Clinical Vignette

The patient, a 69-yr-old man, had seropositive erosive rheumatoidarthritis (RA) diagnosed in 1977. He failed on the conventionaldisease-modifying agents of salazopyrin and methotrexate. Complicationsof Felty's syndrome (splenomegaly, neutropenia) and osteoporosisdeveloped during his disease course. In 1997 he     

Suppression of insulin secretion by falling plasma glucose levels is impaired in type 2 diabetes

The ability of Type 2 diabetic patients to suppress islet B-cell secretion in response to falling plasma glucose levels has been studied with two different protocols. (1) Five diet-treated diabetic patients and 6 normal subjects were studied after the termination of a hyperglycaemic clamp at 15 mmol l-1 for 150 min, with the plasma glucose levels then being allowed to fall and the glucose clamp re-established at 10 mmol l-1. The plasma insulin levels fell in normal subjects from 178 +/- 141 (+/- SD) mU l-1 at the end of the 15 mmol l-1 clamp to 147 +/- 97 mU l-1 (p less than 0.02) 20 min later, whereas in diabetic patients there was no significant change from 61 +/- 41 to 56 +/- 35 mU l-1, respectively (NS). (2) The second study was performed to assess the turn-off of islet B-cell secretion with diabetic patients and normal subjects starting at comparable plasma insulin levels. Twelve diet-treated diabetic patients and 11 normal subjects were given a continuous low-dose glucose infusion for 60 min at a rate of 5 mg kg-1 ideal body weight min-1, after which the infusion was turned off and the plasma glucose level allowed to fall.(ABSTRACT TRUNCATED AT 250 WORDS)     

Health and ill-health in the older population in England and Wales. The Medical Research Council Cognitive Function and Ageing Study (MRC CFAS)

OBJECTIVE: to provide a profile of disorders and disabilities in the older population. DESIGN: the MRC CFAS drew population samples of people aged 64 years and over from Family Health Service Authority lists at five sites and asked participants about sociodemographic variables, physical and cognitive health and activities of daily living, We calculated the prevalence of co-morbidity from the number of different types of complaint or disability (physical, functional and cognitive), and calculated healthy life expectancies in each of these co-morbid states. SETTING: three urban (Newcastle, Nottingham and Oxford) and two rural sites (Cambridgeshire and Gwynedd). RESULTS: the prevalence of morbidity is low at the youngest ages, as is co-morbidity. Women have consistently greater morbidity than men. Morbidity increases sharply with age, with a more dramatic rise in women. Life expectancy without any morbidity is short at all ages over 64, with the number of years expected with two or more areas affected virtually constant up to 90 years. As a proportion of remaining life expectancy, the period of time spent with two or more areas affected rises by the age of 90 to 30% in men and 60% in women. CONCLUSIONS: preventive programmes for the older population should take into account the large differences between the young old, the middle old and the old old. Our study provides a baseline against which to compare future changes in health in older populations, as well as benchmark expectancies for the UK population.     

Surgery in acute leukemia: a review of 167 operations in thrombocytopenic patients

Of 435 consecutive patients with acute leukemia, 95 patients had 167 operations with a platelet count of less than 100 X 10(9)/L and 130 operations with platelet counts of less than 50 X 10(9)/L. Only 7% of operations had intraoperative blood loss of greater than 500 ml, and 7% required greater than 4 units of red cells transfused in the perioperative period. No patient died of bleeding attributable to surgery within 1 month of the operation. Granulocyte count was less than 0.5 X 10(9)/L in 66% of operations with 57% febrile preoperatively. However, no patient developed infection within the surgical field in the postoperative month. Logistic regression analyses were used to assess preoperative factors, which identified those operations at risk for excessive bleeding or postoperative surgical complications. Major (group 1) operations, preoperative fever, and preoperative coagulation abnormalities were associated with operations with an intraoperative blood loss greater than 500 ml and/or perioperative red blood cell RBC transfusions greater than 4 units (P less than .001). Surgery in cytopenic patients with acute leukemia is safe provided optimal supportive care is available.     

A relationship between protein stability and protein function.

Enzymes are thought to use their ordered structures to facilitate catalysis. A corollary of this theory suggests that enzyme residues involved in function are not optimized for stability. We tested this hypothesis by mutating functionally important residues in the active site of T4 lysozyme. Six mutations at two catalytic residues, Glu-11 and Asp-20, abolished or reduced enzymatic activity but increased thermal stability by 0.7-1.7 kcal.mol-1. Nine mutations at two substrate-binding residues, Ser-117 and Asn-132, increased stability by 1.2-2.0 kcal.mol-1, again at the cost of reduced activity. X-ray crystal structures show that the substituted residues complement regions of the protein surface that are used for substrate recognition in the native enzyme. In two of these structures the enzyme undergoes a general conformational change, similar to that seen in an enzyme-product complex. These results support a relationship between stability and function for T4 lysozyme. Other evidence suggests that the relationship is general.     

The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition

CONTEXT: The relationship of reproductive hormones to vasomotor symptoms (VMS) has been incompletely explored, although an increase in such symptoms at midlife and their reduction with hormone therapy suggest a strong and direct relationship. Vasomotor symptoms are reported by 65-76% of women traversing the menopausal transition and are a primary reason for medical intervention during this life stage. OBJECTIVE: The purpose of this report was to relate longitudinal serum concentrations of the reproductive hormones estradiol (E2), FSH, testosterone (T), dehydroepiandrosterone sulfate (DHEAS), and SHBG and the free hormone indices free E2 index (FEI) and free T index (FTI) with the occurrence of VMS in women traversing the menopausal transition. Design and Setting: The Study of Women's Health Across the Nation is a multisite, longitudinal, cohort study of the menopausal transition being conducted in community-based groups of women. PARTICIPANTS AND MAIN OUTCOME MEASURES: At baseline, 3302 menstruating women who belonged to one of five ethnic/racial groups were recruited and followed up with annual visits. Frequencies of symptoms (hot flashes, night sweats) for the prior 2 wk and measures of other covariates as well as potentially confounding variables were self-reported in the annual interview. Serum was obtained annually, on d 2-5 of a spontaneous cycle in cycling women or within 90 d of the anniversary of the baseline study visit in noncycling women and assayed for FSH, E2, T, SHBG, and DHEAS. FTI and FEI were calculated. This analysis incorporated available longitudinal data from 3293 women, excluding information collected at or after first report of hormone therapy use or hysterectomy. Data were analyzed using longitudinal marginal logistic regression models and a partial proportional odds model. RESULTS: After adjusting for age, body mass index, and other related covariates, VMS prevalence increased with higher (log)FSH concentrations, and the increase was greater when blood was drawn more than 5 d after menses began. FSH concentrations were positively associated with the frequency of either hot flashes or night sweats, and higher FSH concentrations were associated with greater odds of reporting more frequent symptoms. Vasomotor symptom prevalence decreased with higher (log)E2, (sqrt)SHBG, and (log)FEI but only when these hormone values were modeled independently of (log)FSH values and the specimens were obtained outside the d 2-5 window. When modeled simultaneously with (log)FSH, (log)E2, (sqrt)SHBG, and (log)FEI were no longer significantly associated with symptom prevalence. (Cubic root)T and (sqrt)DHEAS concentrations and (log)FTI were not associated with the prevalence of VMS. CONCLUSIONS: Annual serum FSH concentrations, but not E2, T, DHEAS, FTI, or FEI when collectively modeled longitudinally, are associated with both the prevalence and frequency of VMS in women at midlife.     

Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative regimens and analysis of prognostic factors

From 1990 to 1993 we performed a prospective study of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 30 patients with refractory anemia (RA) undergoing related (n = 17) or unrelated (n = 13) donor marrow transplantation. Nineteen patients survive disease free (63% 3- year actuarial disease-free survival [DFS]) and no patient relapsed. These results were compared to those of 38 historical controls with RA treated with cyclophosphamide and total body irradiation, of whom 22 are disease-free survivors and 1 relapsed. After correcting for significant variables between the two treatment groups, we found no statistically significant difference in outcome based on preparative regimen. Combining data from these 68 patients plus 2 additional patients with RA treated before 1993 with busulfan and cyclophosphamide, we identified four variables independently associated with improved survival: younger age, shorter disease duration, lower neutrophil count pretransplant, and lower hematocrit pretransplant. We also found that 15 patients 40 to 55 years of age had a 46% 3-year actuarial DFS and 26 patients receiving unrelated or mismatched related donor marrow had a 50% 3-year actuarial DFS. We conclude that there does not appear to be any significant difference in outcome based on preparative regimen in this patient population. In addition, allogeneic bone marrow transplantation may be a reasonable approach to therapy of RA early after diagnosis. However, whether early intervention with transplantation prolongs survival over that expected without transplantation cannot be ascertained with certainty from available data.     

Flow support catheter for prolonged maintenance of coronary blood flow

A newly designed flow support catheter with a supporting wire mesh cage which can be expanded into a tubular configuration and then readily reduced was evaluated in mongrel dogs. Regional myocardial blood flow (RMBF) was measured using the radioactive microsphere technique in the area of both balloon-denuded instrumented and control non-instrumented coronary arteries following placement of either a fixed-wire or a higher profile rapid exchange flow support catheter. At 5, 20, and 180 min following delivery and expansion of either device, RMBF was not significantly different in left ventricular subepicardium and subendocardium perfused by the instrumented vs. the control coronary arteries. Angiography demonstrated widely patent instrumented arteries in 15/18 dogs; in no dog was side branch occlusion observed. Significant cage thrombus deposition was seen angiographically in 3 animals causing temporary total coronary occlusion in 1. Following reduction and removal of the flow support catheter, vessel patency was present in all dogs. The flow support catheter is an effective endovascular stenting device capable of providing structural arterial support, while simultaneously maintaining distal coronary blood flow. It is envisioned that the primary application of this catheter will be to enable primary salvage of vessels acutely injured during coronary angioplasty, by “tacking up” intimal flaps for an extended period. It may also provide a bridge to emergency surgical revascularization.     

Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation

In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen- specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.