Colorectal cancer in patients under forty: presentation and outcome

Colorectal cancer is the third most frequent malignancy in adults of both sexes in this country, with 90 per cent of patients diagnosed after age 50 years. This disease is unusual in patients under 40 years of age, and controversy persists as to prognosis in this subset of patients. Patients diagnosed with invasive adenocarcinoma of the colon and rectum from 1985 to 1997 were identified. They were then grouped according to age (< 40 or > or = 40). Charts were reviewed with respect to patient epidemiologic characteristics, clinical presentation, tumor staging, and survival. Twelve women and 24 men less than 40 years of age (median, 31 years/range, 13-39 years) were diagnosed with colorectal adenocarcinomas. This represented 8.6 per cent of the total patients diagnosed with colorectal cancers during this time. Thirty-five (97%) had symptoms (pain, blood per rectum, weight loss, or alteration in bowel habits) before diagnosis, and 23 (64%) had multiple symptoms. Younger patients had more poorly differentiated tumors (28%) and more mucinous adenocarcinomas (26%) than the older group. Younger patients were more likely to present with stage III or IV disease (78%) as well. Despite these findings, the median survival for younger patients was no different than the older patients when compared by stage. Colorectal cancer in young adults is rare, but should be considered in the differential diagnosis for all patients with gastrointestinal symptomatology. The presentation of these patients is not unlike that of older patients. Those patients with early-stage disease should be treated aggressively, as long-term survival may be anticipated, whereas the outcome for those with metastatic disease is poor.     

Transmyocardial laser revascularization in allograft coronary artery disease

We used transmyocardial laser revascularization to treat accelerated cardiac allograft atherosclerosis in 2 patients. One patient received transmyocardial laser revascularization as sole therapy, the other as an adjunct to coronary artery bypass grafting. The systolic function improved in both patients, although the patient who had adjunctive transmyocardial laser revascularization died of systemic infection and renal failure on postoperative day 55. The second patient is alive and well 1 1/2 years after the laser procedure. We discuss 4 other patients who received transmyocardial laser revascularization treatment elsewhere in the United States. Transmyocardial laser revascularization has the potential to become important in the treatment of transplant atherosclerosis. Randomized clinical trials are warranted to assess the efficacy of transmyocardial laser revascularization in this setting.     

The role of enzyme distortion in the single displacement mechanism of family 19 chitinases

By using molecular dynamics simulations, we have examined the binding of a hexaNAG substrate and two potential hydrolysis intermediates (an oxazoline ion and an oxocarbenium ion) to a family 19 barley chitinase. We find the hexaNAG substrate binds with all sugars in a chair conformation, unlike the family 18 chitinase which causes substrate distortion. Glu 67 is in a position to protonate the anomeric oxygen linking sugar residues D and E whereas Asn 199 serves to hydrogen bond with the C2' N-acetyl group of sugar D, thus preventing the formation of an oxazoline ion intermediate. In addition, Glu 89 is part of a flexible loop region allowing a conformational change to occur within the active site to bring the oxocarbenium ion intermediate and Glu 89 closer by 4-5 A. A hydrolysis product with inversion of the anomeric configuration occurs because of nucleophilic attack by a water molecule that is coordinated by Glu 89 and Ser 120. Issues important for the design of inhibitors specific to family 19 chitinases over family 18 chitinases also are discussed.     

Key amino acids in the gamma subunit of the gamma-aminobutyric acidA receptor that determine ligand binding and modulation at the benzodiazepine site

Pharmacological analyses of gamma-aminobutyric acidA (GABAA) receptor subtypes have suggested that both the alpha and gamma subunits, but not the beta subunit, contribute to the benzodiazepine binding site. We took advantage of the different pharmacological properties conferred by the inclusion of different gamma subunits in the receptor macromolecule to identify amino acids gamma2Phe77 and gamma2Met130 as key determinants of the benzodiazepine binding site. gamma2Phe77 was required for high affinity binding of the benzodiazepine site ligands flumazenil, CL218,872, and methyl-beta-carboline-3-carboxylate but not flunitrazepam. This amino acid was, however, required for allosteric modulation by flunitrazepam, as well as other benzodiazepine site ligands. In contrast, gamma2Met130 was required for high affinity binding of flunitrazepam, clonazepam, and triazolam but not flumazenil, CL218, 872, or methyl-beta-carboline-3-carboxylate and did not affect benzodiazepine efficacy. Introduction of the phenylalanine and methionine into the appropriate positions of gamma1 was not sufficient to confer high affinity for the benzodiazepine site ligand zolpidem. These data show that gamma2Phe77 and gamma2Met130 are necessary for high affinity binding of a number of benzodiazepine site ligands. Although most previous studies have focused on the contribution of the alpha subunit, we demonstrated a critical role for the gamma subunit at the benzodiazepine binding site, indicating that this modulatory site is located at the interface of these two subunits. Furthermore, gamma2Phe77 is homologous to alpha1Phe64, which has been previously shown to be a key determinant of the GABA binding site, suggesting a conservation of motifs between different ligand binding sites on the GABAA receptor.     

Delayed postoperative tethering of the cervical spinal cord

Tethering of the spinal cord in the lumbar and sacral regions of children with congenital anomalies is a well-recognized problem; however, tethering in the cervical region has rarely been reported. A search of the literature revealed no reports of symptomatic postoperative cervical spinal cord tethering. The authors present five cases of delayed postoperative cervical spinal cord tethering and discuss the benefit of detethering in these patients. All five patients were young (16 to 42 years of age) at presentation. All had done well after an initial surgical procedure but returned between 1 and 31 years postoperatively with symptoms including severe headache, upper-extremity pain, and progressive neurological deficits. In each case, magnetic resonance imaging indicated dorsal tethering of the cord in the cervical region. Surgical exploration with microscopic sharp detethering of the cervical cord was performed on each patient with favorable results. To avoid retethering, wide Tutoplast duraplasty is recommended.     

Inherited diseases of the glomerular basement membrane

The inherited diseases of the glomerular basement membrane include Alport's syndrome (AS), nail-patella syndrome, and thin basement membrane nephropathy. Classical AS is inherited in an X-linked manner and accounts for approximately 85% of the cases. Its manifestations include hematuria, sensorineural hearing loss, ocular defects, and a progression to renal failure. A defect(s) in the alpha 5 (IV) chain of type IV collagen is believed to be the etiology of classic AS, and alterations in its encoding gene localized to the X-chromosome have been elucidated. Although isolated cases of anti-glomerular basement membrane glomerulonephritis have been reported following renal transplantation in patients with AS, it is considered an effective form of renal replacement therapy. Less is known regarding the genetic basis of the autosomal-dominant form of AS, which apparently accounts for the remaining 15% of the cases. Nail-patella syndrome is characterized by nail dysplasia, patellar hypoplasia or aplasia, and nephropathy. It is inherited in an autosomal-dominant fashion with the gene locus assigned to the long arm of chromosome 9. Possible linkage between the COL5A1 gene and the gene for nail-patella syndrome has been suggested. Approximately 30% of the patients progress to end-stage renal failure. Renal transplantation has been successful in treating patients who progress to end-stage renal failure. Thin basement membrane nephropathy is an autosomal dominant trait that accounts for approximately 30% of the cases presenting as persistent, asymptomatic hematuria. The cause of thin basement membrane nephropathy is unknown at present. No decline in renal function is associated with thin basement membrane nephropathy.