Graduate Hospital

BACKGROUND: The authors designed a prospective longitudinal study to investigate the hypothesis that advancing age is a risk factor for postoperative cognitive dysfunction (POCD) after major noncardiac surgery and the impact of POCD on mortality in the first year after surgery. METHODS: One thousand sixty-four patients aged 18 yr or older completed neuropsychological tests before surgery, at hospital discharge, and 3 months after surgery. Patients were categorized as young (18-39 yr), middle-aged (40-59 yr), or elderly (60 yr or older). At 1 yr after surgery, patients were contacted to determine their survival status. RESULTS: At hospital discharge, POCD was present in 117 (36.6%) young, 112 (30.4%) middle-aged, and 138 (41.4%) elderly patients. There was a significant difference between all age groups and the age-matched control subjects (P < 0.001). At 3 months after surgery, POCD was present in 16 (5.7%) young, 19 (5.6%) middle-aged, and 39 (12.7%) elderly patients. At this time point, the prevalence of cognitive dysfunction was similar between age-matched controls and young and middle-aged patients but significantly higher in elderly patients compared to elderly control subjects (P < 0.001). The independent risk factors for POCD at 3 months after surgery were increasing age, lower educational level, a history of previous cerebral vascular accident with no residual impairment, and POCD at hospital discharge. Patients with POCD at hospital discharge were more likely to die in the first 3 months after surgery (P = 0.02). Likewise, patients who had POCD at both hospital discharge and 3 months after surgery were more likely to die in the first year after surgery (P = 0.02). CONCLUSIONS: Cognitive dysfunction is common in adult patients of all ages at hospital discharge after major noncardiac surgery, but only the elderly (aged 60 yr or older) are at significant risk for long-term cognitive problems. Patients with POCD are at an increased risk of death in the first year after surgery.

Abstract In order to more precisely define a syndrome of medial temporal lobe epilepsy, histories and physical findings were evaluated in 67 patients studied with intracranial electrodes who had medial temporal seizure onset and became seizure free following temporal lobectomy. Patients with circumscribed, potentially epileptogenic mass lesions were excluded. Fifty‐four patients (81%) had histories of convulsions during early childhood or infancy, 52 of which were associated with fever. Complicated febrile seizures occurred in 33 (94%) of the 35 patients in whom detailed descriptions of the febrile seizures were available. Bacterial (5) or viral (2) central nervous system infections were present in 7 patients with seizures and fevers. Other less common, but probably significant, risk factors included head trauma (10%) and birth trauma (3%). Only 5 patients had no apparent risk factors. The mean age at habitual seizure onset was 9 years. All patients had complex partial seizures, with half having only complex partial seizures. The other half also had secondarily generalized tonic‐clonic seizures, but these were never the predominant seizure type. Only 3 patients had histories of convulsive status epilepticus and no patient had a history of nonconvulsive status epilepticus. All but 3 patients reported auras before some or all of their seizures, with an abdominal visceral sensation being by far the most common type of aura (61%). Of the 60 patients with identified risk factors, all but 2 had an interval between the presumed cerebral insult and the development of habitual seizures, with a mean seizure‐free interval of 7.5 years. Fifteen patients developed a seizure‐free interval following onset of habitual seizures, with a mean duration of 5.9 years. In 22 patients, the seizures had an evolutionary pattern, with seizures becoming progressively more elaborate over time. We conclude (1) there is a very strong relationship between complicated febrile seizures during early childhood or infancy and the later development of medial temporal lobe epilepsy; (2) habitual seizures in most patients from this population begin during, or shortly after, the first decade of life; (3) complex partial seizures are seen in all such patients; (4) generalized tonic‐clonic seizures are not a predominant seizure type in these patients, and convulsive status epilepticus in uncommon; (5) nonconvulsive status epilepticus rarely, if ever, occurs in these patients; (6) auras, particularly abdominal visceral sensations, are very common; and (7) medial temporal lobe epilepsy can be a progressive disease as evidenced by silent intervals and progressive elaboration of seizures.

Abstract In this clinical study, the cerebrospinal fluid (CSF) level of a Novemberel form of the β‐amyloid peptide (Aβ) extending to position 42 (Aβ 42 ) was determined in patients with Alzheimer's disease (AD) as well as controls. In addition to measurement of CSF Aβ 42 levels, total Aβ peptides, microtubule‐associated protein τ, and apolipoprotein E (ApoE) genotype were also assessed. It is interesting that CSF Aβ 42 levels were found to be significantly lower in AD patients relative to controls, whereas total Aβ levels were not. Aβ 42 has recently been shown to preferentially deposit in the brain tissue of patients with AD, suggesting that diminished clearance may account for its reduction in CSF. As previously reported, τ levels were increased in AD patients; however, neither Aβ 42 nor τ levels were apparently influenced by the ApoE genotype.

PURPOSE: The lack of a precise working definition of interstitial cystitis may have resulted in the de facto use of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) "research" definition by clinicians. We evaluated these strict criteria in light of the broader inclusion criteria for patients evaluated in the Interstitial Cystitis Database study to determine their utility in clinical practice as a useful basis for the diagnosis of interstitial cystitis. MATERIALS AND METHODS: A total of 379 women who completed screening for the Interstitial Cystitis Database before January 1, 1996 met the basic criteria of urinary frequency, urgency or pain for at least 6 months in duration without a diagnosable etiology. Of these patients 148 underwent cystoscopy and hydrodistention of the bladder as a part of the evaluation. All patients were followed for a minimum of 1 year. Comparisons were made between patients judged to have a clinical diagnosis of interstitial cystitis and those who met the NIDDK research definition of the syndrome. RESULTS: Almost 90% of patients potentially meeting NIDDK criteria are believed by experienced clinicians to have interstitial cystitis, confirming the research value of these criteria in defining a homogeneous population for study. However, strict application of NIDDK criteria would have misdiagnosed more than 60% of patients regarded by researchers as definitely or likely to have interstitial cystitis. CONCLUSIONS: The NIDDK criteria are too restrictive to be used by clinicians as the diagnostic definition of interstitial cystitis.

Sixty-seven patients with temporal lobe epilepsy without circumscribed, potentially epileptogenic lesions, who were studied with intracranial electrodes and who became seizure free following temporal lobectomy were retrospectively evaluated with regard to preoperative scalp electroencephalographic (EEG) findings, neuropsychological test results, neuroimaging findings, results of surgery, and pathology of resected tissue. Interictal scalp EEG showed paroxysmal abnormalities during prolonged monitoring in 64 patients (96%). These were localized in the anterior temporal region in 60 (94%) of these 64 patients. Bilateral independent paroxysmal activity occurred in 42% of the patients and was preponderant over the side of seizure origin in half. Ictal EEG changes were rarely detected at the time of clinical seizure onset, but lateralized buildup of rhythmic seizure activity during the seizure occurred in 80% of patients. In 13%, the scalp EEG seizure buildup was, however, contralateral to the side of seizure origin as subsequently determined by depth EEG and curative surgery. Lateralized postictal slowing, when present, was a very reliable lateralizing finding. Neuropsychological testing provided lateralizing findings concordant with the side of seizure origin in 73% of patients. When neuropsychological testing produced discordant results or nonlateralizing findings, those patients were usually found to have right temporal seizure origin. Intracarotid amobarbital (Amytal) testing demonstrated absent or marginal memory functions on the side of seizure onset in 63% of patients, but 26 patients (37%) had bilaterally intact memory. In those patients who had magnetic resonance imaging, it was very sensitive in detecting subtle medial temporal abnormalities. These abnormalities were present in 23 of 28 magnetic resonance images, and corresponded with mesial temporal sclerosis on pathological examination in all but 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVES: Proton pump inhibitors owe their clinical efficacy to their ability to suppress gastric acid production. The objective of this study was to evaluate and compare intragastric pH following standard doses of esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole. METHODS: This randomized, open-label, comparative five-way crossover study evaluated the 24-h intragastric pH profile of oral esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, and rabeprazole 20 mg once daily in 34 Helicobacter pylori-negative patients aged 18-60 yr with symptoms of gastroesophageal reflux disease. Patients were randomly assigned to one of five treatment sequences and study drug was taken on 5 consecutive mornings 30 minutes prior to a standardized breakfast. A washout period of at least 10 days separated each treatment phase. RESULTS: Thirty-four patients provided evaluable data for all five comparators. The mean number of hours of evaluable pH data was > or =23.75 hours. On day 5, intragastric pH was maintained above 4.0 for a mean of 14.0 h with esomeprazole, 12.1 h with rabeprazole, 11.8 h with omeprazole, 11.5 h with lansoprazole, and 10.1 h with pantoprazole (p < or = 0.001 for differences between esomeprazole and all other comparators). Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 4.0 for more than 12 h relative to the other proton pump inhibitors (p < 0.05). The frequency of adverse events was similar between treatment groups. CONCLUSIONS: Esomeprazole at the standard dose of 40 mg once daily provided more effective control of gastric acid at steady state than standard doses of lansoprazole, omeprazole, pantoprazole, and rabeprazole in patients with symptoms of gastroesophageal reflux disease.

BACKGROUND: The prognosis for patients with locally advanced carcinoma of the breast remains poor. This study examines the pathologic evidence of response of the mammary tumor and axillary nodes after preoperative chemotherapy. We sought to determine if there was a relationship between the histologic response and clinical outcome. STUDY DESIGN: Between 1987 and 1992, 36 patients with locally advanced carcinoma of the breast received three cycles of chemotherapy after incisional biopsy. Modified radical mastectomy was then performed. The breast and axillary nodes were examined pathologically for therapeutic effect and a grading scale was assigned. Postoperatively, patients received completion chemotherapy with the same agents used preoperatively followed by radiation therapy to the chest wall. RESULTS: Fourteen tumors (39 percent) showed near total therapeutic effect, five (14 percent) showed greater than 50 percent but less than total effect, 12 (33 percent) showed less than 50 percent effect, and five (14 percent) showed no effect. Nodal positivity was seen in 61 percent of the patients. Overall clinical response to induction chemotherapy was seen in 86 percent of the patients. There was poor correlation between clinical and pathologic response. Only 50 percent of the patients with complete clinical response were pathologically free of disease. Patients with excellent pathologic therapeutic response had a 79 percent overall five-year survival rate compared with 34 percent for tumors with a lesser response. This was irrespective of nodal status. While pathologic response was critical in determining outcome, clinical response was not. CONCLUSIONS: These results indicate that patients whose tumors have the best pathologic response to induction chemotherapy experience the best outcome.

BACKGROUND: Omeprazole controls acid but not non-acid reflux. The GABA B agonist baclofen decreases acid reflux through the inhibition of transient lower oesophageal sphincter relaxations (TLESRs) and should similarly decrease non-acid reflux. Using combined multichannel intraluminal impedance and pH (MII/pH), we compared acid and non-acid reflux after placebo and baclofen. METHODS: Nine healthy volunteers and nine heartburn patients underwent two 2-h studies of combined MII/pH in right lateral decubitus after a refluxogenic meal in random order: on placebo and after baclofen 40 mg p.o. Tracings were analysed for acid and non-acid reflux episodes, re-reflux and symptoms in the heartburn patients. RESULTS: In normal subjects baclofen significantly reduced the median number of episodes of acid (7 vs. 1, P = 0.02), non-acid (2 vs. 0, P = 0.005), and all reflux combined (10 vs. 2, P = 0.006); re-reflux was not reduced (0 vs. 0, P = N.S.). In heartburn patients, baclofen significantly decreased the median number of episodes of acid (15 vs. 6, P = 0.004), non-acid (4 vs. 2, P = 0.003), re-reflux (2 vs. 0, P = 0.02), and all reflux combined (23 vs. 8, P = 0.004); it also reduced the median number of acid-related (9 vs. 1, P = 0.008) and non-acid-related (1 vs. 0, P = 0.04) symptoms. CONCLUSIONS: Baclofen reduces post-prandial acid and non-acid reflux and their associated symptoms. GABA B agonists may have a role in treating GERD.

Cerebrospinal fluid from 70 patients with Alzheimer's disease (AD) and 96 patients with non-AD neurological diseases as well as 19 normal control subjects was surveyed by sandwich enzyme-linked immunosorbent assay to quantitate levels of the microtubule-associated protein tau in cerebrospinal fluid. The tau level was significantly increased in AD patients as compared with that in patients with non-AD neurological diseases and control subjects. Increased tau levels were found irrespective of age at onset, apolipoprotein E genotype, and clinical stage. Western blots of AD cerebrospinal fluid proteins revealed two to three tau-immunoreactive bands with an apparent molecular mass between 50 and 65 kd consistent with phosphorylated cerebrospinal fluid tau. Taken together, our results suggest that cerebrospinal fluid tau might reflect the progressive accumulation of altered tau due to the progressive death of neurons in the AD brain, and that the enzyme-linked immunosorbent assay of cerebrospinal fluid tau may prove to be a reliable and early diagnostic test for AD.

OBJECTIVE: To examine the long-term effectiveness of anterior temporal lobectomy for refractory epilepsy with regard to seizure control and related medical and psychosocial measures and to determine how patterns of early seizure recurrence relate to long-term prognosis. DESIGN: A cohort of patients prospectively followed up for 5 years after surgery. SETTING: Tertiary care comprehensive epilepsy center. PATIENTS: Eighty-nine patients with medically refractory epilepsy who were consecutively treated with anterior temporal lobectomy between 1986 and 1990. All patients had noninvasive preoperative evaluations, and 31 were evaluated with intracranial electrodes prior to surgery. MAIN OUTCOME MEASURES: Postoperative seizure frequency, neuropsychologic function, mortality, and postoperative employment status. RESULTS: Five years after surgery, 62 patients (70 percent) were seizure free, 8 (9 percent) had seizures on fewer than 3 days per year or exclusively had nocturnal seizures, 10 (11 percent) had greater than 80 percent reduction in seizure frequency, 5 (6 percent) had less than 80 percent reduction in seizure frequency, and 4 (4 percent) died of causes unrelated to surgery. The proportion of patients in each outcome class remained stable throughout the 5-year period. Fifty-five percent of seizure recurrences happened within 6 months of surgery, and 93 percent occurred within 2 years after surgery. Outcome at 1 year related only moderately well to outcome at 5 years. No significant cognitive or linguistic deficits occurred. All patients who died had persistent seizures after surgery. Underemployment and unemployment declined significantly after surgery, with improvement noted in seizure-free patients. CONCLUSIONS: Temporal lobectomy provides sustained seizure relief over 5 years to most patients who have surgery. Outcome at 2 years predicts long-term outcome. A seizure-free state is associated with reduced mortality and increased employment. Mere reduction in seizure frequency is not associated with improvement in those measures.

Abstract Part I. I. Introduction. The data contained in this paper are collected from the histories of 621 cases of human protein sensitization observed during the past five years and summarized in the protocol herewith published. We were stimulated to this work as the result of a personal experience of one of us in the fall of 1910 with the realities and the possibilities of the protein reaction in sensitized individuals,—both its immediate dangers as well as its ultimate beneficial effect. While not all of the histories cover all of the points discussed throughout the paper, extreme care has been used in eliciting them and only definite and positive facts are included. Any error, therefore, and errors undoubtedly do exist, is due rather to a lack of knowledge on the part of the patient and would appear on the negative rather than on the positive side in our statistics.

Machado-Joseph disease (MJD) is one of at least six neurodegenerative diseases caused by expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. To study the molecular mechanism of disease, we isolated both normal and expanded repeat MJD1 cDNAs, and generated antiserum against the recombinant gene product, called ataxin-3. Using this antiserum, we demonstrate that in disease tissue, both the normal and mutant ataxin-3 protein are expressed throughout the body and in all regions of the brain examined, including areas generally spared by disease. In brain, certain regions (the striatum, for example) express ataxin-3 in only a limited subset of neurons. Immunolocalization studies in normal and disease brain, and in transfected cells, indicate that ataxin-3 is predominantly a cytoplasmic protein that localizes to neuronal processes as well. We conclude that in MJD, as in other polyglutamine repeat diseases, cellular expression of the disease gene is not itself sufficient to cause neuronal degeneration; other cell-specific factors must be invoked to explain the restricted neuropathology seen in MJD. The restricted expression of ataxin-3 in certain regions, however, may influence the pattern of neurodegeneration and provide clues to the protein's function.

It is generally accepted that glutamate serves as the neurotransmitter at most excitatory synapses in the mammalian central nervous system (CNS). Synaptic release of glutamate may trigger a fast and a slow excitatory postsynaptic current (EPSC). The slow EPSC is mediated by N-methyl-D-aspartate (NMDA) receptor channels, whereas the fast EPSC is mediated by non-NMDA receptor channels. The nootropic agent aniracetam selectively and reversibly slows the desensitization kinetics of non-NMDA channels and lengthens their single-channel open times. Antiracetam also modulates the kinetics of the fast EPSC in a manner that mirrors its action on the kinetics of the non-NMDA channels. These results support the hypothesis that the properties of the non-NMDA glutamate channels rather than the rate of neurotransmitter clearance are the primary determinants of the kinetics of the fast EPSC in the mammalian CNS.

Abstract 1.1. A new method for the measurement of ammonia in blood, erythrocytes, plasma, or other labile biologic systems has been described. 2.2. Conditions which produce falsely high or low values encountered in other methods are avoided. 3.3. The ammonia found in freshly drawn human venous blood is believed to be preformed true ammonia, present as ammonium ions and not an artifact. 4.4. The ammonia content of blood, erythrocytes, and plasma in 29 patients free of liver disease is reported. 5.5. Ammonia in erythrocytes is 2.8 times that found in plasma.

Components of the extracellular matrix (ECM) can regulate leukocyte activation and function at inflammatory sites. Low molecular weight fragments of the ECM glycosaminoglycan hyaluronan (LMW-HA) that accumulate in inflammation, but not the ubiquitous high molecular weight form of HA (HMW-HA), have been shown to induce cytokine and/or chemokine production by alveolar and bone-marrow derived macrophages. To determine the cellular requirements for responsiveness to HA, we compared the effects of HMW-HA and LMW-HA on resident and thioglycollate-elicited murine peritoneal macrophages. We demonstrate that treatment of elicited macrophages with LMW-HA, but not with HMW-HA, stimulated production of the chemokines RANTES and macrophage inflammatory protein-1alpha and -1beta. Further, we demonstrate that LMW-HA induced the production of biologically active IL-12, a proinflammatory cytokine not previously known to be regulated by cell-matrix interactions. The LMW-HA-induced production of IL-12 by elicited macrophages was inhibited by an anti-CD44 mAb that blocks HA binding. In contrast to elicited macrophages, freshly explanted resident peritoneal macrophages did not respond to LMW-HA. However, preculture in vitro before stimulation led to adhesion-dependent priming for LMW-HA-induced cytokine and chemokine production by resident macrophages. These results provide further evidence of the potential importance of CD44/LMW-HA interactions in regulating the immune response at sites of inflammation and demonstrate that the state of differentiation of macrophages may determine their sensitivities to matrix components.

Glutamate activates a number of different receptor-channel complexes, each of which may contribute to generation of excitatory postsynaptic potentials in the mammalian central nervous system. The rapid application of the selective glutamate agonist, quisqualate, activates a large rapidly inactivating current (3 to 8 milliseconds), which is mediated by a neuronal ionic channel with high unitary conductance (35 picosiemens). The current through this channel shows pharmacologic characteristics similar to those observed for the fast excitatory postsynaptic current (EPSC); it reverses near 0 millivolts and shows no significant voltage dependence. The amplitude of the current through this channel is many times larger than that through the other non-NMDA (N-methyl-D-aspartate) channels. These results suggest that this high-conductance quisqualate-activated channel may mediate the fast EPSC in the mammalian central nervous system.

Although it is well known that many second language (L2) learners have trouble using articles “properly,” the primary causes of their difficulties remain unclear. This study addresses this problem by examining the metalinguistic knowledge of the English article system that learners employ when selecting articles in a given situation. By doing this, the present study attempts to better understand the process of “making sense” of the English article system by learners who are at different stages in their interlanguage development. Eighty Japanese college students with varying levels of English proficiency participated in this study. Immediately after completing a fill-in-the-article test, a structured interview was conducted to investigate the reasons for their article choices. The quantitative and qualitative analyses reveal a number of conceptual differences with regard to their considerations of the hearer's knowledge, specific reference, and countability, which may account for learners' errors in article use across different proficiency groups.

In a review of arteriograms of 72 unselected consecutive cases of pancreatitis, seven patients were found to have arterial aneurysms involving branches of the peripancreatic vessels. During the same period, arteriograms of 84 cases of carcinoma of the pancreas were reviewed and no aneurysms of any of these vessels were found. The demonstration of aneurysms of the peripancreatic arteries in pancreatitis is an important differential feature from carcinoma of the pancreas. Both carcinoma of the pancreas and chronic pancreatitis can cause encasement of the arterial vessels and obstruction of the splenic or the superior mesenteric vein, therefore resulting in a similar angiographic appearance. Thus an aneurysm seen in such a patient is a helpful distinguishing feature. In addition, these aneurysms are an important source of hemorrhage and mortality in pancreatitis.

OBJECTIVE: Patients with Barrett's metaplasia of the esophagus often lack the appropriate amount of heartburn for their severity of gastroesophageal reflux. Therefore, we studied patients with Barrett's metaplasia by prolonged ambulatory pH monitoring after completely suppressing their heartburn symptoms to determine whether acid reflux was underestimated in symptom assessment. METHODS: Five patients with Barrett's esophagus, all of whom presented with heartburn, were treated with omeprazole (20-60 mg/day) until they were asymptomatic. Twenty-four-hour pH ambulatory monitoring was performed while they were on omeprazole. RESULTS: Four of five patients showed persistent abnormal gastroesophageal reflux after treatment with omeprazole. Two patients showed abnormally increased supine reflux and two patients had an abnormal increase in both supine and upright reflux. Only one patient had complete inhibition of the acid reflux by the omeprazole (20 mg b.i.d.). CONCLUSIONS: Treating the patient with Barrett's esophagus to the endpoint of eradication of heartburn does not insure adequate control of acid reflux. Prolonged ambulatory pH monitoring of the esophagus should be conducted to demonstrate that an adequate dose of omeprazole has been given, despite symptomatic improvement.

OBJECTIVE: To assess the clinical efficacy and side effects of gammalinolenic acid, a plant-seed-derived essential fatty acid that suppresses inflammation and joint tissue injury in animal models. DESIGN: A randomized, double-blind, placebo-controlled, 24-week trial. SETTING: Rheumatology clinic of a university hospital. PATIENTS: Thirty-seven patients with rheumatoid arthritis and active synovitis. INTERVENTION: Treatment with 1.4 g/d gammalinolenic acid in borage seed oil or cotton seed oil (placebo). MEASUREMENTS: Physicians' and patients' global assessment of disease activity; joint tenderness, joint swelling, morning stiffness, grip strength, and ability to do daily activities. RESULTS: Treatment with gammalinolenic acid resulted in clinically important reduction in the signs and symptoms of disease activity in patients with rheumatoid arthritis (P < 0.05). In contrast, patients given a placebo showed no change or showed worsening of disease. Gammalinolenic acid reduced the number of tender joints by 36%, the tender joint score by 45%, swollen joint count by 28%, and the swollen joint score by 41%, whereas the placebo group did not show significant improvement in any measure. Overall clinical responses (significant change in four measures) were also better in the treatment group (P < 0.05). No patients withdrew from gammalinolenic acid treatment because of adverse reactions. CONCLUSION: Gammalinolenic acid in doses used in this study is a well-tolerated and effective treatment for active rheumatoid arthritis. Gammalinolenic acid is available worldwide as a component of evening primrose and borage seed oils. It is usually taken in far lower doses than used in this trial. It is not approved in the United States for the treatment of any condition and should not be viewed as therapy for any disease. Further controlled studies of its use in rheumatoid arthritis are warranted.