Citations

Abstract Context: Whether testosterone (Te) depletion in aging men reflects deficits in the testis, hypothalamus, and/or pituitary gland is unknown. Objective: Our objective was to quantify the impact of age on gonadal Te secretion driven by amplitude-varying pulses of recombinant human LH (rhLH) in the absence of confounding by endogenous hypothalamo-pituitary signals. Design: This was a double-blind, placebo-controlled study. Setting: The setting was an academic medical center. Subjects: Fifteen healthy community-dwelling men ages 22–78 yr were included in the study. Intervention: Saline or four separate rhLH doses were each infused twice iv in randomized order as one pulse every 2 h over 20 h to stimulate Te secretion, after LH secretion was suppressed by a GnRH-receptor antagonist, ganirelix. Main Outcome: LH and Te concentrations were determined in blood samples collected every 5 min. Maximal and minimal (as well as mean) Te responses were regressed linearly on age to reflect LH peak and nadir (and average) effects, respectively. Results: The ganirelix/rhLH paradigm yielded serum LH concentrations of 4.6 ± 0.22 IU/liter (normal range 1–9). By regression analysis, age was associated with declines in rhLH pulse-stimulated peak and nadir (and mean) concentrations of total Te (P = 0.0068), bioavailable Te (P = 0.0096), and free Te (P = 0.013), as well as lower Te/LH concentration ratios (P < 0.005). Deconvolution analysis suggested that the half-life of infused LH increases by 12%/decade (P = 0.044; R2 = 0.28). Conclusions: Infusion of amplitude-varying pulses of rhLH during gonadal-axis suppression in healthy men unmasks prominent age-related deficits in stimulated total (39%), bioavailable (66%), and free (63%) Te concentrations, and a smaller age-associated increase in LH half-life. These data suggest that age-associated factors reduce the efficacy of LH pulses.

Background and Purpose: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are slowly progressive tauopathies characterized by impaired balance, disturbances in gait, and frequent falls, among other features. Wheelchair dependence is an inevitable outcome in people with these disorders. Insufficient evidence exists regarding the effectiveness of exercise in the management of people with these disorders. This case report describes a program of exercise and long-term locomotor training, using a treadmill (both with and without body-weight support), to reduce falls and improve the balance and walking ability of a patient with mixed PSP and CBD features.Case Description: Six years after diagnosis with mixed PSP and CBD features, the client, a 72-year-old dentist, was seen for physical therapy for asymmetric limb apraxia, markedly impaired balance, and frequent falls during transitional movements.Intervention: Over a 2.5-year period, intervention included routine participation in an exercise group for people with Parkinson disease (mat exercise and treadmill training) and intermittent participation in individual locomotor training on a treadmill. The exercise group met for 1 hour, twice weekly. The individual treadmill sessions lasted 1 hour, once weekly, for two 14-week periods during the follow-up period.Outcomes: Over the 2.5-year period, fall frequency decreased, and tests of functional balance showed improved limits of stability (functional reach tests) and maintained balance function (Berg Balance Scale). Tests of walking performance showed only slight declines. A 4-wheeled walker was introduced and accepted by the client early in the intervention period. The client, with supervision, remained ambulatory with this wheeled walker in the community.Discussion: In this case report of a person with mixed PSP and CBD features, a physical therapy intervention, which included locomotor training using a treadmill and a long-term exercise program of stretching and strengthening, appears to have improved some dimensions of balance, slowed the rate of gait decline, prevented progression to wheelchair dependence, and decreased falls. Contrary to the expected decline in function, this client maintained independent mobility over a 2.5-year period. An ongoing, intensive program of exercise and locomotor training may help people with PSP and CBD maintain upright balance, decrease falls, and decrease the rate of decline of ambulation.

Boddaert and colleagues show the positive effects of selective iron chelation in young patients with Friedreich ataxia, a devastating inborn error of mitochondrial iron metabolism.

To compare the validity of direct pediatric developmental evaluation with developmental screening by parent report, parents completed a developmental screen (the Child Development Review), a pediatrician performed a direct developmental evaluation (Capute Scales), and a psychologist administered the Bayley Scales of Infant Development to a group of 30-month-old children. The agreement between these instruments was tested. All developmental quotient scores derived from the Capute Scales were more highly correlated with concurrent Bayley Mental Development Index scores than developmental quotient scores derived from the Child Development Review. Differences between developmental quotient scores derived from the Capute Scales and corresponding Bayley Mental Development Index scores were significantly smaller than those derived from the Child Development Review. Thus, direct pediatric developmental evaluation more reliably predicted concurrent Mental Development Index scores at 30 months of age than developmental screening by parent report. Increased emphasis on training of pediatric health care providers in direct developmental evaluation should be considered.

Purpose A phase II study was conducted to determine the efficacy and toxicity of radiotherapy with concomitant gemcitabine and cisplatin for patients with locally advanced pancreatic adenocarcinoma. Patients and Methods Forty-eight patients with locally advanced pancreatic adenocarcinoma received gemcitabine (30 mg/m2) and cisplatin (10 mg/m2) twice weekly during the first 3 weeks of radiotherapy. The radiation dose to the primary tumor and regional nodes was 45 Gy in 25 fractions, and the gross tumor volume received an additional 5.4 Gy in three fractions. Four weeks after radiotherapy, patients received gemcitabine (1,000 mg/m2) once weekly every 3 of 4 weeks for a 12-week period. The primary end point was survival at 12 months. Secondary end points were time to progression, toxicity, and quality of life. Results Survival at 1 year was 40% for 47 eligible patients. The median survival was 10.2 months. Confirmed responses were observed for 8.5% (two partial, two complete), and median time to progression was 7.3 months. Grade 4 or higher toxicity was observed for 31% and consisted primarily of hematologic and GI toxicity. There was a trend toward improved overall quality of life, measured by the Symptom Distress Scale (P = .06), with significant improvements in domains of insomnia, pain, and outlook. Conclusion The combination of radiotherapy, gemcitabine, and cisplatin was well tolerated. Survival results were similar to those achieved with other treatment regimens for patients with locally advanced pancreatic cancer but did not meet our predefined criteria for additional evaluation of this regimen.

Dihydropyrimidine dehydrogenase (DPD) is one of the factors that determine the efficacy and toxicity of 5-fluorouracil. Variations in DPD activity may result from alterations at the transcriptional level of the DPYD gene. Heterogeneity in DPYD expression has been reported, but the molecular mechanisms responsible for this remain unclear. We investigated methylation of the DPYD promoter as a mechanism for transcriptional regulation of DPYD in the RKO colorectal cancer cell line. We demonstrate that the active transcription machinery for DPYD is present in RKO cells, but promoter binding of Sp1, a transactivator of DPYD, was inhibited, which on subsequent examination was shown to be associated with dense promoter methylation. Treatment with 5-aza-2′-deoxycytidine alone or the combination of 5-aza-2′-deoxycytidine and trichostatin A induced demethylation of the promoter and markedly increased the DPYD mRNA level in RKO cells but not in unmethylated WiDr cells. Furthermore, in vitro methylation of the DPYD promoter decreased promoter activity. These data suggest an important role for methylation in DPYD suppression. The transcriptional suppression of DPYD by methylation may be responsible for the increased 5-fluorouracil sensitivity observed in some patients. This may also provide insight into the mechanism underlying the downregulation of DPYD in some colorectal cancers.

Abstract Purpose: To detect insulin-like growth factor-IR (IGF-IR) on circulating tumor cells (CTC) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-IR. Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (CellTracks) was adapted for detecting IGF-IR–positive CTCs with a diagnostic antibody targeting a different IGF-IR epitope to CP-751,871. This assay was used in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma. Results: There was no interference between the analytic and therapeutic antibodies. Eighty patients were enrolled on phase I studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Before treatment, 26 patients (33%) had CTCs, with 23 having detectable IGF-IR–positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-IR–positive CTCs; these increased toward the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11 of 20). Detectable IGF-IR expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of prostate-specific antigen decline by >50% (6 of 10 versus 2 of 8 patients). A relationship was observed between sustained decreases in CTC counts and prostate-specific antigen declines by >50%. Conclusions: IGF-IR expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer.