Donald Herbert

Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.

Background: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. Objective: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. Methods: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. Results: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden ρ2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. Conclusions: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.

Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease

Increased levels of a 40–42 amino‐acid peptide called the amyloid β protein (Aβ) and evidence of oxidative damage are early neuropathological markers of Alzheimers disease (AD). Previous investigations have demonstrated that melatonin is decreased during the aging process and that patients with AD have more profound reductions of this hormone. It has also been recently shown that melatonin protects neuronal cells from Aβ‐mediated oxidative damage and inhibits the formation of amyloid fibrils in vitro. However, a direct relationship between melatonin and the biochemical pathology of AD had not been demonstrated. We used a transgenic mouse model of Alzheimers amyloidosis and monitored over time the effects of administering melatonin on brain levels of Aβ, abnormal protein nitration, and survival of the mice. We report here that administration of melatonin partially inhibited the expected time‐dependent elevation of β‐amyloid, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice. These findings may bear relevance to the pathogenesis and therapy of AD.

Methodological issues in radiation dose–volume outcome analyses: Summary of a joint AAPM/NIH workshop

This report represents a summary of presentations at a joint workshop of the National Institutes of Health and the American Association of Physicists in Medicine (AAPM). Current methodological issues in dose-volume modeling are addressed here from several different perspectives. Areas of emphasis include (a) basic modeling issues including the equivalent uniform dose framework and the bootstrap method, (b) issues in the valid use of statistics, including the need for meta-analysis, (c) issues in dealing with organ deformation and its effects on treatment response, (d) evidence for volume effects for rectal complications, (e) the use of volume effect data in liver and lung as a basis for dose escalation studies, and (f) implications of uncertainties in volume effect knowledge on optimized treatment planning. Taken together, these approaches to studying volume effects describe many implications for the development and use of this information in radiation oncology practice. Areas of significant interest for further research include the meta-analysis of clinical data; interinstitutional pooled data analyses of volume effects; analyses of the uncertainties in outcome prediction models, minimal parameter number outcome models for ranking treatment plans (e.g., equivalent uniform dose); incorporation of the effect of motion in the outcome prediction; dose-escalation/isorisk protocols based on outcome models; the use of functional imaging to study radioresponse; and the need for further small animal tumor control probability/normal tissue complication probability studies.

Inoperable endobronchial obstructing lung cancer treated with combined endobronchial and external beam irradiation: A dosimetric analysis☆

PURPOSE This study is a dosimetric review of our experience incorporating both external beam radiotherapy and endobronchial brachytherapy in the treatment of inoperable endobronchial obstructing lung cancer. METHODS AND MATERIALS Sixty-five patients with symptomatic inoperable endobronchial obstructing lung cancer received combined external beam radiotherapy and temporary endobronchial iridium (Ir)-192 implants between February 1987 and May 1991. External beam irradiation doses ranged from 55 to 66 Gy. Patients were given 2 to 4 temporary Ir-192 endobronchial implants at the site of endobronchial obstruction. Individual implant doses ranged from 2.7 to 10 Gy. Total implant doses ranged from 6 to 35 Gy. Total treatment doses ranged from 61 to 96.6 Gy. RESULTS Sixty-three percent of patients had a complete local endobronchial response to treatment and 23% had a partial response. Forty-seven percent of patients receiving a total dose of less than 70 Gy experienced a complete local endobronchial response to treatment while 83% of patients receiving a total dose of 85 Gy or greater experienced a complete local endobronchial response to treatment. Sixty-six percent experienced an improvement in their performance status using an Eastern Cooperative Oncology Group performance scale. Survival from the end of treatment was 38% at 1 year and 23% at 2 years, with the median survival at 8 months. Complications occurred in 9/65 (14%) of patients; 0% in patients receiving a total dose of less than 70 Gy, 10% in patients receiving a total dose of 70 to 84.99 Gy, and 24% of patients receiving a total dose of 85 Gy or higher. CONCLUSION The data from this study again confirms the feasibility of this form of treatment for inoperable endobronchial obstructing lung cancer. In addition, there appears to be a dose response for both local response and complications.

Surgical Treatment of Clubfoot: A Comparison of Two Techniques

Between 1977 and 1989, 28 clubfeet were operated on, with follow-up ranging from 2 to 13 ½ years and averaging 79 months. Group I (16 feet; average follow-up 104 months) underwent a modified Turcos posteromedial release. The functional result in this group was satisfactory in general, but approximately one third of this group required a secondary procedure for persistent intoeing or residual metatarsus adductus. Group II (12 feet; average follow-up 45 months) underwent a modified, complete subtalar release of McKay and Simons utilizing the Cincinnati incision. No patient in this second group required a secondary procedure. In our experience, the more complete subtalar release procedure of McKay and Simons resulted in better correction than the Turco posteromedial release. Although follow-up in group II was much shorter than that in group I, we felt that 2 years of minimum follow-up in group II was meaningful, since most of the recurrence or residual deformities were noticed within 18 months after surgery. The Cincinnati incision allowed better exposure and a more complete release. Skin flap necrosis was not a problem in this series.

Misclassification of pulmonary hypertension in adults with sickle hemoglobinopathies using Doppler echocardiography.

Objective To compare the diagnostic utility of Doppler echocardiography–derived tricuspid regurgitant jet velocity (TRV) ≥2.5 m/s to right heart catheterization (RHC) in defining pulmonary hypertension (PH) in adult patients with sickle cell disease (SCD). Methods This is a retrospective chart review of adults with SCD who had a TRV ≥2.5 m/s and RHC. A TRV ≥2.5 m/s is suggestive of PH. Pulmonary arterial hypertension (PAH) was defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg and pulmonary capillary wedge pressure ⩽15 mm Hg. Pulmonary venous hypertension was defined as an mPAP ≥25 mm Hg and pulmonary capillary wedge pressure >15 mm Hg. Results Twenty-five patients with SCD met the inclusion criteria. Nine of the 25 (36%) patients had an mPAP ≥25 mm Hg. Of these 9, 3 (33%) had PAH and 6 (66%) had pulmonary venous hypertension. Patients with PH did not have a higher TRV (3.1 ± 0.68 vs 2.70 ± 0.16 m/s; P = 0.12), but they did have higher cardiac outputs (10.4 ± 2.7 vs 7.81 ± 1.85 L/min; P = 0.012. The specificity of TRV equal to 2.51 m/s in diagnosing PH was 18.8%. At a TRV of 2.88 m/s, the specificity increased to 81%. Conclusions In adults with SCD, a TRV of 2.5 m/s lacks specificity for use as a screening tool in the diagnosis of PH. Using a TRV of ≥2.88 m/s allows the TRV to be used as a screening tool and reduces the false-positive rate and need for unnecessary RHC.

Severe Human Metapneumovirus Infection in Hospitalized Children

Human metapneumovirus is a recently discovered pathogen that causes upper and lower respiratory tract disease in children. This study describes the course of illness in hospitalized children with this infection. During a 6-month period, 11 children were diagnosed with human metapneumovirus infection by reverse transcription-polymerase chain reaction. Oxygen supplementation was required for 82% of patients. Severe disease developed in 45%, and mechanical ventilation was required. An apparent life-threatening event was the indication for hospitalization of 27% of patients infected with human metapneumovirus. Children with underlying asthma or neuromuscular disease had a prolonged hospitalization.

The assessment of the clinical significance of non-compliance with prescribed schedules of of irradiation☆

Abstract The clinical significance of non-compliance with a prescribed treatment regimen is assessed in terms of the change in the expected proportion of local control of disease produced by excursions from the prescribed regimen of the order of ±5% in dose and time. It is shown that the change in the expected proportion can be anticipated from local estimates of the location and shape of the response surface for the binary event, control/recurrence, in the vicinity of the prescribed treatment regimen. It is shown that changes from the prescribed regimen may result in more or less of a clinical fiasco, depending upon the disease, prognostic factors and the level of control initially achieved by the prescribed regimen. The methods are illustrated with clinical data for carcinoma of the oropharynx and for Hodgkins disease.

Iron overload in adults with sickle cell disease who have received intermittent red blood cell transfusions.

Objective:To assess the prevalence of iron overload in adults with sickle cell disease (SCD) not on a chronic transfusion protocol. Design:Retrospective chart review. Data source:University of South Alabama Comprehensive Sickle Cell Center adult outpatient clinic. Results:There was no significant difference in units transfused across the four genotypes (HbSS, HbSC, HbS&bgr;0‐thalassemia, and HbS&bgr;+‐thalassemia). Only individuals with HbSS (n = 63) met criteria for iron overload with ferritins of ≥1500 ng/mL. Forty‐eight had ferritins <1500 ng/mL, eight (13%) had ferritins ≥3000 ng/mL, and seven (11%) had ferritins ≥1500 and <3000 ng/mL. The overall prevalence of iron overload was 9.74% in SCD cohort and 23.8% in the HbSS genotype. Conclusions:Our data support that patients with HbSS are at a particularly high risk for inadvertent iron overload as compared to HbSC, HbS&bgr;0‐thalassemia, and HbS&bgr;+‐thalassemia. Implications for practice:This study supports the need for healthcare providers to closely monitor the number of red blood cell (RBC) transfusions, RBC units transfused, and serial baseline, steady‐state ferritin levels. With closer monitoring, the clinical significance of iron overload in SCD can be established and guide the healthcare providers management in the prevention of iron overload.

Overview of nonlinear dynamical systems and complexity theory

A brief overview is presented of the principal elements of ‘‘nonlinear dynamics’’: catastrophes, fractals, chaos, solitary waves, and coherent and dissipative structures. The text is followed by a set of 10 portraits of the strange and violent world of nonlinear dynamics.