Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.     

β4 integrin and other Schwann cell markers in axonal neuropathy

Schwann cell gene expression is dynamically regulated after peripheral nerve injury and during regeneration. We hypothesized that the changes in protein expression described after rat peripheral nerve injury could be used to identify single Schwann cell-axon units in human axonal neuropathy. Therefore, we performed immunofluorescence staining on sections of injured rat sciatic nerves compared with sections of neuropathic human sural nerves. We chose the markers β4 integrin, P0 glycoprotein, and glial fibrillary acidic protein (GFAP) to characterize Schwann cells, and neurofilament-heavy (NF-H) to recognize axons. Normal rat or human myelin-forming units demonstrated a sharp ring of β4 staining at their outer surface, P0 staining in the myelin sheath, and NF-H staining in the axon. Acutely denervated rat units transited from broken rings of β4 and P0 staining, to diffuse β4 and absent P0 and NF-H staining. Chronically denervated rat Schwann cells re-expressed β4 more highly, but in a diffuse, non-polarized pattern. In contrast, regenerating units re-expressed β4, P0, and NF-H; β4 staining was polarized to the outer surface of Schwann cells. Finally, GFAP staining increased progressively after injury and decreased during regeneration in the distal nerve stump. In neuropathic human sural nerves, we identified units exhibiting each of these β4, P0, and NF-H staining patterns; the proportion of each pattern correlated best with the extent and chronicity of axonal injury. Thus, synchronous injury of rat sciatic nerve predicts patterns of Schwann cell marker expression in human axonal neuropathy. In addition, the unique changes in the polarity of β4 integrin expression, in combination with changes in P0 and NF-H expression, may distinguish normal from denervated or reinnervated myelin-forming Schwann cells in human sural nerve biopsies. © 1996 Wiley-Liss, Inc.     

Sympathetic skin response in multiple sclerosis: a meta-analysis of case-control studies

The usefulness of sympathetic skin responses (SSR) in multiple sclerosis (MS) has been advocated by several studies in the last 20 years; however, due to a great heterogeneity of findings, a comprehensive meta-analysis of case-control studies is in order to pinpoint consistencies and investigate the causes of discrepancies. We searched MEDLINE, EMBASE and Cochrane databases for case-control studies comparing SSR absence frequency and latency between patients with MS and healthy controls. Thirteen eligible studies including 415 MS patients and 331 healthy controls were identified. The pooled analysis showed that SSR can be always obtained in healthy controls while 34% of patients had absent SSRs in at least one limb (95% CI 22–47%; p < 0.0001) but with considerable heterogeneity across studies (I ² = 90.3%). Patients’ age explained 22% of the overall variability and positive correlations were found with Expanded Disability Status Scale and disease duration. The pooled mean difference of SSR latency showed a significant increase in patients on both upper (193 ms; 95% CI 120–270 ms) and lower (350 ms; 95% CI 190–510 ms) extremities. We tested the discriminatory value of SSR latency thresholds defined as the 95% confidence interval (CI) upper bound of the healthy controls, and validated the results on a new dataset. The lower limb threshold of 1.964 s produces the best results in terms of sensitivity 0.86, specificity 0.67, positive predicted value 0.75 and negative predicted value 0.80. Despite a considerable heterogeneity of findings, there is evidence that SSR is a useful tool in MS.     

Diagnostic accuracy of ICD-9 code 780.2 for the identification of patients with syncope in the emergency department

Purpose

Syncope is a common condition that affects individuals of all ages and is responsible for 1–3% of all emergency department (ED) visits. Prospective studies on syncope are often limited by the exiguous number of subjects enrolled. A possible alternative approach would be to use of hospital discharge diagnoses from administrative databases to identify syncope subjects in epidemiological observational studies. We assessed the accuracy of the International Classification of Diseases, Ninth Revision (ICD-9) code 780.2 “syncope and collapse” to identify patients with syncope.

Methods

Patients in two teaching hospitals in Milan, Italy with a triage assessment for ED access that was possibly related to syncope were recruited in this study. We considered the index test to be the attribution of the ICD-9 code 780.2 at ED discharge and the reference standard to be the diagnosis of syncope by the ED physician.

Results

The sensitivity, specificity, positive and negative predictive values of the ICD-9 code 780.2 to identify patients with syncope were 0.63 (95% confidence interval [CI] 0.58–0.67), 0.98 (95% CI 0.98–0.99), 0.83 (95% CI 0.79–0.87) and 0.95 (95% CI 0.94–0.95), respectively.

Conclusions

The moderate sensitivity of ICD-9 code 780.2 should be considered when the code is used to identify patients with syncope through administrative databases.

     

Initial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder

Background

The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD.

Methods

Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5.

Results

Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls.

Conclusions

: The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing.     

Peak and decline in cancer incidence, mortality, and prevalence at old ages

BACKGROUND:

Cancer incidence and mortality increase with age through much of adulthood, but earlier work has found that these rates decline among the very elderly. To compare incidence and mortality at the oldest ages, the authors investigated both in the same large population, which comprised 9.5% of the United States in 2000. The authors also report age‐specific prevalence among the elderly, which has received little attention.

METHODS:

Twenty‐three cancer types were studied in men, and 24 cancer types were studied in women. Patient records were obtained from the SEER 9 cancer registries, and population figures were taken from the 2000 US Census. The authors explored the reliability of census data on the oldest old, which has been questioned.

RESULTS:

Age‐specific incidence, prevalence, and mortality results are presented for the years 1998 to 2002. Incidence and mortality usually decreased or plateaued at very old ages. Prevalence usually decreased swiftly at ages >90 years. When there was statistical power, incidence normally peaked between ages 75 years and 90 years, dropping abruptly afterward. With several large exceptions, peak incidence and mortality coincided within ±5 years. Both rates often trended toward zero among centenarians, who may be asymptomatic or insusceptible.

CONCLUSIONS:

The current results were found to be consistent with autopsy and survival studies. Most age‐specific models of carcinogenesis are based on cancer rate data for ages <85 years. The authors argue that these models could not fit the current results without fundamental modification and outline biologic mechanisms for such modification, mostly cellular and tissue senescence. They also recommend caution to researchers who use census data on the very elderly. Cancer 2012;. © 2011 American Cancer Society.     

Radiographic findings in Wiedemann-Rautenstrauch syndrome

We describe a girl who presents the features of Wiedemann-Rautenstrauch syndrome. This autosomal recessive condition has characteristic radiographic findings which can be considered manifestations of the syndrome.     

Periodontal disease,oral microbial flora and salivary antibacterial factors in diabetes mellitus type 1 patients

One hundred and thirty-one patients with diabetes mellitus type 1 (IDDM) and 20 healthy controls were checked for the presence of periodontal diseases and for some oral microbiological parameters. Results demonstrated that IDDM patients, who were well compensated from both the metabolic and clinical point of view, showed a prevalence for periodontopathies, which only differed slightly from controls. Only the presence of gingivitis was significantly higher in IDDM patients than in healthy subjects. Both anaerobic and aerobic microbial flora did not show substantial differences for either group. Among the salivary antibacterial factors studied, lysozyme was significantly decreased in diabetic patients compared to controls. It is concluded that IDDM patients undergo periodontal complications with a frequency quite close to that of non-diabetic healthy subjects, when the disease is under strict metabolic and clinical control.     

Protection from complement-mediated injury in livers and kidneys of transgenic mice expressing human complement regulators

Abstract: The major problem in the use of phylogenetically distant donors is a fast, strong reaction called hyperacute rejection. This reaction mediated by complement is directed against the vascular endothelia of the transplanted organ. Complement activation is tightly controlled by several regulatory proteins which inhibit the formation and function of different complement components. To verify the hypothesis that organs expressing such inhibitory factors could be spared from complement-mediated hyperacute rejection, we have generated mice transgenic for the human complement inhibitor membrane cofactor protein (hMCP) and decay accelerating factor (hDAF). Different levels of hMCP and/or hDAF expression, according to the promoter used, were detected by RNA analysis in the major organs, specifically on the organ vascular endothelia, as revealed by immunohistochemical analysis. The development of an in vivo model of human plasma perfusion allowed the characterization of complement-mediated damage in control animals and the degree of protection due to the presence of hMCP, hDAF, or both in the organs derived from single or double transgenic mice. In this paper we compare the level of expression of complement regulators with the degree of protection in two major organs: liver and kidney.     

Diagnostic test restraint and the specialty consultation

Object:To assess the effect consultants had on the diagnostic process in the management of patients admitted to the medical service of a university hospital. Design:Cohort study utilizing prospective evaluation by residents, retrospective chart review, and direct communication with the patient, a family member, or the patient’s physician one year after admission to the hospital. Setting:The medical inpatient service of an urban university hospital. Patients:The 580 patients admitted to the medical service during one month in 1984 for whom complete data were available. Main results:Sixty-three percent of the patients had consultations. Seventy percent (198/284) of the patients admitted by generalists had consultations, while 57% (170/296) of the patients admitted by subspecialists had consultations. Of the 1,422 major diagnostic tests performed on these patients, 504 (35%) were first recommended by consultants, and the consultants recommended cancellation of only ten major diagnostic tests. Patients who were seen by consultants had a length of stay that was more than double that of patients not seen by consultants. Consultation was associated with prolonged stay when patients were stratified by important clinical variables and remained an important independent factor in a multivariate model. The prolongation of hospitalization was principally due to delays in scheduling and interpreting sophisticated tests recommended by the consultants. When stratified into prognostically similar clinical groupings, there was no significant difference in in-hospital mortality between patients seen and those not seen by a consultant. Conclusion:Efforts to foster diagnostic restraint in the management of hospitalized patients should be broadened to include attention to the specialty consultation process. Received from the Cornell University Medical College, New York, New York.