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Importance Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology. Objective To investigate whether cognitive reserve (CR) modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD. Design, Setting, and Participants A cross-sectional cohort of 268 individuals (211 in a cognitively normal group and 57 in a cognitively impaired group) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center participated in this study. They underwent lumbar puncture for collection of CSF samples, from which Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed. In addition, we computed t-tau/Aβ42 and p-tau/Aβ42 ratios. Cognitive reserve was indexed by years of education, with 16 or more years taken to confer high reserve. Covariate-adjusted regression analyses were used to test whether the effect of age on CSF biomarkers was modified by CR. The study dates were March 5, 2010, to February 13, 2013. Main Outcomes and Measures Cerebrospinal fluid levels of Aβ42, t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42. Results There were significant age × CR interactions for CSF t-tau (β [SE] = −6.72 [2.84],P = .02), p-tau (β [SE] = −0.71 [0.27],P = .01), t-tau/Aβ42 (β [SE] = −0.02 [0.01],P = .02), and p-tau/Aβ42 (β [SE] = −0.002 [0.001],P = .004). With advancing age, individuals with high CR exhibited attenuated adverse alterations in these CSF biomarkers compared with individuals with low CR. This attenuation of age effects by CR tended to be more pronounced in the cognitively impaired group compared with the cognitively normal group. There was evidence of a dose-response relationship such that the effect of age on the biomarkers was progressively attenuated given additional years of schooling. Conclusions and Relevance In a sample composed of a cognitively normal group and a cognitively impaired group, higher CR was associated with a diminution of age-related alterations in CSF biomarkers of AD. This suggests one pathway through which CR might favorably alter lifetime risk for symptomatic AD.

S100P, and SAT remained elevated 2 weeks after surgery (P .05). Cytokeratin 14 (CK14) exhibited the greatest diminution in array expression pattern 2 weeks after surgery for OSCC and confirmed with qPCR. Using t test comparisons, postoperative CK14 gene expression was lower than before surgery (P .05) and no different vs control subjects. (P .05). Conclusions: While IL8, IL1B, DUSP1, HA3, OAZ1, S100P, and SAT hold promise for detecting OSCC in saliva, salivary CK14 mRNA can serve as a detection marker as well as a prognostic marker for therapeutic response to surgery in OSCC. Creating a saliva-based panel of these biomarkers could be used to diagnose and follow up patients with OSCC.

S100P, and SAT remained elevated 2 weeks after surgery (P .05). Cytokeratin 14 (CK14) exhibited the greatest diminution in array expression pattern 2 weeks after surgery for OSCC and confirmed with qPCR. Using t test comparisons, postoperative CK14 gene expression was lower than before surgery (P .05) and no different vs control subjects. (P .05). Conclusions: While IL8, IL1B, DUSP1, HA3, OAZ1, S100P, and SAT hold promise for detecting OSCC in saliva, salivary CK14 mRNA can serve as a detection marker as well as a prognostic marker for therapeutic response to surgery in OSCC. Creating a saliva-based panel of these biomarkers could be used to diagnose and follow up patients with OSCC.

Background: Restricted activity is common among community-living older persons, but its prognostic significance is not known. We performed a prospective cohort study to evaluate the association between the occurrence of restricted activity and functional decline over an 18-month period. Methods: We studied 680 community-living persons, 70 years or older, who were categorized into 3 groups according to their risk for disability (low, intermediate, or high) in activities of daily living (ADL). Participants were subsequently followed up with monthly telephone interviews to ascertain the occurrence of restricted activity, defined as having stayed in bed for at least half a day and/or having cut down on their usual activities due to an illness, injury, or other problem in the past month. Functional decline was defined as an increase in ADL disability scores between the baseline and 18-month follow-up assessments, which were completed in the home. Results: After adjusting for the baseline risk of disability and other covariates, the disability score at 18 months increased (ie, worsened) by 11.2% (95% confidence interval [CI], 7.0%-15.6%) for each additional month with restricted activity. The association between restricted activity and functional decline differed significantly by risk group (P.001). For the low- and intermediate-risk groups, the adjusted disability scores increased by 18.7% (95% CI, 10.3%-27.8%) and 7.5% (95% CI, 2.7%-12.5%), respectively, for each additional month with restricted activity. There was no association between restricted activity and functional decline in the high-risk group, as evidenced by a nonsignificant increase in the adjusted disability score of 2.7% (95% CI, �6.6% to 12.9%). Conclusion: For older persons who are not otherwise at high risk for ADL disability, restricted activity is an important predictor of functional decline and not just a benign feature of old age. Arch Intern Med. 2003;163:1317-1322

Background: Hypoalphalipoproteinemia (low serum concentration of high-density lipoprotein cholesterol [HDL-C]) is a common pattern of dyslipidemia associated with coronary heart disease. High doses of nicotinic acid effectively raise HDL-C levels in this condition, but they are commonly accompanied by side effects. The efficacy of low doses of nicotinic acid that may produce fewer side effects has not been adequately studied. Objective: To determine the effects of low-dose nicotinic acid on HDL-C levels in patients with hypoalphalipoproteinemia. Methods: Forty-four men with low HDL-C levels ( Results: Of the 44 patients who entered the study, 37 completed the low-dose phase (1.5 g/d); the remaining patients were withdrawn because of side effects to nicotinic acid. Four other patients who completed the low-dose phase were excluded from the higher dose phase because of side effects that developed when they were receiving the low dose. Ten other patients withdrew during the high-dose phase because of side effects. In both groups, responses to nicotinic acid therapy tended to be dose-dependent. For both groups, the higher dose generally produced a greater reduction in apolipoprotein B—containing lipoproteins and a greater rise in HDL-C levels. However, for both groups, the low dose of nicotinic acid gave an average 20% increase in HDL-C levels. Conclusions: A low dose (1.5 g/d) of crystalline nicotinic acid causes an average 20% increase in HDL-C levels and significantly lowers triglyceride levels in both normolipidemic and hyperlipidemic patients with low HDL-C levels. Although the changes induced by this dose are less than those that can be achieved by a higher dose, the lower dose is better tolerated. Nicotinic acid may be useful in combined drug therapy for secondary prevention of coronary heart disease, and if higher doses cannot be tolerated, use of a lower dose should still be useful for producing a moderate rise in HDL-C levels in patients with hypoalphalipoproteinemia. (Arch Intern Med. 1996;156:1081-1088)

Objective. —To test the hypothesis that uptake of circulating choline into the brain decreases with age, because alterations in metabolism of choline may be a factor contributing to age-related degenerative changes in the brain. Design. —Cohort comparison in younger and older adults. Participants. —Subjects were chosen consecutively from lists of healthy volunteers screened by medical and psychiatric interviews and laboratory tests. Younger adults (n=12) were between the ages of 20 and 40 years (mean age, 32 years), and older adults (n=16) were between the ages of 60 and 85 years (mean age, 73 years). Interventions. —After fasting overnight, subjects received choline, as the bitartrate, to yield free choline equal to 50 mg/kg of body weight. Blood was drawn for determination of plasma choline concentration by high-performance liquid chromatography, and proton magnetic resonance spectroscopy (1H-MRS) was performed to determine the relative concentration of cytosolic choline—containing compounds in the brain at baseline and after ingestion of choline. Main Outcome Measures. —Plasma choline and cytosolic choline—containing compounds in the brain, estimated as the ratio of the choline resonance to the creatine resonance on1H-MRS scans of the basal ganglia, were compared following blinded analyses of data from subject cohorts studied at baseline and 3 hours after choline ingestion. Results. —Levels of plasma choline and cytosolic choline—containing compounds in brain were similar at baseline in younger and older subjects. Following ingestion of choline, plasma choline concentration increased by similar proportions (76% and 80%) in both younger and older subjects. Brain cytosolic choline— containing compounds increased substantially in younger subjects (mean increase, 60%;P Conclusion. —Uptake of circulating choline into the brain decreases with age. Given the key role of choline in neuronal structure and function, this change may be a contributing factor in onset in late life of neurodegenerative, particularly dementing, illnesses in which cholinergic neurons show particular susceptibility to loss. (JAMA. 1995;274:902-907)

• Extracorporeal photochemotherapy is a well-tolerated treatment of palliative benefit for patients with the Sezary syndrome, but up to 25% of patients do not respond to this form of therapy. Interferon alfa is a glycoprotein with immunomodulatory properties that is also an active agent in the treatment of Sezary syndrome; however, dose-related toxic effects often limit its long-term use. A patient with rapidly advancing Sezary syndrome was treated with a combination of extracorporeal photochemotherapy and low doses of subcutaneous interferon alfa-2b. In addition to the almost complete clearing of his skin lesions and the marked diminution of his extensive lymphadenopathy after 16 weeks of combined therapy, disappearance of the malignant T-cell clone from the peripheral blood was documented by Southern blot analysis. Normalization of the peripheral blood lymphocyte phenotypic profile and an increase in natural killer cell activity were also observed. The excellent clinical response to combined therapy has been sustained, without adverse effects, during 18 months of treatment and 22 months of continued follow-up. The long-term disappearance of the malignant clone from the blood of a patient with Sezary syndrome in response to therapy has not been previously described and thus represents a novel observation. Extracorporeal photochemotherapy and low-dose interferon alfa are well-tolerated therapies that, when combined, may have additive efficacy in the treatment of Sezary syndrome. These results suggest that further exploration of this therapeutic combination is warranted. ( Arch Dermatol. 1991;127:1535-1540)

Hematologic profiles of 462 persons, mostly active-duty service members, were studied to determine whether hematologic differences between blacks and whites exist in a healthy population. Whites had significantly greater mean concentrations of leukocytes (6.73 vs 5.95×10 9 /L), neutrophils (3.96 vs 3.16 × 10 9 /L), and hemoglobin (153 vs 135 g/L for men, 147 vs 125 g/L for women). The mean differences were largely due to relatively symmetric shifts in the frequency distributions for these cell concentrations. No significant correlation was found between neutrophil count and morbidity from infection as measured by a standardized questionnaire. The use of separate hematologic reference values for blacks and whites should be considered. ( Arch Intern Med. 1991;151:501-505)

Strawberry, or capillary, hemangiomas are common vascular neoplasms, with an incidence of approximately 2.6% in neonates. They usually develop in the first few weeks of life, so that between 1 month and 1 year the incidence rises to between 8.7% and 10.1%. These lesions may grow quite large in the first year of life, and they may ulcerate or obstruct a vital organ or function. The great majority will spontaneously regress after the first year of life. Parents are often alarmed at the sight of these hemangiomas and need reassurance that the great majority will regress spontaneously. Treatments such as cryosurgery, irradiation, radium instillation, corticosteroid therapy, or surgical excision are often ineffective or cause significant morbidity. We describe 10 children with capillary hemangiomas treated with the flash lamp-pumped pulsed dye laser. The patients ranged in age from 7 weeks to 5.5 years at the beginning of laser therapy. The patients underwent 3.1 +/- 1 (mean +/- SD) laser treatments, with a mean regression of the lesions of 69.9% +/- 4.5%. All patients demonstrated some diminution in the size and color of their hemangiomas after the treatments, and there were no ill effects, such as ulceration, hemorrhage, infection, or scarring. There was no evidence of hyperpigmentation or hypopigmentation. Pulsed dye laser therapy should be considered as an option in the treatment of capillary hemangiomas, preferably prior to their full evolution. It is also a useful therapeutic approach in those hemangiomas that are slow to regress in older children.

• The expression of type VII collagen and 19-DEJ-1 antigen was examined in 73 and 71 patients, respectively, with recessive dystrophic epidermolysis bullosa (RDEB), comprising gravis, mitis, inversa, and indeterminant subsets, to better determine the specificity and sensitivity of two monoclonal antibodies directed against these dermoepidermal junctionspecific epitopes. Type VII collagen (LH 7:2 epitope) was usually absent (in 90%) in patients with the gravis variant of RDEB, whereas its expression was most often diminished (in 67%) in those with the mitis form of the disease. Only 2% and 5% of patients with gravis and mitis variants, respectively, had apparent normal amounts of type VII collagen within their skin. In contrast, six (86%) of seven patients with the inversa variant had normal expression of the antigen. Only 25% of all patients with RDEB lacked the 19-DEJ-1 antigen; of these, however, most had the gravis variant, although absence or diminution was also infrequently observed in those with the mitis and inversa forms. Intermediate findings were noted in patients classified as having indeterminant forms of RDEB. Some variability in antigen expression was also noted among affected siblings. We conclude that assessment of expression of the LH 7:2 epitope of type VII collagen may be diagnostically useful, although considerable overlap does exist between individual patients with gravis and mitis forms. 19-DEJ-1 expression is a far less sensitive probe in RDEB, although such data may prove useful in the assessment of newborns lacking the characteristic features of gravis disease. In addition, based on our experience with inversa RDEB, it would appear that altered expression of type VII collagen cannot be attributed to blister formation in this latter rare subset, since this antigen is usually strongly detected along the dermoepidermal junction, even in perilesional skin sites. ( Arch Dermatol. 1990;126:1587-1593)

The use of the low pressure chamber in relieving sinusitis was first reported by Andrews, Roth and Ivy in 1940.1They studied the effects of reduced atmospheric pressure in 16 cases of advanced sinus disease and noted subjective relief of symptoms in 14 cases. The patients reported a marked increase in drainage, with diminution of pain, pressure and nasal congestion. In that preliminary report a simple nontraumatic method of promoting drainage and aeration of sinuses was presented and its possible application as a practical therapeutic measure in cases of sinus disease was suggested. The principle was first used by Behnke2in 1932; he used slow compression followed by rapid decompression in the high pressure chamber. In the past two years the decompression method has been used by us in the treatment of a series of 125 patients with subacute and chronic sinusitis, and the effects on the progress of their

The picture of epithelial dystrophy as described by Fuchs1is so characteristic that it could hardly fail to be recognized by any one having the condition in mind. Little has been added to his classic description of the condition given in 1910. In its essentials, the condition consists in an edema of the corneal epithelium with the formation of numerous blebs of varying size, associated with punctate grayish opacities in the epithelium and grayish lines and dots in the parenchyma. The condition begins insidiously, the only symptom being gradual diminution of vision, which was reduced to 6/60 or even counting fingers in most of Fuchs' cases. The sensation of the cornea is greatly diminished or absent, and Fuchs believed the cause of the condition to be a disturbance of nutrition affecting the superficial corneal nerves. All of his patients were over 48 years of age, and nine women

Atrophic rhinitis is degenerative rhinitis in which the normal ciliated columnar type of epithelium is replaced by a nonciliated, stratified squamous type. The mucus-secreting glands are greatly diminished in number but not totally absent, so that mucus is still secreted. Textbooks of otolaryngology describe two groups of cases: (1) cases in which no odor is present in the nose and (2) cases in which there is a fetid odor. The condition in the latter group is commonly called ozena. CLINICAL CLASSIFICATION OF CASES OF ATROPHIC RHINITIS From a clinical point of view atrophic rhinitis should be considered as of four types: Latent Atrophic Rhinitis.—This type is characterized merely by a diminution in size of one or more turbinates and may be asymptomatic, requiring no treatment. Simple Mild Atrophic Rhinitis.—This type is characterized by atrophy of either the middle or the inferior turbinate or both, on one or both sides, but

Malignant tumors of the middle ear are rather rare. Among these tumors, adenocarcinoma of the middle ear, either primary or secondary, is one of the most infrequent, as was pointed out by Rosenwasser1and by Peele and Hauser.2This fact, as well as the further fact that the case to be described differs in many respects from the cases reported in the literature, suggests its publication. REPORT OF A CASE E. H., a housewife 47 years old, had noticed poor hearing in both ears at the age of 27. The hearing in the left ear improved after treatment with air inflations and massage, whereas the hearing in the right ear became progressively worse. In October 1937, the patient observed diminution of hearing and felt intermittent pain in the left ear. The consulted otologist diagnosed acute otitis media and advised conservative treatment. A slight hemorrhagic discharge occurred, which lasted for three

Recent literature has pointed to new trends in the treatment of atrophic rhinitis. Soskin and Bernheimer 1 have pointed out that the good results reported with the use of estrogenic substances in the treatment of atrophic rhinitis were due to the secondary hyperemia associated with direct nasal application of estrogens. They expressed the belief that the primary hormonal effects were not the essential factor and used prostigmine methylsulfate successfully to produce a prolonged hyperemia in patients with atrophic rhinitis. Whether the pathologic change of atrophic rhinitis is primary, as the so-called ozena, or secondary in type, resulting from infection, the atrophy is dependent on limitation of the blood supply. The other changes, such as mucoid degeneration of the epithelium with later squamification, periglandular lymphocytic infiltration, glandular proliferation and diminution in volume of tissue, are directly and indirectly related to the local changes in blood volume. In ozena the obliterative endarteritis brings

A double-blind trial was conducted using heparin to prevent thrombosis in 2-mm rabbit neck veins joined by the Nakayama technique. Four groups of rabbits were used and heparin administered to the experimental groups as a local wash, a stat intravenous injection, and a stat intravenous injection plus one week of intramuscular heparin. Results show a similar and highly significant statistical diminution in thrombosis rates, when using the latter two methods. Adoption of the technique utilizing one intravenous injection of heparin preoperatively is suggested for future use in reconstructive surgery if autologous tissue based on a free vascular pedicle is to be employed.

Many are familiar with the properties of the synthetic levorotatory tartaric acid alkaloid derived from the suprarenal capsule, the so-called links or laevoglaucosan that was introduced by Hamburger in 1923. Used in 2 per cent solution and combined with methylamino-acetopyrocatechol in the same strength, it can be used by instillation and produces the following effects: (1) intense ischemia of the conjunctiva, with bloodless islets appearing in the cheek, lid and temple; (2) widening of the palpebral aperture ; (3) regular and wide dilatation of the pupil, and (4) a diminution in intra-ocular tension (sometimes preceded by an initial rise). I have used laevoglaucosan in cases of glaucoma simplex for three years, and believe it to be a valuable adjuvant to miotics. It is not universally successful in reducing tension; some failures must be admitted. Laevoglaucosan has the following drawbacks : ( 1 ) it is furnished in small ampules, each containing only a

Mayer waves and undulating ventricular waves were produced in hydrocephalic and nonhydrocephalic animals. Carotid sinus stimulation resulted in an increase in both wave forms, whereas carotid sinus denervation resulted in their diminution. The reflex pathway involved in the production of the waves constitutes a feedback mechanism between carotid sinus, the peripheral proprioceptor, and medullary vasomotor center. The ventricular fluid pressure wave forms are the intracranial manifestations of passively transmitted changes occurring in the systemic circulation secondary to dysfunction of the brain stem.

Herpes simplex infection of the cornea, unlike infection of the skin, tends to be chronic and to lead to opaque and blinding scars. A recent review of a large series of cases indicated that spontaneous clearing of herpetic keratitis within a reasonable period of time does not occur in more than 10% of cases. Temporary diminution of vision seems to be the rule, and "permanent diminution of vision was probably obtained in the majority of cases." 1 Present therapy of herpes simplex keratitis consists primarily of the removal of infected tissue. When only the corneal epithelium is involved by the infection, removal of the area of ulcer seems to speed healing. This removal may be facilitated by the use of denaturing agents such as iodine or silver nitrate, by mechanical curettage, or by the use of enzymes such as chymotrypsin. Some of the agents which precipitate tissue protein also kill

The precise nature of the leukocytic reactions during measles still remains a subject concerning which there are surprising differences of opinion. Although it is generally held that a leukocytosis is present during the incubation period, followed as a rule by a leukopenia during the acute febrile stage, 1 there is a lack of agreement regarding the changes in the differential count. It was early pointed out by several investigators 2 that the fall in the blood count was due chiefly to a diminution in the number of lymphocytes. Diametrically opposed to this finding, however, have been the reports of a lymphocytosis occurring simultaneously with the rash. 3 Moreover, it has been maintained 4 that variations in the number of polymorphonuclear cells principally account for the leukocytosis or the leukopenia observed in the different phases of the disease. More recent workers, 5 on the other hand, have laid great stress on

• We studied the effects of topical dinoprostone on the nasal blood vessels of patients with allergic rhinitis. The outstanding changes noted were constriction of the arterioles and capillaries (to a lesser extent) and tight closure of the interendothelial junctions. These changes caused a diminution of nasal blood flow and edema fluid formation, a reduction in the size of the turbinates, and consequently, an increase in nasal patency. However, dinoprostone had no effect on the nasal venules. ( Arch Otolaryngol 1983;109:815-817)

The experience of Dr. Norbury is new to us. We have not noticed any impairment of renal function in prolonged starvation, with the exception of diminution of uric acid clearance. However, we have not treated anyone with known renal disease and have in fact rejected some obese patients because they were known to have a history of pyelonephritis and glomerulonephritis. We cannot offer a good explanation of the course of events in Dr. Norbury's patient. One may speculate that in a previously damaged kidney the accumulation of ketones may impair clearance of other metabolites and not just of uric acid. I agree with the suggestion that a creatinine clearance should be carried out either before, or perhaps 48 hours after, onset of starvation when ketosis has developed. The comments of Dr. Farber are well taken. In our report, we intended to emphasize metabolic changes during starvation. The psychological aspects of

Optic neuritis with diminution of visual acuity was observed in six children with cystic fibrosis. Postmortem examination of the eyes was made in two of them. Strong circumstantial evidence suggested that chloramphenicol administered for prolonged courses of treatment was responsible. Special attention should be paid to diminution of visual acuity in the course of chloramphenicol therapy and this drug should be administered whenever possible in courses not exceeding four weeks. In cystic fibrosis, two separate types of ocular lesions are encountered: retinal vascular changes which do not affect vision and optic neuritis following prolonged chloramphenicol therapy. Both conditions are apt to coexist in fibrocystics with severe pulmonary involvement.

Iodine has been used in the treatment of exophthalmic goiter for more than a hundred years. It was not until 1923, however, that Plummer1first presented convincing evidence of the value of medication with iodine as an adjunct to surgery in the treatment of hyperthyroid patients. Today the administration of iodine in the form of compound solution of iodine (Lugol's solution) or potassium iodide is employed in a routine manner as a preoperative measure by the majority of physicians and surgeons both in this country and abroad. Properly used, iodine appears to effect striking clinical improvement, as manifested by a diminution of the nervous symptoms, a fall in the basal metabolic rate, a decrease in pulse rate and frequently an appreciable gain in weight. As a result of the alleviation of many of the signs and symptoms of the disease the patient is better prepared to withstand the shock

As recently as a year ago it was considered imperative to confirm any presumptive diagnosis of herniated nucleus pulposus of the lower lumbar intervertebral disks by roentgenologic examination of the spinal canal after injection of some contrast medium.1However, even a year ago in cases of severe, persistent sciatic pain associated with pain low in the back and rigidity, together with hypesthesia of the lateral aspect of the involved leg and diminution of the ankle jerk, surgical exploration gave positive results regardless of the type of defect demonstrated with iodized oil. Conversely, all too frequently in cases of what were thought to be characteristic defects demonstrable with iodized oil but in which the neurologic evidence was less characteristic, exploration gave negative results. On the basis of our experience with a series of eighty-five low intraspinal lesions treated surgically we shall present what we have found to be the characteristic

In 1938 Dodds, Goldberg, Lawson and Robinson 1 announced the synthesis of a new estrogenic agent, diethylstilbestrol (4: 4-dihydroxy-alpha: beta-diethyl stilbene). As can be seen from its formula,it does not contain the phenanthrene ring system formerly thought to be necessary for estrogenic activity. It was found an extremely powerful estrogenic agent in animals, suffering little diminution in potency by the oral as compared to the parenteral route. 2 It reproduced the effects of the natural estrogens in animals and was about two and one-half times as active as estrone by injection. By the oral route the superiority over the natural estrogen was far greater, since the naturally occurring compounds lose a high percentage of their activity when given by mouth. In man the loss of activity of the natural estrogens given by mouth has been shown to be as much as 95 per cent, as judged by vaginal smears.

The clinical significance of gastrointestinal disturbances in the angina pectoris syndrome and other cardiac disorders has been conceded by various authors. 1 Experimental studies, however, have never to our knowledge been reported on the attempt to investigate the relationship and interdependence of the digestive tract and cardiovascular disease in the human subject, such as this report entails. This study was first suggested to us by several observations. First, several of our patients with angina pectoris and gastrointestinal disturbances had for some time experienced indifferent results from the usual methods of management of angina pectoris, including administration of the xanthine derivatives (theophylline, theophylline with ethylene diamine) as well as glyceryl trinitrate, curtailment of activity and other measures. On intensive therapy directed to the gastrointestinal tract much better clinical results were obtained for the first time in the diminution of the frequency and intensity of paroxysms of anginal pain. Second, great interest

• Of 138 patients with polymorphous light eruption originally investigated in 1972, one hundred fourteen were contacted seven years later (1979), and 47 subjected to a clinical and laboratory reevaluation. Sixty-four of the 114 patients (57%) described a diminution of sun-related skin complaints, including 12 patients who reported a total freedom from sun sensitivity during the previous two years. In contrast, two patients who in 1972 had claimed temporary freedom from sun sensitivity had again noted their reactions to sunlight by 1979. In five of 43 cases examined at uninvolved skin sites, weak (1+) positive direct immunofluorescence staining for basement membrane zone immunoglobulins was reported by both laboratories employed in this study. Low or moderate antinuclear antibody serum titers were found in nine patients. No patient, however, met diagnostic criteria for systemic lupus erythematosus. (Arch Dermatol1984;120:862-865)

Two patients had acute, self-limiting, unilateral brachial plexus neuropathy in association with desensitizing subcutaneous injections of extracts of dusts and molds. Diminution of pain and return of function of the affected limb followed a short course of prednisone therapy, although a beneficial effect of the steroid cannot be considered proved. There is a large variety of antigenic substances already known to produce neuropathy following intramuscular injection; desensitizing antiallergy injections should be added to this list. ( JAMA 234:620-621, 1975)

In a fracture healing experiment using rabbit tibiae, apparatus was used to produce a constant measured compression at the site of surgically produced fractures. The apparatus did not hold the fracture rigidly immobilized, but permitted a degree of motion. Under these conditions, compression itself was not a uniformly beneficial factor in fracture healing. In excess, compression acted adversely on the healing process, resulting in slower healing and a bulkier, less mature callus. Excess compression was also related to an adverse response in the diaphysis manifested by resorption of bone along Haversian canals with resultant diminution of structural substance of the cortex.

The differentiation of two types of renal graft rejection may be made early in incipient stages by means of a comprehensive renal function study. In the acute cell-mediated form, prolongation of orthoiodohippurate renal transit time as reflected in a diminished excretory index (El) is first observed, followed by a diminution in the effective renal plasma flow (ERPF). On reversal of the process, El precedes ERPF in returning to normal. In chronic humoral rejection, the principle feature is simple reduction of ERPF; transit time within the kidney appears normal. No reversal processes have been observed, although the process may be decelerated. At approximately 100 ml/min ERPF, these kidneys may undergo an acceleration of the clinical failure with rapid deterioration in El and in ERPF. At this point, surgical removal of the kidney has been carried out. ( Arch Intern Med 137:738-742, 1977)

THE CIRCULATING concentration of free thyroxine indicates, with rare exception, the physiologic status in regard to euthyroidism, hyperthyroidism, or hypothyroidism. Yet only a very small portion (about 0.05%) of the serum total thyroxine exists in this form. The remainder is bound to the thyroxine-binding proteins, notably thyroxine-binding globulin. Measurement of total serum thyroxine (TT 4 ) levels do not necessarily reflect the physiologic status of the patient since an increase or diminution in the binding protein concentration will cause a corresponding change in the serum TT 4 level without affecting either the free thyroxine concentration or the euthyroid state. These same binding-protein changes produce an opposite effect on another test of thyroid function, the triiodothyronine (resin, red blood cell [RBC], or surface adsorbent) uptake test (T 3 uptake). In this test, the free protein-binding sites of the serum compete in the test tube with resin (or RBCs or adsorbent) for added

• Ketoconazole, a new oral drug used to treat systemic and superficial mycoses, inhibits sterol synthesis in fungi. The development of gynecomastia in two patients prompted us to investigate the effect of the drug on testosterone production. After a 200-, 400-, or 600-mg dose, volunteer male testosterone serum concentrations fell markedly, but returned toward baseline eight to 24 hours later as ketoconazole serum concentrations waned. A marked but transient drop in testosterone levels occurred in patients receiving long-term therapy, and continuous testosterone depression was noted in one. A block of synthesis was demonstrated in vitro. Ketoconazole at concentrations achievable in serum with currently used doses blocked basal and gonadotropin-stimulated testosterone production by rat Leydig cells. The diminution of testosterone synthesis could be significant as further therapeutic trials may use larger doses or more than once-daily administration. The paucity of reports of endocrinologic toxicity may relate to the "escape" from the block demonstrated in vivo. (Arch Intern Med1982;142:2137-2140)

Telemetric activity recordings were obtained during predrug base line and drug treatment periods in a group of 11 hospitalized depressives in order to assess whether there are specific psychomotor activity patterns in particular types of affective illness and whether the amount of psychomotor activity on admission has any diagnostic or prognostic value. Seven unipolar depressives and four bipolar (manic depressive) depressed patients were studied. Results indicate that unipolar patients exhibit significantly more psychomotor activity prior to treatment than do bipolar depressives and that as each group improves clinically, these differences disappear. When unipolar patients do not improve, their telemetric activity levels do not diminish, whereas a statistically significant diminution in activity levels occurs in the improved unipolar patients.

In Reply .—We read with interest the letter from Neuvonen and Kivisto commenting on our case observation on the use of cholestyramine in the treatment of digoxin intoxication. 1 They raised concern about our digoxin half-life calculation during treatment with cholestyramine. While it may have been optimal to have several serum concentrations to determine the half-life, our main point in presenting this information was the fact that concurrent to the administration of cholestyramine there was a dramatic diminution of the signs and symptoms of digoxin toxicity validating the rapid fall in serum digoxin concentrations secondary to enhanced clearance with cholestyramine therapy. The patient had displayed elevated digoxin concentrations and signs and symptoms of toxic side effects for the four previous days of his admission. Furthermore, there is no reason to believe that the digoxin volume of distribution would have independently and dramatically changed for no apparent reason temporally with the

Considerable erythrocytosis was noted in six patients with parenchymal renal disease. Kidney biopsies performed in four patients revealed focal sclerosing glomerulonephritis in two and chronic vascular changes with interstitial scarring in two others. The remaining two patients had heavy proteinuria suggestive of glomerular involvement. No known causes of secondary erythrocytosis were found. The findings in these patients as a group did not fit the criteria for polycythemia vera. Three patients who progressed to chronic renal failure had diminution of erythrocytosis. It is concluded that parenchymal renal disease, primarily of a glomerular or vascular type may provoke erythrocytosis. Explanations of the pathogenetic mechanism for this association remain speculative.

After 20 years of undeserved neglect, nitroglycerin ointment is now coming into its own. The need for it is obvious. Sublingually administered nitroglycerin, with its fleeting effect, is inadequate for unstable nocturnal or variant angina. Long-acting nitroglycerin preparations for oral administration lose much of their effectiveness through inactivation of nitrate in the liver. In bypassing the portal circulation, nitroglycerin ointment offers a logical alternative. That the alternative is also practical has been confirmed by recent clinical trials. Reichek and associates 1 reported gratifying subjective and objective results with the use of this ointment. Not only was angina forestalled in the 14 patients they studied, but there was a substantial enhancement of exercise capacity, lowering of systolic blood pressure, increase in heart rate, and diminution of exerciseinduced ST segment depression. These effects, which lasted three to five hours, were undiminished after a three-month trial in six of these patients. No evidence

• Nine patients with acquired cold urticaria were studied to assess the effects of β-adrenergic agents, xanthines, and corticosteroids on cold-evoked histamine release from skin in vivo. The patients, in all of whom an immediate urticarial response developed after cooling of the forearm, demonstrated release of histamine into the venous blood draining that forearm. Following treatment with aminophylline and albuterol in combination or prednisone alone, suppression of histamine release occurred in all but one patient. In some patients, this was accompanied by a subjective diminution in pruritus or burning, but there was no significant improvement in the ensuing edema or erythema. In one patient, total suppression of histamine release was achieved without any effect on whealing and erythema in response to cold challenge. Our results suggest that histamine is not central to the pathogenesis of vascular changes in acquired cold urticaria. ( Arch Dermatol 116:174-177, 1980)

The first recorded utilization of the x -ray for the treatment of leukemia was by Pusey, 1 who observed no effect whatever in a case of the splenomyelogenic type, but in one of the lymphatic type he noticed a marked diminution in the size of the glands. More recently a fresh interest in the subject has been aroused by the favorable reports of Senn, 2 Brown 3 and others. 4 In all we have seen reports of 11 cases of well-verified leukemia treated in this way. All but one of these belonged to the splenomyelogenic type. In every instance the splenic tumor decreased in size, in 3 cases becoming barely palpable. The leucocytes in all cases excepting Pusey's diminished in number. Four reporters record a white count under 10,000, with entire disappearance of the myelocytes. An improvement in the hemoglobin and red corpuscles always took place, but was

The pathologic physiology of bronchial asthma is manifested by an edema of the mucous membranes and a spasm of the smooth muscle of the bronchi and bronchioles. The air passages become closed, and owing to this closure, there is subsequent difficulty in breathing, particularly in expiration. As a result of prolonged and frequent attacks of this type of dyspnea, the lungs become distended and emphysema supervenes. In the latter condition, the alveoli are distended, causing a flattening of the alveolar wall with consequent narrowing, tearing and even destruction of the capillaries, which results in diminution of alveolar circulation and increased pressure within the pulmonary arteries. Theoretically, this should result in increased work for the right ventricle. This assumption seems to be borne out by Kahn,1who concluded from an electrocardiographic study of fifty cases of bronchial asthma that the majority of his patients demonstrated a state of hypertrophy of

To the Editor:— Clinical experience with any new drug substantiates the fact that physicians must remain alert to any unusual adverse reaction. Recent studies suggest that some cases of idiopathic retroperitoneal fibrosis may be produced by the long-term ingestion of methysergide maleate (Sansert). 1-5 The present communication reports a case in which this drug apparently produced a reversible vasculitis involving the iliac vessels with secondary ureteral obstruction, bilateral hydronephrosis, and diminution of renal function. Report of a Case: A 43-year-old white woman was seen on June 9, 1966, for a nontraumatic, painful swelling of the left foot and ankle. This had been present for approximately five weeks and had not responded to conservative treatment by another physician. X-ray and physical examination revealed no other abnormalities. During the following weeks, progressive intermittent chest and left arm pain developed, similar to angina, in addition to abdominal and back discomfort, and finally, urgency

Although infectious mononucleosis is usually a relatively benign disease, complications sometimes occur. Skin eruption, hepatitis, splenic rupture, myocarditis, pulmonary infiltration, central nervous system involvement, hemolytic anemia, and thrombocytopenia have all been reported. Splenic rupture has probably been the most frequent fatal complication. Thrombocytopenic purpura is one of the most uncommon complications, but due to the potential danger of cerebral and other hemorrhage and because of the favorable response to treatment it is important to recognize the condition early. In reported cases 1-6 with only symptomatic treatment thrombocytopenia persisted up to 14 days before spontaneous recovery. In the single reported case treated with adrenocorticotropin 7 recovery was much more rapid. Adrenocorticotropin or cortisone has been used in toxic cases of infectious mononucleosis without thrombocytopenia 8-11 with good results. Typical response was disappearance of fever and increase in strength and appetite, all within 12 hours, and rapid diminution in size of liver

To the Editor: —The case report inThe JournalMay 15, 1954, page 252, by Grant and Leopold, of Guillain-Barre syndrome occurring during cortisone therapy was of extreme interest and importance. The report indicates that resumption of cortisone (100 mg. daily) and later hydrocortisone (60 mg. daily) may have been a factor in the improvement that occurred after the second week. From my own experience with two cases and from the reported experience of others, it appears that large doses (200 to 400 mg.) of cortisone are necessary to relieve paralysis and that treatment must be continued throughout the period during which symptoms would be expected to endure. Premature diminution or cessation of cortisone administration has been responsible for severe relapses. Rather than curing the Guillain-Barre syndrome, cortisone appears to keep paralysis in abeyance until the episode runs its course. For the stated reasons, it is not too surprising that

In a previous paper Darrow and Gellhorn1showed that epinephrine in physiologic concentrations produces inhibitory effects on both branches of the autonomic nervous system. It was shown that in the presence of epinephrine the sympathetic responses of the pupil, blood pressure, nictitating membrane and foot pads (galvanic reactions) are reduced, and that the responses involving inhibition of the parasympathetic constrictor tonus of the sympathectomized eye are increased. The close association of sympathetic discharges with convulsions produced by insulin (Gellhorn2) and metrazol (Gellhorn and Darrow3) made it desirable to investigate whether the inhibitory effects of epinephrine extend to the somatic nervous system and lead to diminution or suppression of the convulsions. Such an investigation is particularly indicated because of the report by Hall and Leibel4that epinephrine increases metrazol convulsions and the finding of Schweitzer and Wright5that it inhibits the knee jerk. METHODS Insulin and

To the Editor:— Since the report by Edith Paterson and her co-workers (Lancet1:677 [May 11] 1946) on the remarkable effect of urethane in the treatment of leukemia, the validity of this observation has been confirmed by a number of workers in this country (personal communications) and in our own clinic. The British investigators noted, however, that other forms of malignant neoplasia were not appreciably affected by the drug. In 3 of 13 cases of advanced carcinoma of the breast and in 4 of 11 other forms of malignant disease the tumor masses underwent only temporary diminution in size. We have recently observed a man aged 44 who in June 1946 observed the generalized appearance of multiple skin tumors which in the next three months increased rapidly in size and number. When he first came under our observation he was covered with hard tender skin nodules which varied in

To the Editor:— Dr. Wishnofsky is correct in that "wear-and-tear protein" is not scientific terminology but rather a figure of speech, and the amount of protein does not refer to an irreducible minimum with a diet which contains any protein. Gamble showed in studies of a week's duration that the protein-sparing action of more than 100 gm. of carbohydrate was negligible. However, Kolff found that after 12 to 20 days on a Borst diet, patients did have a slow reduction in nitrogen excretion, indicating a diminution in protein breakdown and an increase in protein-sparing action (probably mostly by carbohydrate) beyond the amount found by Gamble in his short-term experiments. A proteinfree diet, as Doctor Wishnofsky points out, would be of value in cases ofacuterenal failure but not in chronic cases, except in brief acute exacerbations.

It has long been recognized that in certain cases of obstructive jaundice there is a tendency to hemorrhage due to the delayed coagulation of the blood. Morawitz and Bierich 1 studied the causes of bleeding in cholemia and came to the conclusion that the altered coagulation time in these cases could be traced to delayed formation of fibrin ferment. They attributed this delay to a diminution or absence of thrombokinase. They believed that the altered coagulation time was not due to the presence of cholates or biliary acids in the blood and was independent of the duration or intensity of the jaundice. Kunika 2 investigated the clinical value of the determination of the coagulation time in cases of icterus and concluded that the delay was due to a decrease in the liver function. King and Stewart, 3 in the course of an investigation of the cause of

To the Editor.— Lerner discovered melatonin (N-Acetyl-5-methoxytryptamine)1and showed that this pineal hormone can induce sedation in man.2This agent antagonizes the darkening of the skin and, therefore, perhaps also some other action of melanophore-stimulating hormone (βMSH).3Since injections of βMSH had aggravated the tremor of parkinsonism,4we had administered this antagonist of βMSH to a patient but induced only a diminution of tremor.3Others, however, reported impressive improvement of several symptoms of parkinsonism5at a time when we had reversed the adventitious movements caused by levodopa [3-(3, 4-dihydroxyphenyl)-L-alanine] with melatonin in experimental animals.6We conducted therefore a single-blind study in patients with parkinsonism who received either melatonin alone or melatonin plus levodopa, which had caused intermittent adventitious movements.7 The inpatients listed in the Table and all of the outpatients had idiopathic parkinsonism except patient 11 who had postencephalitic disease. Among

The use of benzol (benzene, C6H6), as a medicinal agent was suggested by the observations of Selling,1who studied its influence in the anemia of certain factory-girls whose occupation led to the inhalation of banzol gas. His subsequent experimental work on animals showed that benzol caused, first, a marked reduction in the white blood-cells, and later a diminution in the red blood-cells. Examination of the tissues of animals thus poisoned indicated a selective action on the bone-marrow. Von Koranyi2was the first to make practical use of those observations. Stimulated by Selling's work, he administered benzol to a patient with splenomyelogenous leukemia and produced a remarkable fall in the leukocyte-count as well as reduction in the size of the spleen and improvement in the patient's general condition. He recommends its use in leukemia and also suggested that it might be of value in polycythemia. Numerous

As far as can be determined, convincing evidence of bronchial asthma as a manifestation of sulfonamide sensitivity has not been described, although it has been mentioned in this respect. 1 We report 2 cases, each with a history of asthma following the ingestion of a sulfonamide drug. In 1 instance the trial ingestion of sulfathiazole produced a severe paroxysm of asthma; in the second case the trial ingestion of sulfadiazine, although not producing clinical asthma, resulted in a definite diminution in the vital capacity. Case 1.— F. F., a man aged 44, a metal worker, was admitted to the University Hospital in status asthmaticus Sept. 21, 1943. The history as obtained from the patient and his local physician revealed that seven days prior to admission he had sought advice regarding a chronic nasal infection, presumably resulting from plucking nasal hairs. Large white tablets were prescribed with instructions to take two