Search

Purpose: To delineate the clinical and MR findings in children with an unusual type of spinal dysraphism, the terminal myelocystocele. Infants with a terminal myelocystocele carry a favorable neurologic prognosis if the entity is diagnosed early. Understanding the MR characteristics of this entity will allow for earlier and more accurate diagnosis., Method: Analysis of the medical charts and MR studies in 15 children with surgically and histologically proven myelocystocele., Results: In all 15 children, MR demonstrated the primary findings of a terminal cyst of the central canal of the spinal cord which is tethered and herniated with arachnoid and cerebrospinal fluid through an area of spinal dysraphia onto the back as a mass. Of these children, 10 had additional findings (one or more) on MR of Chiari I (five cases), Chiari II (one case), cervicothoracic hydromyelia (two cases), lumbar hydromyelia (two cases), hydrocephalus (2 cases) segmentation anomalies of vertebrae (3 cases) and partial agenesis of sacrum (six cases). Of the clinical findings, all 15 children had a back mass, 10 also had cloacal exstrophy. One had imperforate anus, 10 were girls, five had ambiguous genitalia and all were neurologically intact., Conclusion: Children with a terminal myelocystocele present with a back mass and there is a high association with cloacal exstrophy. MR is the best noninvasive modality to diagnose all of the components of a terminal myelocystocele and the associated central nervous system findings.

Current guidelines and recommendations for genotoxicity testing of pharmaceuticals are disparate, both in terms of the most appropriate tests to use and the protocols to follow. Recent attempts have been made to standardise genotoxicity testing procedures, coinciding with the current review of the OECD guidelines and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). However, as with other aspects of non-clinical safety assessment of pharmaceuticals, guidelines have been prepared by evaluation of general chemical data due to the lack of specific information on pharmaceuticals. To address this, a project was undertaken to collect and collate information specifically pertaining to the genotoxicity testing of pharmaceuticals in order to obtain a clear understanding of international strategy and procedures in the pharmaceutical industry. It is clear that the practices and regional variations are strongly influenced by national guidelines and do not necessarily follow companies' preferences. However, there is a surprising amount of variation in approach between companies on some issues. This is evident in how companies define a genotoxin. This ranges from a positive result in an in vivo assay as indicative of a genotoxin (43%) to any positive result in vitro or in vivo (30%). Indeed many companies (particularly in Japan) will terminate development on the strength of a clear positive result in an Ames test. There is much debate within the ICH process concerning tests to detect gene mutations in mammalian cells as part of a primary test battery. This survey shows that in general, the pharmaceuticals industry has severe doubts about these assays. Thirty-seven (78%) of the 47 participating pharmaceutical companies include an in vitro test to detect gene mutation in mammalian cells as part of their routine test battery. The HPRT test using Chinese hamster cells has the most widespread use, although there is only limited use of such tests in Japan. Compound development has been affected by the results of such tests, but usually only in terms of clarification of equivocal results in other genotoxicity tests in the test battery. The majority (63%) of companies do not support its use as a primary regulatory requirement, and 83% do not consider the mouse lymphoma assay (L5178Y) an acceptable replacement for in vitro mammalian cytogenetics. In conclusion, this survey has provided valuable information on the current modus operandi of the international pharmaceutical industry for consideration in current harmonisation initiatives.

Soil erosion is a major environmental threat to the sustainability and productive capacity of agriculture. During the last 40 years, nearly one-third of the world's arable land has been lost by erosion and continues to be lost at a rate of more than 10 million hectares per year. With the addition of a quarter of a million people each day, the world population's food demand is increasing at a time when per capita food productivity is beginning to decline.

To study the relative expression of lactase, sucrase-isomaltase, dipeptidyl peptidase IV, and the Na(+)-dependent glucose transporter mRNA transcripts in small samples of human tissue, we have developed and validated a very simple semiquantitative RNA polymerase chain reaction method that can be used on as little as 5-10 mg of tissue. Here we report the use of this method to study the expression of these genes at different stages of development, in different tissues and in different parts of the intestine, in comparison with another intestinal marker, the colon-specific transcript of carbonic anhydrase 1. Lactase, sucrase-isomaltase, and the Na(+)-dependent glucose transporter mRNA are expressed predominantly in the small intestine, although lactase mRNA is expressed at a very low level in fetuses. Dipeptidyl peptidase IV mRNA shows a much wider tissue distribution. Sucrase-isomaltase and dipeptidyl peptidase IV mRNA are present at high levels in fetal colon and also at surprisingly high levels in adult colon. Lactase mRNA, on the other hand, is present at very low levels in fetal colon and is not detectable at all in adult colon. The Na(+)-dependent glucose transporter mRNA in contrast is expressed at higher levels in the adult colon than in the fetal colon. This is also the case for the carbonic anhydrase 1 transcript, although this transcript is not expressed in the small intestine. Thus, each of these genes shows different developmental and cell-specific regulation.

A panel of microcell hybrids containing fragments of chromosome 2 was analyzed for the presence of human DPP4, the gene that codes for dipeptidyl peptidase IV (or CD26), by specific PCR amplification of a fragment of the 3' untranslated region of the gene. This analysis placed DPP4 between LCT and GAD in bands q21 to q31. The localization was confirmed by in situ hybridization using two genomic probes that each revealed a hybridization signal in band q24. We also use the recent identification of the ADA binding protein as DPPIV to propose that the gene ADCP2 should be renamed DPP4.

The genetic mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting from the partial catabolism of several glycosaminoglycans (GAGs). Depending on the particular enzyme deficient in activity, the MPS syndromes are defined into groups MPS I through VII, with several subgroups for a total of 10 disorders. In humans, clinical features include dysostosis multiplex, hepatosplenomegaly, hypertelorism, macroglossia, hypoplastic and irregularly shaped teeth, hyperplastic lips and gingiva, facial dysmorphia, corneal clouding, and mental retardation. MPS I (alpha-L-iduronidase deficiency) and VI (arylsulfatase B deficiency) have been described in cats, MPS VII (beta-glucuronidase deficiency) in dogs. Biochemically, these syndromes appear the same as their human counterparts and have similar clinical characteristics. All are inherited as autosomal recessive traits. The purpose of this study was to analyze the craniofacial aspects of these diseases in the animal models and compare these data with descriptions of the human syndromes. A total of 28 live animals were examined. Thirty-one skulls prepared from postmortem specimens were measured directly and radiographed. Controls were closely related family members of the same sex and similar age without the disease, clinically or biochemically. The data indicated that, as in the human syndromes, each is distinct, and the skull bones most severely affected are those of endochondral origin.

Purpose/objective: To review and discuss the economic and care delivery implications of the healthcare reform currently being debated., Data Sources: Projections are based on synthesis of multiple scholarly, professional, and governmental sources of information., Data Synthesis: Future projections regarding the hallmarks of healthcare reform (e.g., universal access, fewer payors, rationing of care), changes in practice settings, and novel communications technologies are discussed., Conclusions: Opportunities for nurses resulting from these changes include roles as resource allocators, cost-benefit analysis, cancer system liaisons, satellite-program builders, and quality-assessment experts., Implications for Nursing Practice: Changes will challenge nurses to assume multiple responsibilities as clinicians, administrators, educators, and researchers who will need to integrate input from numerous sources to make decisions that take into account competing and contradictory factors.

Describing yourself on paper is an important marketing tool for the nurse for professional opportunities today. Using a curriculum vitae (CV) serves to best illustrate relevant experiences that a nurse has had toward fulfillment of a professional objective. A readable, truthful, and polished curriculum vitae and cover letter can help nurses present themselves in a very positive manner.

Rigors are not a recognized characteristic of miliary tuberculosis. We report two patients presenting with persistent rigors, thought to be suggestive of acute pyogenic infection, who were subsequently found to have miliary tuberculosis. In both cases, there was significant diagnostic delay. Miliary tuberculosis should therefore be included in the differential diagnosis of any patient presenting with unexplained rigors.

Periodontitis is a common condition in dogs. Treatment of periodontitis consists of mechanical removal of plaque and calculus by scaling, root planing, and polishing the teeth. Antimicrobial therapy can provide additional improvement in severe or refractory cases of periodontitis when combined with dental prophylaxis if ongoing plaque control is not provided. The ability of various antimicrobials to reach therapeutic levels in the periodontal tissues differs greatly. The efficacy of antimicrobials against common periodontal pathogens also varies greatly. Choosing an appropriate antibiotic to treat periodontitis should be based on these considerations. Amoxicillin-clavulanate, clindamycin, and nitroimidazoles, such as metronidazole and tinidazole, seem to be particularly effective based on pharmacokinetic and clinical studies.

Rates of invasive Haemophilus influenzae type b (Hib) disease in children decreased very rapidly after licensure of Hib conjugate vaccines. A role for a vaccine-related reduction in nasopharyngeal carriage of Hib has been suggested. We studied oropharyngeal carriage of Hib and vaccination rates in a population of 2- to 5-year-old children in metropolitan Atlanta. Among 584 children 75% were vaccinated with an Hib conjugate vaccine, 17% had not been vaccinated and 8% had no vaccination records available. Forty-one percent of the children were colonized with H. influenzae. One child was colonized with Hib. Hib carriage (0.17%; upper 95% confidence interval boundary, 0.97%) was substantially lower than the estimates of Hib carriage from prior studies of children who had not received Hib conjugate vaccines. Our data are consistent with a decline in Hib carriage induced by widespread use of conjugate Hib vaccines, which may have contributed to the decline of Hib disease in United States children.

The role of the adult oncologists in the area of pediatric cancer treatment previously has been unmeasured. A questionnaire bearing regarding the practice of 447 adult oncologists was administered in June 1991. The membership list of the Association of Community Cancer Centers was used to identify contact oncologists. One hundred thirty-one questionnaires (29.3%) were returned for analysis. The data reveal that 204 patients younger than 21 years of age were treated during the last year in 63 adult oncology practices. Most of these patients were more than 15 years of age. Only a minority (53) were treated in rural practices. In addition, only a minority (27%) of these patients are reported to be enrolled in clinical trials. In addition, adult oncologists appear to regard physiologically mature adolescents (age 16-21 years) as adults. They do not seem to make a distinction between patients 16-21 years old and those older than 21 years.

New estimates of the direct costs of traumatic spinal cord injuries (SCI) are obtained from a comprehensive survey of the US SCI population. These direct costs, defined as the value (in 1988 dollars) of resources used specifically to treat or to adapt to the SCI condition, represent the average experience of the US SCI population. Responses to a detailed questionnaire administered to a sample of traumatic SCI persons in the United States provide the primary source of data for this study. Analysis of this survey data indicates that more recently injured SCI persons (ie those injured since 1970) spent an average of 171 days in a hospital over the first 2 years post injury. Initial hospital expenses will average $95,203. Home modification costs in excess of $8,000 can also be expected. After recovery and rehabilitation, a SCI person will pay, on average, $2,958 per year in hospital expenses and $4,908 per year for other medical services, supplies and adaptive equipment. Personal assistance costs and costs of institutional care will average $6,269 per year. These cost estimates represent the incremental costs of SCI, ie they exclude any costs that would have been incurred in the absence of SCI.

Hearing preservation in acoustic neuroma surgery is possible in a limited number of cases. Although there have been many articles published about hearing preservation, there have been few studies of long-term hearing results, nor is it known if there is an increased rate of tumor recurrence when hearing preservation is attempted. Twenty-two patients who underwent a hearing preservation procedure via the retrosigmoid approach were selected from 80 consecutive patients with cerebellopontine angle tumors operated on from February 1984 to November 1987. Useful hearing was retained in 11 cases as reported in a previously published study. Seven patients continue to have useful hearing after 3 to 5 years; 3 have shown a gradual but slight decline. There has been no tumor recurrence in these patients, but 2 patients, operated on early in the series and who had lost hearing, had recurrent tumor.

The cardioprotective effects of the K channel activator drugs celikalim (WAY-120,491) and cromakalim were studied in a canine model of myocardial infarction consisting of 90 min of ischemia and 5 h of reperfusion. Intracoronary infusion of cromakalim and celikalim at 0.2 microgram/kg/min beginning 10 min before occlusion of the left circumflex coronary artery and continuing throughout the duration of the reperfusion period appeared to exacerbate ischemic injury. Infarct size (percent of risk area) was 27.7 +/- 5.6% in vehicle control animals (n = 5), 40.3 +/- 6.2% for cromakalim (n = 5) and 55.7 +/- 6.4% (p less than 0.05 vs. vehicle) for celikalim-treated animals (n = 5). When these compounds were administered intravenously, using doses shown to increase total coronary flow in nonoccluded control animals, no exacerbation of ischemic injury was observed. Anatomic infarct size was 32.8 +/- 7.1% for vehicle animals (n = 5) and 32.6 +/- 13.3 and 30.9 +/- 9.8% for cromakalim- (n = 6) and celikalim-treated (n = 5) animals, respectively. Intravenous diltiazem decreased myocardial infarct size to 16.3 +/- 7.3% (n = 5) of area at risk (p = NS vs. vehicle). The anatomic area at risk was similar in all three treatment groups, and no significant differences in rate-pressure product were observed. Results of this study suggest that K-channel-activating drugs such as cromakalim and celikalim may not be effective agents in the acute therapeutic management of myocardial ischemic injury.

The purpose of this study was to determine if idazoxan, an alpha 2-adrenergic antagonist, could enhance the antithrombotic activity of pelrinone, a PDE III inhibitor, in a canine model of coronary thrombosis that uses electrical current to injure the coronary endothelium. Thrombus mass in vehicle-treated animals was 37.9 +/- 8 mg. Pelrinone, 0.625 and 2.5 mg/kg decreased thrombus size by 46 and 21%, respectively, while idazoxan, 0.75 mg/kg decreased thrombus mass by 43%. When this dose of idazoxan was combined with pelrinone, 0.625 and 2.5 mg/kg, thrombus mass was decreased by 71 and 91%, respectively. Antithrombotic efficacy correlated with the ability of these treatments to inhibit epinephrine-sensitized, collagen-induced platelet aggregation. Sixty minutes following drug administration, idazoxan, 0.50 mg/kg inhibited aggregation by 50%, while pelrinone, 0.625 and 2.5 mg/kg inhibited aggregation by 55 and 68%, respectively. Combined administration of idazoxan with pelrinone, 0.625 and 2.5 mg/kg resulted in 80 and 95% inhibition of aggregation, respectively. Similar trends in inhibiting platelet aggregation to epinephrine-sensitized ADP and arachidonic acid were also observed. Experimental treatments did not affect hematocrit or circulating platelet count, although pelrinone was observed to prolong prothrombin time slightly. To examine the effect of drug-induced increases in coronary blood flow on thrombus formation, the potassium channel activator drug cromakalim was studied at a dose (0.1 mg/kg) that increased coronary blood flow by 25-35 ml/min above baseline in sham control animals. Animals treated with cromakalim showed a shorter time to coronary occlusion (103 +/- 11 min) vs. vehicle (173 +/- 24 min) and developed larger thrombi (53.7 +/- 19 mg). These results demonstrate that coronary vasodilation does not contribute to antithrombotic activity in this model. Results from the study also show that alpha-adrenergic inhibition of platelet function can potentiate phosphodiesterase inhibitor antiaggregatory and antithrombotic activity.

A study was designed to determine if cold preservation induces an increase in lymphocyte adherence to liver sinusoids on reperfusion. Rat livers were stored at 1 degree C in University of Wisconsin solution for 45 min, 8 hr, or 30 hr, and then reperfused for 90 min at 37 degrees C in an isolated perfused rat liver apparatus. Just prior to reperfusion, isogeneic rat lymphocytes prepared on a Ficoll-Paque gradient were added to the perfusate. In some studies lymphocytes were labeled with a fluorescent lipophilic membrane marker. There was no change in the number of circulating lymphocytes in an anhepatic circuit. When livers were present in the circuit, lymphocytes were lost from the perfusate into the liver in all studies, with the most rapid decrease occurring within 10 min of reperfusion. The length of preservation had a marked and statistically significant effect on the rate of disappearance of lymphocytes from the perfusate. Reduction by 50% of the number of lymphocytes infused did not affect the results when expressed as percent lymphocytes remaining in perfusate. To exclude the possibility that the loss of lymphocytes into the liver was due to a damaged subpopulation of lymphocytes, two livers stored 3 for 45 min were put into the circuit in sequence. The percent reduction in cells due to exposure to a second liver was not significantly different from that observed when cells were exposed only to a single liver. Histological studies showed fluorescence-labeled lymphocytes adherent in sinusoids, and the number of labeled cells was directly related to the length of preservation. Cold preservation induces an increase in lymphocyte adherence in the reperfused liver, which might be important in graft malfunction and rejection.

Expression of PRL, a member of the GH family of genes, is restricted to the lactotroph cells of the anterior pituitary. The proximal promoter of the rat PRL (rPRL) gene contains four factor-binding sites. Three nonadjacent elements, footprints (FP) I, III, and IV, are separated by an integral number of helical turns and bind a pituitary-specific factor, LSF-1. FP II binds another factor present in pituitary and nonpituitary cells. The mechanisms by which DNA-bound proteins influence RNA polymerase-II activity over large distances are not fully understood, but protein-protein interactions, with looping of intervening DNA, may bring distant sites into close proximity. Here, we demonstrate, using protein titration studies, that LSF-1 binds to the most proximal FP I element with the highest affinity, whereas it binds the more distal elements, FP III and FP IV, with progressively lower affinities. Time-course and salt-sensitivity studies reveal that binding of LSF-1 to all three pituitary-specific rPRL promoter sites occurs rapidly (less than or equal to 1 min) and requires fairly high salt concentrations (greater than or equal to 300 mM KCl) to destabilize protein-DNA interactions. Moreover, once bound, the pituitary nuclear factor(s) induces a conformational change in rPRL DNA structure with greatly delayed kinetics (greater than 15 min) and at a different salt concentration than are required for simply factor binding. Taken together, these data suggest a model in which LSF-1 initially binds fairly rapidly to multiple nonadjacent elements and then interacts with itself or other DNA-bound proteins much more slowly, possibly looping or bending the rPRL promoter.(ABSTRACT TRUNCATED AT 250 WORDS)

In the 1982-84 Hispanic Health and Nutrition Examination Survey, the prevalence of cigarette smoking was examined among Mexican Americans, Puerto Ricans, and Cuban Americans in the United States. Among 20-74 years olds, the age-adjusted smoking rates for Mexican American, Puerto Rican, and Cuban American men were high--42.5, 39.8, and 41.6 percent, respectively. Quite striking among Cuban American men was the high smoking rate among 20-34 year olds (50.1 percent), the highest smoking rate in the three Hispanic groups compared. The age-adjusted smoking rates for Mexican American, Puerto Rican, and Cuban American women were much lower than those for men-23.8, 30.3, and 24.4 percent, respectively. Both Puerto Rican and Cuban American men were more likely to be heavy smokers (52.3 and 64.1 percent, respectively, smoking a pack or more a day) as compared to the Mexican Americans (33.8 percent smoking a pack or more a day). The pattern was the same for women, with Mexican American women being lighter smokers (18.8 percent smoking a pack or more a day) as compared to heavy smoking among Puerto Rican and Cuban American women (35.1 and 48.6 percent, respectively, smoking a pack or more a day). Given the health hazards of smoking, future research and intervention are required for those groups with high exposure to cigarette smoking.

New estimates of traumatic spinal cord injury (SCI) prevalence are developed from a survey specifically designed to identify the SCI population in both institutional and non-institutional settings. The survey utilised a mixed-mode sampling design based on probability sampling methods. Detailed interviews were conducted with SCI persons identified in this survey. We estimate that the traumatic SCI prevalence rate in the United States is 721 cases per million, and that there are about 177,000 SCI persons residing in the United States.

Lipoprotein lipase (LPL) is an important enzyme involved in triacylglycerol metabolism in plasma. We have characterized the deficiency in LPL activity in hypertriglyceridemic cats. Pre- and postheparin plasma contain a similar high level of LPL mass, which has no enzymatic activity. This indicates that the cats produce an abnormal LPL protein which is inactive and fails to bind to the endothelium. This phenomenon is similar to the Class III type defect characterized in human LPL deficiency. Molecular analyses indicate that there is no major structural rearrangement in the LPL gene, and that the mRNA and protein products are normal with respect to size and quantity. These cats present unique animal model for human LPL deficiency.

One hundred sixty patients with idiopathic scoliosis underwent preoperative and postoperative sagittal plane analysis of the thoracic spine, thoracolumbar junction, and lumbar spine. The data suggest that mild to moderate improvements in thoracic hypokyphosis are possible. When crossing the thoracolumbar junction, reversal of rod bend and reversal of hooks on the derotation rod appears to provide the most physiologic sagittal contour. Cotrel-Dubousset instrumentation to the mid and distal lumbar spine can preserve and, at times, enhance lumbar lordosis.

Ceranapril (SQ 29,852) is a new inhibitor of angiotensin I (AI) converting enzyme (ACE) belonging to the hydroxylphosphonate class. The purpose of the present report is to present the in vivo pharmacology of ceranapril in conscious animal models. In conscious, normotensive rats, ceranapril administered i.v. (ED50 = 63 nmol/kg) or p.o. (ED50 = 530 nmol/kg) inhibited an AI pressor response with potency equal to that of captopril. However, in conscious dogs, ceranapril was a relatively poor inhibitor of the AI pressor response after both i.v. (ED50 = 300 nmol/kg) and p.o. (ED50 = 18 mumol/kg) administration; in monkeys ceranapril was a good inhibitor of the AI pressor response after i.v. (ED50 = 60 nmol/kg) but not p.o. (ED50 = 18 mumol/kg) administration. In rats, the duration of ceranapril's inhibition of an AI pressor response was longer than an equimolar dose of captopril. Similarly, in SHR, ceranapril's blood pressure lowering effect had a longer duration than that of captopril. Ceranapril's ACE inhibitory effects were longer lasting in anephric rats than in sham rats, suggesting a renal route of excretion for ceranapril. Ceranapril administration to conscious female dogs resulted in significant increases in renal plasma flow and GFR. In SHR, doses of 23 and 68 mumol/kg resulted in significant blood pressure lowering that lasted 24 h. Oral doses of 2.3, 6.8, 23, and 68 mumol/kg in two-kidney, one-clip hypertensive rats resulted in significant and dose-related falls in arterial pressure, which again persisted for 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

The blood pressure lowering and renal hemodynamic effects of fosinopril, the chemically novel inhibitor of angiotensin I converting enzyme (ACE), was assessed in conscious animal models. In conscious dogs, intravenous infusion of SQ 27,519 [0.5 mg/kg (1.1 mumol/kg) bolus plus 0.1 mg/kg/min (0.22 mumol/kg/min)], the active moiety of the prodrug fosinopril, increased PAH clearance and GFR by 25 and 16%, respectively (p less than 0.05, each) without changing arterial pressure (AP). Urine volume, sodium excretion, and potassium excretion were elevated, although not significantly increased. In sodium-depleted cynomolgus monkeys, 1.5 and 5.0 mumol/kg (0.88 and 2.9 mg/kg) p.o. of fosinopril lowered arterial pressure from 115 +/- 5 to 99 +/- 5 mm Hg and from 116 +/- 3 to 87 +/- 4 mmHg, respectively (p less than 0.05, each). When given orally to SHR at 10 and 30 mg/kg (5.9 and 17.6 mumol/kg), fosinopril lowered AP by 23 (183 +/- 4 to 160 +/- 5 mm Hg) and 20 mm Hg (176 +/- 4 to 156 +/- 4 mm Hg), respectively. The combination of fosinopril [10 mg/kg (5.9 mumol/kg)] plus hydrochlorothiazide (10 mg/kg) reduced AP from 206 +/- 4 to 167 +/- 2 mm Hg when given orally to SHR. Fosinopril was more effective in two-kidney, one-clip hypertensive rats relative to SHR; AP fell from 201 +/- 9 to 160 +/- 7 mm Hg after 10 mg/kg (5.9 mumol/kg), and from 205 +/- 7 to 145 +/- 7 mm Hg after 30 mg/kg (17.6 mumol/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Allergic bronchopulmonary aspergillosis often requires treatment with oral corticosteroids to control the host response to Aspergillus fumigatus. In a double blind study 25 patients with allergic bronchopulmonary aspergillosis taking maintenance oral corticosteroids were randomly allocated to receive 5 mg natamycin or placebo by nebuliser twice daily for one year. The primary aim of the study was to assess the steroid sparing potential of natamycin. Standardised reductions in corticosteroid dosage were therefore undertaken every five weeks, unless clinically contraindicated. Five patients were withdrawn in the first four months: two (1 natamycin, 1 placebo) died, two (1 natamycin, 1 placebo) had suspected drug reactions, and one (natamycin) was non-compliant. The pretreatment characteristics of the 20 patients (10 in each group) who completed the study were similar, 17 (9 natamycin, 8 placebo) having evidence of recent disease activity. At the end of the study prednisolone dose had been reduced by a similar amount in each group (median natamycin 2.25 mg, placebo 2.5 mg). Evidence of disease activity during the study year (transient shadowing on the chest radiograph, blood eosinophilia, or increases in antibodies to A fumigatus, or any combination of these) was observed in similar numbers of patients in each group (5 natamycin, 7 placebo). There was no evidence that natamycin conferred benefit on these patients with allergic bronchopulmonary aspergillosis.

Recognition of prodromal symptoms of schizophrenia offers the potential of early intervention to avert relapse and re-hospitalization (Carpenter & Heinrichs, 1983). The present study investigated how a strategy to detect prodromal signs might be effectively applied in the clinical setting. A standard monitoring system was developed involving completion of a new early signs scale (ESS) measuring changes in key symptoms phenomenologically (self-report) and behaviourally (observer report). The ESS was subject to rigorous psychometric evaluation and tested in a prospective pilot investigation. The ESS reliably identified early signs and predicted relapse with an overall accuracy of 79%. Several different patterns of relapse were identified. Observer reports compensated for loss of insight in some patients. In two cases where early signs indices were detected, prompt increases in medication appeared to arrest relapse and avert readmission. The ESS offers itself as a reliable, valid and administratively feasible measure and demonstrates considerable potential as a cost-effective procedure for secondary prevention.

Glycosylated hemoglobin (GHb) was measured by a chromatographic method using HPLC (HbA1c) as well as a colorimetric method using thiobarbituric acid (TBA) on samples collected from 40 diabetic subjects. GHb measured by HPLC correlated well with the colorimetric method (r = 0.7). Freezing the samples caused an immediate increase of the HbA1a+b but not the HbA1c results. 4 weeks storage of the red cells at room temperature, 4 degrees C or -20 degrees C altered the results of GHb measured by HPLC but not the TBA reaction. Half of the total ketoamine linked hexoses detected by the TBA reaction was found in the HbA0 fraction as measured by ion exchange chromatography. The colorimetric method (r = 0.53) had better correlation than the HPLC method (r = 0.27) with mean blood glucose values during the 4 weeks preceding sample collection. GHb measured by the TBA reaction more accurately represents the ketoamine linked sugar in hemoglobin, is less subject to handling artifacts and more accurately reflects the blood glucose values during the preceding 4 weeks.

A synthetic DNA fragment of 19 residues was enlarged by the enzymatic addition of deoxyadenylate residues to its 3'-end with calf thymus terminal deoxynucleotidyl transferase. The 3'-terminus of this elongated DNA strand was blocked with 2', 3'-dideoxyadenylate to prevent hydrolysis by the 3'-exonuclease function of E. coli DNA polymerase I. This elongated and 3'-blocked fragment was annealed to an oligomeric primer and used as a template for the synthesis of a complementary copy of the synthetic 19-mer. The product of such a repair synthesis was separated by gel filtration and analyzed by nearest neighbor techniques. All template strands were copied with complete repair in over 90% of the chains. Facile recovery of the elongated template by virtue of its size permitted repetition of the copy process, thus allowing accumulation of the desired strand.

The purpose of this prospective study was to evaluate the effects of the active phase of labor and route of delivery on the frequency of germinal layer/intraventricular hemorrhage in 89 infants with ultrasound-estimated fetal weights less than or equal to 1750 gm. Twenty-eight infants (31.5%) had germinal layer/intraventricular hemorrhage within 1 hour after birth and an additional 15 infants (17%) had germinal layer/intraventricular hemorrhage beyond 1 hour after birth. Infants with germinal layer/intraventricular hemorrhage had a significantly lower gestational age (p less than 0.003) and birth weight (p less than 0.007). Germinal layer/intraventricular hemorrhage within 1 hour after delivery was increased in the infants of women who experienced the active phase of labor regardless of the route of delivery. However, the incidence of germinal layer/intraventricular hemorrhage beyond 1 hour after delivery and the overall incidence were similar in the vaginal delivery and cesarean delivery groups. In addition, there was an increased incidence of progression to grades III and IV hemorrhage regardless of route of delivery in the infants whose mothers experienced the active phase of labor.

Studies suggesting that transplantation is better than dialysis for diabetic patients with renal failure may be biased by the more favorable pretreatment prognosis of transplanted patients. Therefore, to provide a fairer comparison we controlled for pretreatment clinical state, categorized treatment received, and assessed mortality, major morbid events, and hospitalization in 51 diabetic patients who began therapy between 1970 and 1980. Fourteen patients were treated by transplantation and 37 by dialysis. The mean waiting period for transplantation was 5 months. The average age of transplanted patients was 40.9 years and of dialyzed patients 59.6 years. When we controlled for this age disparity and other factors (duration of diabetes and heart failure) that affect prognosis in end-stage renal disease (ESRD), the mortality with both transplantation and dialysis was similar to that expected from the overall mortality rate of the 51 study patients. Treatment received had no effect on mortality; the observed deaths compared with deaths expected from pretreatment status were 8 and 7.3 for transplantation and 30 and 30.7 for dialysis. We also compared major morbid events (blindness, amputation, stroke, severe heart failure, and myocardial infarction) and hospitalization in transplanted patients with the 24 dialyzed patients who survived long enough (5 months) to be eligible for transplantation. The number of major morbid events was 2.7 per 10 patient-years in the transplanted group and 3.4 in the dialyzed group. Hospitalization was 151.3 d/yr in transplanted patients and 55.6 d/yr in dialyzed patients (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The structural requirements for the inhibition of ferrochelatase by N-alkylated porphyrins were investigated and experiments carried out to explore the mechanism of enzyme inhibition. Three dicarboxylic porphyrins, all substrates of the enzyme, are strongly inhibitory when N-alkylated; in contrast, uroporphyrin and coproporphyrin (which are not substrates) do not inhibit after N-alkylation. Free carboxylic acid functions are required for inhibition, as the methyl ester derivatives are not themselves inhibitory. Porphyrins bearing the alkyl group on the pyrrole nitrogen of rings C and D are less effective inhibitors, particularly when zinc is chelated in the centre of the tetrapyrrole or the N-alkyl group is relatively large in size. The substituents at the 2- and 4-positions of the porphyrin system may also affect the inhibitory activity, particularly for the isomers with ring C and D alkylated. The zinc chelates of several N-alkylprotoporphyrins are inhibitory towards haem oxygenase, another haem-binding enzyme, and also in this case increasing the size of the alkyl group decreased the inhibitory activity, particularly for isomers with ring C or D alkylated. The inhibition could be reversed by prolonged incubation with excess porphyrin substrate, but dealkylation of the N-alkylporphyrin during enzyme inhibition could not be demonstrated. It is concluded (a) that N-alkylated dicarboxylic porphyrins compete reversibly with the porphyrin substrate for the enzyme active site and (b) that the structural and steric factors discussed above affect the inhibitory activity by modifying the affinity of the N-alkylporphyrin inhibitor for the enzyme.

The ability of drugs to cause uroporphyria in hepatocytes from 17-day-old chick embryos has been investigated and the response of the cells in culture compared with that of the intact liver of the embryos in ovo. In this chick-embryo system, drugs that cause accumulation of uroporphyrin within 19-24 h can only do so in culture; in contrast, 2-allyl-2-isopropylacetamide and 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which stimulate production of protoporphyrin, are effective both in culture and in ovo. A role of exogenous iron in worsening drug-induced uroporphyria was demonstrated in cultures of hepatocytes; iron also caused preferential accumulation of uroporphyrin from added 5-aminolaevulinate in the absence of a porphyrogenic chemical. Uroporphyria was induced in cultures of hepatocytes by drugs of widely different structures, suggesting that the primary molecular target with which they interact may be relatively aspecific in its binding characteristics. These results are briefly discussed, and two alternative hypotheses for the drug-induced effect in uroporphyrinogen metabolism are considered.

The appearance of IgG and IgE binding components in the medium of shake cultures of Aspergillus fumigatus has been studied. Cultures were grown in synthetic asparagine medium at 35 degrees C and flasks harvested in duplicate 1, 2, 3, 4, 7 and 14 days after inoculation. The pH of the medium dropped from its initial value of 5.5 to pH 3, and then after 4 days gradually increased up to pH 7.5 in the 14-day medium. The weight of mycelium, after an initial peak followed by a slight decline, increased as the pH of the medium increased. Components able to bind IgG and IgE from pooled ABPA sera were detected by crossed immunoelectrophoresis/self-crossed radioimmunoelectrophoresis within 24 h of growth, but maximal release of both antigens and allergens coincided with the increase in pH of the medium and was seen in the 14-day culture filtrate. Two recognised "major" antigens, Ag 7 and Ag 13, detected using the relevant monospecific antisera, were present in the culture medium after 14 days of growth and similarly for Ag 3, the major allergen, although another allergen, Ag 1, was identified in the 1-day extract. None of the culture filtrates was found to contain the "C-substance" polysaccharide.

The amino acid sequence of a biologically active polypeptide isolated from calf thymus, termed thymosin alpha1, has been determined. Thymosin alpha1 is a heat stable, highly acidic molecule composed of 28 amino acid residues. This peptide is one of several present in thymosin fraction 5 that may participate in the regulation, differentiation and function of thymus-dependent lymphocytes (T cells). A nomenclature for the family of polypeptides present in thymosin fraction 5 is suggested.

Homozygotes, obligatory heterozygotes and potential carriers of the Friedreich's Ataxia gene were tested with an oral glucose tolerance in order to assess a. the prevalence of abnormalities in glucose handling, b. the secretory pattern of two "diabetogenic" hormones, growth hormones and prolactin and c. to evaluate the possibility for detection of an abnormal trend in these hormones to be used as a genetic marker. Despite the high prevalence of glucose abnormalities horizontally and vertically in these families, the basal output and responses of these metabolic hormones to a glucose challenge were appropriate and thus not characteristic of any of the above groups.