Revision of the Ontario phenylalanine equivalency system and development of a low protein equivalency system

The Phenylalanine Content of Foods, an equivalency system used in the dietary treatment of phenylketonuria, was prepared in 1975. Recently this system was revised to include a total of 372 food items in various raw and processed states. Food lists are available in a simple version for parents listing the serving size per phenylalanine equivalent, and in a more comprehensive version for dietitians providing weights for the serving sizes as well as values for phenylalanine, protein, and energy per equivalent. Subsequently, the system was modified to form a low protein equivalency system for use in designing low protein diets for a number of other inherited metabolic disorders.     

Characteristics of optic disc changes in Taiwanese patients with primary angle-closure glaucoma.

BACKGROUND AND PURPOSE: Primary angle-closure glaucoma (PACG) is the predominant form of glaucoma among Asians. Although numerous studies have been done to describe the characteristic optic disc changes in patients with primary open angle glaucoma (POAG) which is the predominant form of glaucoma among Western populations, few studies have evaluated the optic disc changes in patients with PACG. The aim of this study was to elucidate the characteristic intrapapillary and parapapillary disc changes in PACG in a cross-sectional study and to develop a practical approach to the detection of glaucomatous optic disc changes in PACG by ophthalmoscopic examination. METHODS: A total of 103 eyes in 103 PACG patients were studied. Forty one eyes of 41 age- and sex-matched healthy subjects served as controls. Three glaucoma-trained subspecialists examined stereophotographs of optic discs to evaluate the intrapapillary and parapapillary changes. The differences in PACG and control group eyes were compared. RESULTS: Concentric steep enlargement of the optic disc was found in 99 PACG eyes (96%). Local notching was noted in only 3 eyes, and vertically oval-shaped cupping of the optic disc in only 1 eye. Disc hemorrhage was not detected in any eye. Parapapillary atrophy of the alpha zone involving both temporal and nasal side of the optic disc and parapapillary atrophy of beta zone were significantly more frequent in the PACG group. The presence of an alpha zone or a beta zone simultaneously involving both the temporal and nasal side of the optic disc was associated with more severe optic nerve head damage. CONCLUSIONS: The intrapapillary change in the PACG group eyes reflected the development of cupping in PACG patients with small and compact optic discs. The parapapillary atrophy paralleled the intrapapillary optic disc cupping in eyes of the PACG group.     

Association of SULT1A1 phenotype and genotype with prostate cancer risk in African-Americans and Caucasians.

Exposure to heterocyclic amines may increase prostate cancer risk. Human sulfotransferase 1A1 (SULT1A1) is involved in the bioactivation of some dietary procarcinogens, including the N-hydroxy metabolite of the food-borne heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine. This study compares a polymorphism in the SULT1A1 gene, SULT1A1 enzyme activity, meat consumption, and the risk of prostate cancer in a population based case-control study. Prostate cancer patients (n = 464) and control individuals (n = 459), frequency matched on age and ethnicity, provided informed consent, answered a survey, and provided a blood sample. Platelets were isolated for phenotype analysis, and DNA was isolated from lymphocytes for genotype determination. Meat consumption was assessed using a dietary questionnaire. Caucasians homozygous for the SULT1A1*1 high activity allele were at increased risk for prostate cancer [odds ratio (OR), 1.68; 95% confidence interval (CI), 1.05-2.68] compared with individuals homozygous for the low-activity allele. The association between SULT1A1 genotype and prostate cancer risk in African-Americans did not reach significance (OR, 1.60; 95% CI, 0.46-5.62). When SULT1A1 activity was considered, there was a strong association between increased SULT1A1 activity and prostate cancer risk in Caucasians (OR, 3.04; 95% CI, 1.8-5.1 and OR, 4.96; 95% CI, 3.0-8.3, for the second and third tertiles of SULT1A1 activity, respectively) compared with individuals in the low enzyme activity tertile. A similar association was also found in African-American patients, with ORs of 6.7 and 9.6 for the second and third tertiles of SULT1A1 activity (95% CI, 2.1-21.3 and 2.9-31.3, respectively). When consumption of well-done meat was considered, there was increased risk of prostate cancer (OR, 1.42; 95% CI, 1.01-1.99 and OR, 1.68; 95% CI, 1.20-2.36 for the second and third tertiles, respectively). When SULT1A1 activity was stratified by tertiles of meat consumption, there was greater risk of prostate cancer in the highest tertile of meat consumption. These results indicate that variations in SULT1A1 activity contributes to prostate cancer risk and the magnitude of the association may differ by ethnicity and be modified by meat consumption.     

Inhibition of the allograft response by donor specific blood transfusion: association with reduced local TH1 cytokines and nitric oxide but enhanced prostaglandin E2 production

BACKGROUND: Donor-specific blood transfusion (DST) may improve allograft survival in human and animal models, but the mechanisms for this graft protective effect are incompletely understood. The sponge matrix allograft model was used to determine if DST induces regulatory factors within the allograft. METHODS: C57BL/6 (H-2b) recipients received donor-specific (DBA/2J, H-2d) or syngeneic (C57BL/6) blood 7 days before sponge matrix allograft (DBA/2J) implantation. Fourteen days postgrafting, the sponge infiltrating cells (SIC) were examined for cytotoxic T cell (CTL) and natural killer (NK) activity, and sponge exudate fluid (SEF) was assessed for nitric oxide (.N=O) and prostaglandin E2 (PGE2) content. Interleukin- (IL) 2, IL-4, IL-10, and interferon-gamma (IFN-gamma) production by SIC was also determined. Recipient splenocytes were simultaneously assessed for anti-donor cytotoxic and proliferative responses and .N=O production. RESULTS: SIC from mice receiving syngeneic transfusions (ST) acquired both CTL and NK activity postgrafting, with maximal activity by day 14. DST suppressed both CTL and NK activity throughout the postgrafting period. Limiting dilution analysis (LDA) of SIC to determine precursor and native CTL frequency showed significantly lower responder cell frequency after DST compared with ST. SEF .N=O levels and SIC production of IL-2 and IFN-gamma in grafted DST mice were significantly lower than in grafted mice receiving ST. No significant amounts of IL-4 and very low levels of IL-10 were produced by SIC from grafted mice after either ST or DST. Conversely, PGE2 content of sponge fluid and serum from DST mice was higher than in mice receiving ST. Antigen stimulated splenocyte proliferation and CTL development assessed by LDA were also inhibited by DST. CONCLUSIONS: Reduction in local TH1 cytokines, absence of detectable TH2 cytokines, with enhanced PGE2 and depressed .N=O were observed in the local graft environment after DST. These data support the hypothesis that DST induces donor-specific intragraft suppressor factors, accompanied by reduced local and systemic immune activation.     

Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors.

PURPOSE: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore, we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting the function of Hsp90. EXPERIMENTAL DESIGN: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts. RESULTS: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1. Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear, but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex. CONCLUSIONS: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.     

Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors

Purpose: The activity of vinorellbine, a new semisynthetic vinca alkaloid, was evaluated against a battery of human tumor xenografts derived from adult and pediatric CNS malignancies. Methods: Tumors included adult high-grade gliomas (D-54 MG, D-245 MG), childhood high-grade gliomas (D-212 MG, D-456 MG), medulloblastomas (D-341 MED, D-487 MED), ependymomas (D-612 EP, D-528 EP), and a mismatch repair-deficient procarbazine-resistant glioma [D-245 MG (PR)]. Tumors were grown subcutaneously in athymic nude mice and vinorelbine was administered at a dose of 11 mg/kg on days 1, 5, and 9. Additionally, vinorelbine was also administered in combination with BCNU against D-54 MG. Results: Vinorelbine produced statistically significant growth delays in D-456 MG, D-245 MG, and D-245 MG (PR). No statistically significant growth delays were observed in D-54 MG, D-487 MED, D-212 MG, D-528 EP, D-341 MED or D-612 EP. The antitumor effects of the vinorelbine/BCNU combination were additive. Growth delays observed in the procarbazine-resistant line [D-245 MG (PR)] were greater than twofold the delays seen in the parent line (D-245 MG). Vincristine was equally potent against D-245 MG and D-245 MG (PR). Taxol demonstrated little activity against D-245 MG but produced 32- and 18-day growth delays in D245 MG (PR). Conclusions: These studies indicate that vinorelbine possesses antitumor activity against several glioma tumor xenografts with marked activity in a mismatch repair deficient-tumor. Received: 10 February 1998 / Accepted: 1 April 1998     

A comparison of cause of death determination in men previously diagnosed with prostate cancer who died in 1985 or 1995

PURPOSE: We quantified the agreement between the underlying cause of death determination from information in hospital medical records and on death certificates, and determined whether the frequency of assigning death from prostate cancer had changed since the introduction of testing for prostate specific antigen. MATERIALS AND METHODS: We retrospectively reviewed and analyzed the information in hospital medical records and on death certificates for men previously diagnosed with prostate cancer who died in 1985 or 1995. RESULTS: The underlying cause of death determinations from a review of 201 hospital medical records agreed with those from information on part 1 of the death certificate in 87% of cases and with those using the International Classification of Diseases-9 system coding rules in 80%. Agreement was higher in men who were older than those who were younger at the time of death, and higher in those diagnosed with prostate cancer several years before death than in those diagnosed shortly before death. CONCLUSIONS: There was a high level of agreement concerning the underlying cause of death after a review of the information in hospital medical records and on death certificates for men with prostate cancer when cause of death was viewed as a dichotomous variable. The International Classification of Diseases-9 coding rules concerning the underlying cause of death favor overreporting rather than underreporting prostate cancer deaths compared with a review of hospital medical records. Cause of death determination does not appear to have changed after the introduction of prostate specific antigen testing.     

Incidence and implications of systemic to pulmonary collaterals after bidirectional cavopulmonary anastomosis

BACKGROUND: Systemic to pulmonary arterial collaterals often develop after bidirectional cavopulmonary anastomosis (BCPA). It has been proposed that such collaterals may be related to perioperative outcome and duration of effusions after the modified Fontan procedure. However, the incidence and significance of collaterals after BCPA remain uncertain. METHODS: To evaluate risk factors for, and significance of, such collaterals, we reviewed angiographic and clinical data for all 76 patients who underwent BCPA between January 1990 and June 1996 and had follow-up catheterization during or before 1997. RESULTS: The median age at BCPA was 10 months, and the median duration from BCPA to follow-up catheterization was 18 months. Arterial collaterals were detected on follow-up catheterization in 45 patients (59%). Factors associated with collateral development included a prior right-sided systemic-to-pulmonary arterial shunt, lower pre-BCPA end-diastolic ventricular pressure and pulmonary vascular resistance, and use and duration of cardiopulmonary bypass during the BCPA operation. Fourteen of the 45 patients (30%) underwent coil embolization of the collaterals. Forty-three patients have undergone extracardiac conduit Fontan, with 1 early and 1 late death. Collaterals were present in 22 of these patients, 7 of whom underwent pre-Fontan embolization. The duration from BCPA to Fontan was longer in patients with collaterals, but these patients were not more likely to have prolonged effusions than those without, and the duration of tube thoracostomy was significantly shorter in patients with collaterals. Embolization of collaterals did not affect the duration of effusions. CONCLUSIONS: Systemic-to-pulmonary arterial collaterals are common after BCPA. In contrast to prior reports, collaterals were not associated with a higher incidence of prolonged effusions after the Fontan procedure in our experience, and did not correlate with poor outcome.