Meniscal abnormalities: prospective correlation of double-contrast arthrography and arthroscopy

In a prospective study conducted over a 12-month period, 30 patients underwent double-contrast arthrography of the knee followed by arthroscopic study. An 80% correlation rate was found between results. Arthrography had a higher rate of accuracy (93%) than arthroscopy (84%) and had a 7% false-positive and 0% false-negative rate. A commonly overlooked arthrographic sign--the triple-S or stuck sail sign--was 91% accurate in the prediction of meniscal tears. The complementary nature of the two examinations is discussed.     

Coralline hydroxyapatite bone graft substitutes: preliminary report of radiographic evaluation

A new bone graft substitute made by conversion of the calcium carbonate exoskeleton of reef-building sea coral into hydroxyapatite has recently become clinically available. The normal radiographic appearance of two forms of this material is described. In the immediate postoperative period, the exoskeletal architecture of these implants is readily appreciated. With graft incorporation over the ensuing months, their intrinsic structure is gradually lost in association with poor marginal definition. Evolving radiographic findings reflect the biocompatible nature of these implants, which provides the potential for ingrowth of native bone with preservation of the coralline scaffold, resulting in enhanced biomechanical properties.     

Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.     

The relationship of antipsychotic drug use, behavior, and diagnoses among nursing home residents

Nursing homes have been criticized for frequent use and possible misuse of psychoactive agents. These issues are of clinical concern and policy relevance, especially since the passage of the Omnibus Budget Reconciliation Act (OBRA) of 1987. Using a sample of 419 residents, the authors examined the relationships among antipsychotic drug (AP) use, behavior, and mental health diagnoses. Only 23.2% of the residents were administered APs on a routine and/or "as-needed" basis. Based on the Multidimensional Observation Scale for Elderly Subjects (MOSES) ratings, AP users were more irritable, disoriented, and withdrawn than were nonusers. Also, AP users demonstrated agitated behaviors more frequently. Notably, AP users and nonusers differed significantly in terms of documented mental health diagnoses. Among AP users, 70.1% had documented dementia, 8.3% were psychotic or had other psychiatric disorders, and 21.6% had no mental health diagnoses. In contrast, the majority of nonusers had no mental health disorders. Logistic regression revealed that diagnostic factors, frequency of agitation, level of withdrawal, and marital status were significant predictors of AP use.     

Divided attention performance in cannabis users and non-users following alcohol and cannabis separately and in combination

The effect of 9-tetrahydrocannabinol ( 9-THC) and alcohol, singly and in combination, on divided attention performance was investigated in cannabis users and non-users who were matched for alcohol use. Both cannabis and alcohol produced decrements in central and peripheral signal detections. Drug and alcohol effects were greater for signal presentations in the periphery. Cannabis users were less impaired in peripheral signal detection than non-users while intoxicated by cannabis and/or alcohol. These findings suggest the development of tolerance and cross-tolerance in regular cannabis users and/or the ability to compensate for intoxication effects.     

Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees

Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21- hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.      

Identification of cathepsin C mutations in ethnically diverse papillon-Lefèvre syndrome patients

INTRODUCTION—Papillon-Lefèvre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar keratoderma and severe, early onset periodontitis, which results from deficiency of cathepsin C activity secondary to mutations in the cathepsin C gene. To date, 13 different cathepsin C mutations have been reported in PLS patients, all of which are homozygous for a given mutation, reflecting consanguinity.
AIM—To evaluate the generality of cathepsin C mutations in PLS, we studied an ethnically diverse group of 20 unrelated families.
METHODS—Mutations were identified by direct automated sequencing of genomic DNA amplified for exonic regions and associated splice site junctions of the cathepsin C gene. Long range PCR was performed to determine the genomic structure of the cathepsin C gene.
RESULTS—The cathepsin C gene spans over 46 kb, with six introns ranging in size from 1.6 to 22.4 kb. Eleven novel mutations and four previously reported mutations were identified in affected subjects from 14 families. Missense mutations were most common (9/15), followed by nonsense mutations (3/15), insertions (2/15), and deletions (1/15). Among these 14 probands, two were compound heterozygotes. Affected subjects with transgressions of the dermal lesions onto the knees or elbows or both had mutations in both the pro- and mature regions of the enzyme, although most were in the mature region.
CONCLUSION—Mutations in the mature region of cathepsin C were more likely to be associated with the transgressions of the dermatological lesions, although the results were not statistically significant. A comprehensive list of all cathepsin C mutations described to date, representing 25 mutations from 32 families with PLS and related conditions, is also presented.


Keywords: cathepsin C; genetics; severe early onset periodontitis; hyperkeratosis