My fifty-year odyssey in obstetrics and gynecology: Presidential address

(Am J Obstet Gynecol 1997;176:1244-9.)     

Protection Against Exercise-Induced Bronchoconstriction Two Hours After a Single Oral Dose of Montelukast

The objective of this double-blind cross-over study was to evaluate montelukast for the prevention of exercise-induced bronchoconstriction (EIB). Sixty-two patients with EIB (post-exercise decrease in forced expiratory volume in 1 second (FEV₁) ≥ 20% at pre-randomization) were randomized to montelukast 10 mg or placebo, followed by exercise-challenge 2, 12, and 24 hours postdose. The primary endpoint was the maximum percent-fall in FEV₁ (from pre-exercise FEV₁) during 60 minutes after exercise-challenge at 2 hours postdose. This endpoint was improved after montelukast (mean ± SD = 11.7% ± 10.8) versus placebo (17.5% ± 13.8) (p ≤ 0.001); numerically greater improvements were seen at 12 hours and 24 hours. A quicker time to recovery after challenge (p ≤ 0.001) and a smaller area under the curve for percent-fall in FEV₁ during 60 minutes after challenge (p ≤ 0.01) were seen with montelukast at 2 hours. At this timepoint, more patients taking montelukast (45/54) than taking placebo (37/54) were protected against EIB (p = 0.039). We concluded that montelukast provided significant protection against EIB at 2 hours after a single dose.     

Dementia with Lewy bodies may present as dementia and REM sleep behavior disorder without parkinsonism or hallucinations.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disturbance that commonly occurs in Dementia with Lewy bodies (DLB). Retrospective examination of DLB course has shown that RBD and cognitive decline may precede the onset of parkinsonism and visual hallucinations. Therefore, some patients with DLB may initially present with dementia and RBD, but would not meet current formal criteria for probable DLB at that time. The purpose of this study is to determine whether patients with dementia and RBD, who do not have parkinsonism or visual hallucinations, have cognitive profiles that can be distinguished from autopsy-confirmed definite AD, but not from clinically probable DLB. If so, this would support the hypothesis that the presence of RBD and dementia, as the only presenting symptoms, reflects the early manifestation of DLB. Results show that early dementia in probable DLB and dementia with RBD are neuropsychologically indistinguishable. Both groups differ from definite AD of a similar early stage with significantly worse visual perceptual organization, sequencing and letter fluency but significantly better confrontation naming and verbal memory. In addition, follow-up data from a subset of patients with dementia and RBD reveal the subsequent development of parkinsonism or hallucinations 1 to 6 years later. Results indicate that the presentation of dementia and RBD is suggestive of underlying Lewy body disease and not Alzheimer's disease. This provides further evidence in support of including RBD as one of the core diagnostic features of DLB.     

Long-term cardiopulmonary function after human heart-lung transplantation

We present cardiac and pulmonary function data obtained at serial annual reviews in 21 heart-lung transplant (HLT) recipients followed for up to four years postoperatively, reflecting the entire Stanford experience as of June 1987. A total of 50 cardiac catheterisation procedures and endomyocardial biopsies yielded the following results: rejection on biopsy (0/50) (0% of patients), angiographic coronary artery disease (1/50) (5%), pulmonary hypertension (2/50) (10%), elevated pulmonary vascular resistance (PVR) (1/50) (5%), and low cardiac index (CI) (4/50) (14%). Systemic hypertension was common, with an elevated systemic vascular resistance (SVR) (26/44) (76%) and an elevated mean aortic pressure (MAP) (22/44) (67%). Pulmonary function testing frequently revealed abnormalities. Airflow limitation was manifested by a reduction in both FEV,/FVC ratio (17/50) (52%) and FEF_25–75 (30/50) (71%), and was often associated with arterial hypoxaemia (13/50) (52%). Subsequently, five patients with these findings have died with obliterative bronchiolitis (OB), one underwent retransplantation for OB, six have stable OB, and one has progressive OB. Length of survival was highly correlated with the resting Pa02 at the first annual review (r = 0.99) (p < 0.001), and, to a lesser degree, on the reduction in FEF_25–75 (r = 0.73) (p<0.05) and FEV₁/FVC ratio (r = 0.77) (p<0.05). Resting Pa02 was determined by ventilatory (r = 0.80) (p< 0.001) rather than circulatory factors and all patients with airflow limitation who died had OB at post-mortem examination. These results support the continued study of HLT as a therapeutic modality for selected patients with irreversible pulmonary hypertension. They demonstrate that, in the absence of severe OB, haemodynamics, cardiac function, and coronary patency are preserved for several years after HLT. Whereas the value of regular pulmonary function testing has become evident, there does not appear to be a clinical need for annual surveillance with invasive cardiac procedures in long-term survivors of HLT.     

Genome regulation in mammalian cells

A theory is presented proposing that genetic regulation in mammalian cells is at least a two-tiered effect; that one level of regulation involves the transition between gene exposure and sequestration; that normal differentiation requires a different spectrum of genes to be exposed in each separate state of differentiation; that the fiber systems of the cell cytoskeleton and the nuclear matrix together control the degree of gene exposure; that specific phosphorylation of these elements causes them to assume a different organizational network and to impose a different pattern of sequestration and exposure on the elements of the genome; that the varied gene phosphorylation mechanisms in the cell are integrated in this function; that attachment of this network system to specific parts of the chromosomes brings about sequestration or exposure of the genes in their neighborhood in a fashion similar to that observed when microtubule elements attach through the kinetochore to the centromeric DNA; that one function of repetitive sequences is to serve as elements for the final attachment of this fibrous network to the specific chromosomal loci; and that at least an important part of the calcium manifestation as a metabolic trigger of different differentiation states involves its acting as a binding agent to centers of electronegativity, in particular proteins and especially phosphorylated groups, so as to change the conformation of the fiber network that ultimately controls gene exposure in the mammalian cell. It would appear essential to determine what abnormal gene exposures and sequestrations are characteristic of each type of cancer; which agonists, if any, will bring about reverse transformation; and whether these considerations can be used in therapy.