A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning.

INTRODUCTION: Acetylcysteine prevents hepatic injury when administered soon after acetaminophen overdose. The most commonly used treatment protocols are a 72-hour oral and a 21-hour intravenous (IV) protocol. Between 1984 and 1994, 409 patients were enrolled in a study to describe the outcomes of patients who were treated using a 48-hour IV protocol. In 1991, an interim analysis reported the first 223 patients. The objective of this manuscript is to report the rates of hepatotoxicity and adverse events occurring during a 48-hour IV acetylcysteine protocol in the entire 409 patient cohort. METHODS: This was a multicenter, single-arm, open-label clinical trial enrolling patients who presented with a toxic serum acetaminophen concentration within 24 h of acute acetaminophen ingestion. Patients were treated with 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses. Serum aminotransferase activities were measured every 8 h during the protocol, and adverse events were recorded. The primary outcome was the percentage of subjects who developed hepatotoxicity defined as a peak serum aminotransferase greater than 1000 IU/L. RESULTS: Four hundred and nine patients were enrolled, and 309 met inclusion for the outcome analysis. The overall percentage of patients developing hepatotoxicity was 18.1%, and 3.4% of patients treated within 10 h developed hepatotoxicity. One acetaminophen-related death occurred in a patient treated at 22 h. Adverse events occurred in 28.9% of enrolled subjects; the most common adverse events were nausea, vomiting, and flushing, and no events were rated as serious by the investigator. CONCLUSIONS: Acetaminophen-overdosed patients treated with IV acetylcysteine administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses had a low rate of hepatotoxicity and few adverse events. This protocol delivers a higher dose of acetylcysteine which may be useful in selected cases involving very large overdoses.

The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol - a randomized study.

BACKGROUND: Retrospective accounts suggest that therapeutic doses of paracetamol can produce severe hepatic injury in patients with putative high-risk conditions, including alcoholism and infectious hepatitis. Metabolism of paracetamol to its hepatotoxic metabolite is enhanced in patients who abuse alcohol, who also have compromised liver defences from depressed hepatic glutathione. AIM: To determine the effect of paracetamol on serum liver tests of newly abstinent subjects who abuse alcohol, including subjects with hepatitis C infection. METHODS: A randomized, double-blind, placebo-controlled study. Adult alcohol abusers with a current drinking episode longer than 7 days received either placebo or paracetamol 4 g/day for 5 days. RESULTS: Of 142 subjects enrolled, 74 received paracetamol and 68 received placebo. Mean ALT activity during treatment increased from 48 to 62 IU/L in the paracetamol group and from 47 to 49 IU/L in the placebo group. Maximum ALT was 238 and 249 IU/L in the paracetamol and control groups respectively. The INR remained unchanged and serum bilirubin decreased in both groups. Subgroup analyses for subjects with alcoholic hepatitis, hepatitis C virus antibody and other subgroups showed no statistical difference between groups. CONCLUSION: Administration of paracetamol 4 g/day appears safe in newly abstinent patients who abuse alcohol.

Vision-related quality of life in patients with diabetic macular oedema.

AIMS: The aim of this study was to determine the impact of diabetic macular oedema (DME) on the quality of life (QOL) in patients with type 2 diabetes mellitus. METHODS: The study was a prospective, consecutive, non-comparative case series. An observational study evaluated the quality of vision and vision-specific QOL using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). Mean VFQ-25 subscale scores in type 2 diabetic study patients were compared with mean VFQ-25 subscale score in groups of patients with type 1 diabetic retinopathy (T1DR) and varying degrees of age-related macular degeneration (ARMD), glaucoma and cataracts and in reference populations. RESULTS: Thirty-three patients completed the NEI VFQ-25. The mean age of the study population was 64 years. When performing a comparison of those patients with DME versus those with isolated T1DR we found that for the general health subscale, the DME versus T1DR group means were 42+/-4.4 versus 61+/-1.0 respectively. The DME versus T1DR quality of vision categorical mean scores were 69+/-4.1 versus 93+/-3.9. The DME versus T1DR VR-QOL categorical mean scores were 62+/-5.0 versus 93+/-1.0. The DME group was significantly worse in each of these three categories compared with the T1DR group (p<0.01). An additional analysis was performed to examine the differences in VR-QOL in the DME group versus varying common ocular diseases, including age-related macular degeneration (ARMD), glaucoma, cataracts and disease-free reference groups. The mean values of VFQ-25 subscale in the DME group were significantly lower then the glaucoma group in ten of 12 subscales, the cataract group in 11 of 12 subscales, and the reference group in 12 of 12 subscales. However, the mean values of VFQ-25 subscale in the DME group were only significantly different from the ARMD group in three of 12 subscales. CONCLUSIONS: Type 2 diabetes patients with macular oedema experience a decreased VR-QOL compared with type 1 diabetic patients with diabetic retinopathy, glaucoma or cataracts. However, VR-QOL in type 2 diabetic patients with macular oedema was similar to those individuals with ARMD.

The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients--a multicenter randomized study.

BACKGROUND: Hepatic failure has been associated with reported therapeutic use of acetaminophen by alcoholic patients. The highest risk period for alcoholic patients is immediately after discontinuation of alcohol intake. This period exhibits the largest increase in CYP2E1 induction and lowest glutathione levels. Our hypothesis was that common liver tests would be unaffected by administration of the maximum recommended daily dosage of acetaminophen for 3 consecutive days to newly-abstinent alcoholic subjects. METHODS: Adult alcoholic subjects entering two alcohol detoxification centers were enrolled in a prospective double-blind, randomized, placebo-controlled trial. Subjects were randomized to acetaminophen, 4 g/day, or placebo for 3 consecutive days. The study had 95% probability of detecting a 15 IU/L difference in serum ALT. RESULTS: A total of 443 subjects were enrolled: 308 (258 completed) received acetaminophen and 135 subjects (114 completed) received placebo. Study groups did not differ in demographics, alcohol consumption, nutritional status or baseline laboratory assessments. The peak mean ALT activity was 57 +/- 45 IU/L and 55 +/- 48 IU/L in the acetaminophen and placebo groups, respectively. Subgroup analyses for subjects presenting with an elevated ALT, subjects fulfilling a diagnosis of alcoholic hepatitis and subjects attaining a peak ALT greater than 200 IU/L showed no statistical difference between the acetaminophen and control groups. The one participant developing an increased international normalized ratio was in the placebo group. CONCLUSION: Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.

A prospective observational study of 5-, 7-, and 10-day antibiotic treatment for acute otitis media.

OBJECTIVE: To compare 5-, 7- and 10-day duration of antibiotic therapy for acute otitis media (AOM) in children. STUDY DESIGN AND SETTING: Prospective nonrandomized 1-year evaluation of 3 treatment durations for AOM in a private pediatric setting. Outcomes assessed at 14 +/- 4 days after start of therapy with clinical response categorized as cure, improvement, or failure. RESULTS: A total of 2172 children were studied; 46.4% were < or =2-years-old. Antibiotics used were amoxicillin (61.9% of patients), trimethoprim/sulfamethoxazole (11.7%), cephalosporins (14.2%), amoxicillin/clavulanate (5.2%), and macrolides/azalides (4.8%). No overall difference in outcome was observed comparing the 5-day (n = 707), 7-day (n = 423), or 10-day (n = 1042) treatments, including children < or =2-years-old. However, in the subset who had an episode of AOM in the preceding month, outcome differed; 5-day treatment was followed by more frequent failure than 10-day treatment (P < 0.001). In logistic regression analysis, variables identified as contributing to a cure were: >2-years-old (P < 0.0001), no AOM in the preceding month (P = 0.07), or preceding 12 months (P = 0.03). CONCLUSIONS: Our study supports the transition from 10 to 5 days for standard AOM antibiotic treatment duration in most patients. A 10-day regimen may be superior in children who have experienced an episode of AOM within the preceding month, a known risk factor for resistant bacterial infection in the otitis-prone patient.

Outcomes after judicious antibiotic use for respiratory tract infections seen in a private pediatric practice.

BACKGROUND: Most respiratory tract infections (RTIs) in children have a viral cause, they resolve on their own, and antibiotics need not be prescribed. OBJECTIVE: We sought to provide evidence that judicious antibiotic use can be accomplished in private pediatric practice without observing an increase in return office visits or in the rate of bacterial infections that may follow. STUDY DESIGN: This was a prospective 12-month study from July 1, 1996 through June 30, 1997. On the same 1 day each week, a representative convenience sample of acute respiratory tract illness patients was enrolled, and laboratory studies performed as appropriate, including viral cultures on all. Children were then followed for 30 days to ascertain the outcomes of not prescribing antibiotics except when specific bacterial infections were present at the initial visit. RESULTS: Three hundred eighty-three children were enrolled; 293 (77%) did not receive antibiotics at the enrollment visit. Ninety children (23%) received antibiotics based on a diagnosis of acute otitis media (n = 53), acute streptococcal tonsillopharyngitis (n = 18), or other presumed or documented bacterial infections (n = 19). An unscheduled return visit related to the initial visit occurred for 86 (29%) of the 293 children not receiving antibiotics initially and in 40 (44%) of 90 children receiving antibiotics initially. Eighty-seven children (23%) had positive viral culture results. The most frequently isolated viruses were adenovirus, enterovirus, parainfluenzae virus, and influenza virus. CONCLUSION: Children with RTIs without a concomitant presumed or proven bacterial infection do not require antibiotics. In this busy office practice, >75% of the children presenting with an RTI did not have a presumed or proven bacterial infection. These children did not have a higher rate of return office visits or an increase in bacterial infections. This reinforces the judicious use of antibiotics in managing children with RTIs.outcomes, antibiotic, respiratory infections.

Epidemiology of lung cancer with special reference to genetics, bioassays, women, and developing countries.

The twentieth century may be looked back upon as the century of lung cancer. At the beginning of the century lung cancer was quite rare, but this century the rates have increased approximately 10-fold and it is the second most common type of cancer and has become the leading cause of death due to cancer in the United States. The rate of lung cancer among U.S. women continues to rise, in contrast rates in U.S. men have been declining since about 1990. Cigarette smoking accounts for 85-90% of lung cancer deaths in the United States. However, only 10-15% of smokers eventually develop lung cancer. In the past 25 years, since the U.S. Surgeon General's ground breaking report in 1964, overall smoking rates have been declining, but smoking still remains a significant behavior. More troubling, the rates of smoking continue to increase in many parts of the world. Advances in molecular biology and early diagnosis have increased the understanding of lung cancer etiology and may be effective in uncovering more efficient detection and treatment regimens. These advances will hopefully make lung cancer as uncommon at the end of the twenty-first century, as it was at the beginning of the twentieth century.

MiAMP1, a novel protein from Macadamia integrifolia adopts a Greek key beta-barrel fold unique amongst plant antimicrobial proteins.

MiAMP1 is a recently discovered 76 amino acid residue, highly basic protein from the nut kernel of Macadamia integrifolia which possesses no sequence homology to any known protein and inhibits the growth of several microbial plant pathogens in vitro while having no effect on mammalian or plant cells. It is considered to be a potentially useful tool for the genetic engineering of disease resistance in transgenic crop plants and for the design of new fungicides. The three-dimensional structure of MiAMP1 was determined through homonuclear and heteronuclear ((15)N) 2D NMR spectroscopy and subsequent simulated annealing calculations with the ultimate aim of understanding the structure-activity relationships of the protein. MiAMP1 is made up of eight beta-strands which are arranged in two Greek key motifs. These Greek key motifs associate to form a Greek key beta-barrel. This structure is unique amongst plant antimicrobial proteins and forms a new class which we term the beta-barrelins. Interestingly, the structure of MiAMP1 bears remarkable similarity to a yeast killer toxin from Williopsis mrakii. This toxin acts by inhibiting beta-glucan synthesis and thereby cell wall construction in sensitive strains of yeast. The structural similarity of MiAMP1 and WmKT, which originate from plant and fungal phyla respectively, may reflect a similar mode of action.

A family of antimicrobial peptides is produced by processing of a 7S globulin protein in Macadamia integrifolia kernels.

A new family of antimicrobial peptides has been discovered in Macadamia integrifolia. The first member of this new family to be purified from nut kernels was a peptide of 45 aa residues, termed MiAMP2c. This peptide inhibited various plant pathogenic fungi in vitro. cDNA clones corresponding to MiAMP2c encoded a 666 aa precursor protein homologous to vicilin 7S globulin proteins. The deduced precursor protein sequence contained a putative hydrophobic N-terminal signal sequence (28 aa), an extremely hydrophilic N-proximal region (212 aa), and a C-terminal region of 426 aa which is represented in all vicilins. The hydrophilic portion of the deduced protein contained the sequence for MiAMP2c as well as three additional segments having the same cysteine spacing pattern as MiAMP2c. Each member of the MiAMP2 family (i.e. MiAMP2a, b, c and d) consisted of approximately 50 amino acids and contained a C-X-X-X-C-(10-12)X-C-X-X-X-C motif. Subsequent isolations from seed exudates led to the purification of the predicted family members MiAMP2b and 2d, both of which also exhibited antimicrobial activity in vitro. These results suggest that some vicilins play a role in defence during seed germination.

Purification and characterization of a plant antimicrobial peptide expressed in Escherichia coli.

MiAMP1 is a low-molecular-weight, cysteine-rich, antimicrobial peptide isolated from the nut kernel of Macadamia integrifolia. A DNA sequence encoding MiAMP1 with an additional ATG start codon was cloned into a modified pET vector under the control of the T7 RNA polymerase promoter. The pET vector was cotransformed together with the vector pSB161, which expresses a rare arginine tRNA. The peptide was readily isolated in high yield from the insoluble fraction of the Escherichia coli extract. The purified peptide was shown to have an identical molecular weight to the native peptide by mass spectroscopy indicating that the N-terminal methionine had been cleaved. Analysis by NMR spectroscopy indicated that the refolded recombinant peptide had a similar overall three-dimensional structure to that of the native peptide. The peptide inhibited the growth of phytopathogenic fungi in vitro in a similar manner to the native peptide. To our knowledge, MiAMP1 is the first antimicrobial peptide from plants to be functionally expressed in E. coli. This will permit a detailed structure-function analysis of the peptide and studies of its mode of action on phytopathogens.

Impact of p16 expression on surgical management of malignant melanoma and pancreatic carcinoma.

BACKGROUND: Recent advances in molecular oncology have provided explanations at the DNA level for the malignant transformation and metastatic potential of various cancers. Malignant melanoma and pancreatic cancer may be classified together in both these cancers exhibit mutations in, or loss of, the cell-cycle inhibitory gene, p16. This paper reviews the current literature on p16 expression in melanoma and pancreatic cancer, explores factors that place patients with these cancers in categories of high risk for metastases or recurrence, and addresses whether aberrant gene expressions should influence awareness of and current recommendations for the management of these aggressive cancers. METHODS: A computerized literature search was performed utilizing OVID Technology's Medline database from 1993 to 1998. RESULTS: Both familial as well as sporadic cases of malignant melanoma and pancreatic carcinoma are reported in the literature. Although a low percentage of cases of either malignancy have p16 mutations, a higher risk of their development has been reported to occur in certain families with p16 germline mutations. CONCLUSIONS: The increased risk determined in these families may serve to heighten awareness of the influence of positive family history of these cancers in the evaluation of patients.

Purification, characterisation and cDNA cloning of an antimicrobial peptide from Macadamia integrifolia.

An antimicrobial peptide with no significant amino acid sequence similarity to previously described peptides has been isolated from the nut kernels of Macadcamia integrifolia. The peptide, termed MiAMP1, is highly basic with an estimated pI of 10.1, a mass of 8.1 kDa and contains 76 amino acids including 6 cysteine residues. A cDNA clone containing the entire coding region corresponding to the peptide was obtained. The deduced amino acid sequence of the cDNA indicated a 26-amino-acid signal peptide at the N-terminus of the preprotein. Purified MiAMP1 inhibited the growth of a variety of fungal, oomycete and gram-positive bacterial phytopathogens in vitro. Some pathogens exhibited close to 100% inhibition in less than 1 microM peptide (5 microg/ml). Antimicrobial activity was diminished against most, but not all, microbes in the presence of calcium and potassium chloride salts (1 mM and 50 mM, respectively). MiAMP1 was active against bakers yeast, was inactive against Escherichia coli and was non-toxic to plant and mammalian cells. Analysis of genomic DNA indicated that MiAMP1 was encoded on a single copy gene containing no introns. The MiAMP1 gene may prove useful in genetic manipulations to increase disease resistance in transgenic plants.

Mutagenicity of benzo[a]pyrene bay-region sulfonates.

The interaction between the sulfite anion and specific benzo[a]pyrene (B[a]P) derivatives produces a novel class of benzo[a]pyrene sulfonates. (+/-)-7,8,9-Trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-10-sulfonate (B[a]PT-10-sulfonate) is formed in high yields in incubations containing (+/-)-7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyre ne (anti-BPDE) and sulfite, and sulfite strongly enhances the mutagenicity of the diolepoxide toward Salmonella typhimurium under those conditions. Although B[a]PT-10-sulfonate itself shows little direct mutagenicity over a 1-20 microM concentration range, this reactive bay-region intermediate does enhance the mutagenicity of anti-BPDE in strains TA98 and TA100 by up to 280%. No significant enhancement was seen when up to 20 microM B[a]PT-10-sulfonate was used in concert with another direct-acting mutagen, N-acetoxy-acetylaminofluorene (N-AcO-AAF). The isomeric product derived from sulfite and (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol) is (+/-)-7,8,10-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-9-sulfonate (B[a]PT-9-sulfonate). Like B[a]PT-10-sulfonate, B[a]PT-9-sulfonate is not mutagenic to strains TA97, TA98 and TA100. This sulfonate exhibited little enhancing activity with anti-BPDE over a 1-20 microM concentration range, but did enhance the mutagenic response of strain TA98 to 0.2 microM N-Aco-AAF by up to 128%. Sulfite, anti-BPDE and B[a]PT-sulfonates were also examined for the ability to induce a forward mutation at the hgprt locus (8-azaguanine resistance) in strains of S.typhimurium. Sulfite caused a marked enhancement of forward mutation due to anti-BPDE in both TA98 and TA100. Surprisingly, concurrent administration of B[a]PT-10-sulfonate with anti-BPDE did not increase the number of mutant colonies. The extensive conversion of anti-BPDE to B[a]PT-10-sulfonate under conditions where sulfite enhances diolepoxide mutagenicity, when coupled with this enhancement of diolepoxide mutagenicity by B[a]PT-10-sulfonate in the reverse mutation assay, supports this novel B[a]P derivative as a mediator of the sulfite-dependent enhancement of B[a]P genotoxicity. Determining why this enhancing effect was not seen when selecting for mutation at the hgprt locus of S.typhimurium will require further study.

Theoretical and experimental comparison of three types of electromagnetic hyperthermia applicator.

There is evidence that heating of malignant tissue in the treatment of cancer may be beneficial and so the performance of different applicator designs needs to be established. A theoretical model of the dielectric loaded waveguide applicator is compared with models of two other applicators which depend on energy radiated from conductors carrying high frequency current. The latter are exemplified by the compact resonant patch applicator and the lightweight inductive current sheet applicator. It is shown that heating profiles and field penetration of each applicator are similar for equal radiating areas, and these results have been substantiated experimentally. Impedance match as a function of frequency and load is also compared for the three types of applicator.

Benzo[a]pyrene bay-region sulfonates, a novel class of reactive intermediates.

The mutagenicity of 7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) toward Salmonella typhimurium strain TA98 is enhanced by over 1.5-fold by the addition of 1-10 mM sulfite to the incubations. Sulfite itself is neither mutagenic nor toxic to the bacteria under these conditions. Analysis of anti-BPDE-derived products from these bacterial incubations demonstrates that, in addition to the expected hydrolysis products of the epoxide, novel more polar metabolites are produced. These same more polar compounds are produced by the addition of anti-BPDE to buffered aqueous solutions of sulfite. The major product of this reaction has been characterized by UV/visible and fluorescence spectroscopy, NI-FAB mass spectrometry, and proton NMR spectroscopy and is identified as 7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-10-sulfonate (BPT-10-sulfonate). This derivative is formed by the nucleophilic addition of sulfite to the 9,10-oxirane ring of anti-BPDE. This product is easily differentiated both spectrally and chromatographically from the isomeric 7,8,10-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-9-sulfonate reported from the attack of the sulfite anion radical on the activated aliphatic double bond of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) [Curtis et al. (1988) Carcinogenesis 9, 2015]. The nucleophilic trapping of diol epoxides by water or thiols is assumed to represent a detoxication of this class of mutagen. In contrast, the extensive conversion of anti-BPDE to BPT-10-sulfonate in the bacterial incubations correlates with a marked enhancement of resultant mutagenicity. Further support for a key role of BPT-10 sulfonate in the enhancement of anti-BPDE mutagenicity is provided by our findings on the reactivity of this compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

An update on vitrectomy surgery and retinal detachment repair in sickle cell disease.

Eighteen patients (19 eyes) with sickling hemoglobinopathies underwent vitrectomy or scleral buckling operations. The indications for surgery were tractional or rhegmatogenous retinal detachment or vitreous hemorrhage. The retina was reattached in all four patients with rhegmatogenous detachments requiring scleral buckling surgery but no vitrectomy. All had excellent visual acuity postoperatively. Four of the five patients with vitreous hemorrhage requiring vitrectomy without buckling had substantial improvement in visual acuity. In ten patients with vitreous hemorrhage with either preexisting or iatrogenic retinal breaks, rhegmatogenous detachment, or tractional detachment, the rate of improvement in visual acuity was only 50%. Problems associated with vitreous or retinal surgery in patients with sickling hemoglobinopathies include iatrogenic retinal breaks, intraocular bleeding and secondary glaucoma, anterior segment ischemia, and systemic sickling.

Argon endolaser.

We developed an endolaser probe that is capable of delivering argon laser light for photocoagulation of retinal breaks or vascular fronds. Energy is transmitted through a fiberoptic cord from a console outside of the surgical area to an endolaser probe inside the operating suite. The probe can be fired into fluid- or gas-filled media. With the use of this system, panretinal photocoagulation can be performed rapidly and conveniently during a vitrectomy procedure. We have also successfully managed posterior retinal tears and bleeding fibrovascular fronds with this system.

Role of the CO2 laser in chorioretino-iridocyclectomy.

Surgical extirpation of a uveal melanoma was performed by a sclerochorioretino iridocyclectomy using an externally focused CO2 laser. This was followed by a lens extraction and partial vitrectomy. The uveal melanoma proved to be of a mixed cell type. The minimal operative and postoperative hemorrhaging was attributed in part to the cauterizing cutting characteristics of the CO2 laser. Extensive coagulation necrosis produced by the CO2 laser precluded histopathologic evaluation of the resected tissue margin.