotide (PS-ODN) with sequence identical to the repeat sequence of the mammalian telomere, 5'-d(TTAGGG)-3', was incubated with a Burkitt's lymphoma-derived (OMA-BL1) cell line. This hexanucleotide inhibits telomerase activity in cell lysates, lengthens cell doubling time, and induces apoptosis. Concatenated repeats (12-, 18-, and 24-mers) of the 5'-d(TTAGGG)-3' motif induce similar cellular responses. Scrambled sequences do not efficiently inhibit telomerase activity or significantly alter cell growth and viability. The in vivo efficacy of this PS-ODN was evaluated in a xenograft human-nude mouse model. Once tumors were established these animals were administered the telomere mimic, 5'-d(TTAGGG)-3', a control scrambled sequence 5'-d(TGTGAG)-3', or saline for 14 days via a subcutaneous osmotic pumps in a blinded study monitoring tumor size with dose and time. A significant decrease in tumor size was observed in animals given 50 micrograms/mouse/day 5'-d(TTAGGG)-3', but not following 5'-d(TGTGAG)-3', relative to the saline-treated animals. The antitumor activity of the 6-mer telomere mimic demonstrated a dose dependency including a reduction in metastatic nodules in the spleen. No activity was observed with the scrambled controls. In addition to antitumor activity we observed an increase in the mouse hematopoietic progenitor cell populations, BFU-e and CFU-GM. These results demonstrated the effects of a short hexameric oligonucleotide telomere mimic in vitro and in vivo and the potential utility of short oligonucleotides as telomerase inhibitors.

Animals↗

PubMed1997

Recurrence-free long-term survival after liver transplantation for hepatitis B using interferon-alpha pretransplant and hepatitis B immune globulin posttransplant.

OBJECTIVE: The authors determined whether pretransplant reduction of hepatitis B virus (HBV) load using alpha-interferon-2b (IFN) and passive immunoprophylaxis using hepatitis B immunoglobulin (HBIg) posttransplantation can prevent HBV recurrence in patients undergoing liver transplantation (LT) for HBV cirrhosis. SUMMARY BACKGROUND DATA: Liver transplantation in patients with HBV cirrhosis is associated with a high rate of recurrence and reduced survival. In patients with evidence of replicating virus (HBV-DNA or hepatitis B e antigen [HBeAg]-positive serum or both), recurrence is nearly universal. Passive immunoprophylaxis with HBIg alone is not effective in preventing HBV recurrence posttransplant, especially in patients with evidence of active viral replication pretransplant. Higher doses of HBIg posttransplant has reduced recurrence rates to 30% to 50%. Lamivudine, a nucleoside analogue that has shown early promise, also is associated with significant HBV recurrence. The authors report a reliable method of preventing viral recurrence in patients even with evidence for active HBV replication pretransplant. METHODS: Pretransplant patients with evidence of replicating HBV were given IFN starting at 1 million IU 3 times per week subcutaneously. This dose was increased to 2 and then 3 million IU 3 times per week when patient's side effects permitted and was maintained until the patient underwent a LT. All patients were tested every 4 weeks for hepatitis B surface antigen (HBsAg), HBeAg, and HBV-DNA. When patients became negative for HBeAg and HBV-DNA, they were listed for LT. Patients that were only HBsAg positive were listed immediately and received a LT without prior IFN treatment. Post-LT, all patients began receiving HBIg 2000 IU (10 mL) daily from days 1 to 20 and then weekly for the first 2 years. After 2 years, all patients received 2000 IU (10 mL) monthly. Additional HBIg immunoprophylaxis was given during intense immunosuppression for rejection. Posttransplant serum was tested for HBsAg, HBeAg, and HBV-DNA in all patients 1 week, 1 month, and every 3 months thereafter. Liver biopsies were done at least yearly and when liver enzymes were abnormal and were always tested for HBsAg and HBcAg by immunoperoxidase. RESULTS: Thirteen patients with decompensated HBV cirrhosis were transplanted. Pretransplant, eight patients had evidence of active viral replication at the initial assessment (HBeAg or HBV-DNA-positive serum or both). All eight were successfully treated with IFN (median duration, 24 weeks; range, 8-53) and converted to a negative status before transplantation. Side effects from IFN were minimal and well tolerated, except in one patient who required 6 million IU to convert to a nonreplicating status. The five patients that were only HBsAg positive were not treated with IFN pretransplant. After surgery, HBIg given as described achieved consistently serum levels greater than 1000 IU/L. Twelve of the 13 patients are alive with normal liver function and without serologic evidence of HBV recurrence at a median follow-up of 32 months (range, 9-56 months). None have evidence of HBV recurrence as measured by serum HBsAg/HBeAg/HBV-DNA at recent follow-up. The sera of the seven longest survivors has tested negative for HBV-DNA using the polymerase chain reaction method. In addition, a liver biopsy was obtained in six of these patients, the results of which also tested negative for HBV-DNA using polymerase chain reaction. Liver biopsy specimens have been negative for the presence of HBsAg and HBcAg by immunoperoxidase staining in all 12 patients. CONCLUSION: A reduction of viral load pretransplant with IFN and posttransplant HBIg prevents recurrence of hepatitis B and permits LT for HBV cirrhosis, even in patients with evidence of replicating virus. The IFN pretransplant was well tolerated, and the small frequent dosing of HBIg posttransplant did not cause side effects while achieving serum levels > 1000 IU/L.

Adult↗