Coxsackie virus infection in association with heart affection in man

The frequency of actual infections by selected types of coxsackie virus (B1-B6, A7, A9) has been followed up in adult patients hospitalized for reason of heart disease. Criteria of actual coxsackie virus infection have been defined, including a significant rise of titer of virus neutralizing antibodies and/or presence of virus-specific IgM antibodies. An actual coxsackie virus infection has been found in 71 (46.3%) out of 153 patients. Most frequently coxsackie B1 virus infection (24 times) and B4 (17 times) could be proved. In sera of patients with actual coxsackie virus infection, a higher proportion of infection with some types of coxsackie viruses, along with the presence of antibodies against a larger number of coxsackie virus types has been found, as compared to sera from patients without actual coxsackie virus infection, and/or, in sera of healthy blood donors (control group). The role of repeated infections with different types of coxsackie virus in the etiology of heart disease has been discussed.     

Contribution of NZB autoimmunity 2 to Y-linked autoimmune acceleration-induced monocytosis in association with murine systemic lupus

The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of the Y-linked autoimmune acceleration (Yaa) mutation, which induces an age-dependent monocytosis. Using a cohort of C57BL/6 (B6) x (NZB x B6)F1 backcross male mice bearing the Yaa mutation, we defined the pathogenic role and genetic basis for Yaa-associated monocytosis. We observed a remarkable correlation of monocytosis with autoantibody production and subsequent development of lethal lupus nephritis, indicating that monocytosis is an additional useful indicator for severe SLE. In addition, we identified an NZB-derived locus on chromosome 1 predisposing to the development of monocytosis, which peaked at Fcgr2b encoding FcgammaRIIB and directly overlapped with the previously identified NZB autoimmunity 2 (Nba2) locus. The contribution of Nba2 to monocytosis was confirmed by the analysis of Yaa-bearing B6 mice congenic for the NZB-Nba2 locus. Finally, we observed a very low-level expression of FcgammaRIIB on macrophages bearing the NZB-type Fcgr2b allele, compared with those bearing the B6-type allele, and the development of monocytosis in FcgammaRIIB haploinsufficient B6 mice carrying the Yaa mutation. These data suggest that the Nba2 locus may play a supplementary role in the pathogenesis of SLE by promoting the development of monocytosis and the activation of effector cells bearing stimulatory FcgammaR, in addition to its implication in the dysregulated activation of autoreactive B cells.     

Messages from the morgue to rheumatology: from Chagas disease to giant cell arteritis

Autopsy rates have fallen from over 50% to less than 10% in recent decades. The drastic decline creates uncertainty regarding causes of death and has negative effects for research, training, and patient safety, despite advances in imaging and laboratory testing. Rheumatology is as much at a loss as other specialties. Examples are given of important missed diagnoses revealed only at autopsy.When I was a medical school student in the 1950s and a resident and junior staff member in the 1960s and 1970s, regular visits to the morgue were an indispensable part of our workday routine. No first-class teaching hospital could operate without an adequate post-mortem service. The contact between clinicians and pathologists in the morgue was an essential part of ultimate quality control and teaching and could stimulate collaborative research. In the city of Malmö, where the autopsy rate exceeded 80% of the population in the 1970s, it is now less than 10%. When I asked a resident when he last had been to a morgue, he answered ‘I was there once when still a medical student’. Do the improved diagnostic instruments available today fully compensate for the lack of direct information given by careful autopsies, or are we missing valuable information by neglecting routine autopsy? All evidence indicates that we are indeed missing important information.In the 1970s, a 65-year-old man received treatment for systemic sclerosis on the basis of skin thickening, dysphagia, constipation with abdominal pain, and cardiomegaly. Two days before Christmas Eve he died of heart failure. The next day, the professor in the morgue greeted us with a big smile: ‘Today it is Christmas even here. I have today sectioned my first case of Chagas disease’. The patient, a teacher, had spent time in Colombia, a fact the clinicians had paid little attention to. The physician in charge of the patient did research in scleroderma and learned a lesson for life.Professor Kuntal Chakravarty, of Romford, UK, recently told me of a 36-year-old woman with a 5-year history of scleroderma who was admitted with acute abdominal pain, vomiting, and fever. X-rays and ultrasound did not reveal a cause. Owing to her scleroderma, the surgeons were reluctant to perform laparotomy, and she was treated with parenteral antibiotics and intravenous fluid. Her condition improved initially but later deteriorated and she died. The clinical diagnosis was peritonitis and ruptured intestine. The consulting rheumatologist (KC) and the family insisted on an autopsy, which unexpectedly showed uncomplicated volvulus.In 1975, we published an article on cause of death in 104 patients with rheumatoid arthritis (RA) based on routine post-mortem examination of patients during 5 years in a chronic care hospital in Malmö [1]. Cervical spine compression was identified as the cause of death in 11 patients. Only two of the cases had been diagnosed before death, although all patients had been hospitalized for months or years [1]. Although cervical spine instability is now rare, it still occurs and may be prevalent in communities with undeveloped health systems [2].Very high autopsy rates generated accurate prevalence studies of atherosclerosis [3], thromboembolism [4] and cancer [5,6]. In 1969, when the autopsy rate was 65%, Görel Östberg examined all 1,097 (!) temporal arteries from patients dying in 1 year in the city of Malmö, which had 250,000 inhabitants. The prevalence according to the literature was 2 out of 100,000, but Östberg identified not fewer than 16 out of 1,000 patients with a male/female ratio of 6/10. Only two of the patients had received a clinical diagnosis of temporal arteritis (retrospectively), and only a couple had suggestive symptoms [7]. Even more interesting is her systematic study of large vessel involvement in polymyalgia rheumatic and temporal arteritis, showing their overlap and coexisting polyarteritis nodosa and Takayasu’s disease [8]. This work has recently been fully acknowledged and extended by Gary S Hoffman and the US Vasculitis Clinical Research Consortium [9].In Finland, rheumatologists have published a number of articles illustrating substantial discrepancies between clinical and autopsy-based causes of death. In 36% of 371 autopsied patients, significant infections were identified, only half of which had been diagnosed in vivo[10]. Amyloidosis was the cause of death in 9.5% of patients between 1950 and 1991; of these cases, 35% had not been diagnosed in vivo[11]. Coronary heart disease showed an increasing prevalence in the same time period in the RA patients in contrast to autopsied non-RA patients and were likewise often not detected before death [12].In the US, the autopsy rate dropped from above 70% in the 1960s to 20% in 2005 at the Mayo Clinic and the Brigham and Women’s Hospital. The overall rate in the US is now 4.3% in non-forensic cases [13]. Although advances in diagnostic tools have improved accuracy of clinical diagnostics, 8% of major errors were found in a systematic review of 53 publications [14]. Post-mortem imaging has been investigated as an alternative to autopsy [15]. An ambitions blinded comparison between computed tomography (CT), magnetic resonance imaging (MRI), and autopsy of 182 cases reported to the coroner between 2006 and 2008 showed that CT was as accurate as the clinical diagnosis but that nevertheless causes of sudden death were often missed. MRI was less accurate than CT [16]. Even in the context of experimental medicine, the trend is the same. In the Autologous Stem Cell Transplantation International Scleroderma trial of stem cell transplantation versus cyclophosphamide in diffuse systemic sclerosis, autopsy was performed in 7 out of 44 cases (Jaap van Laar, of Newcastle, UK, and Kamran Naraghi, of Middleborough, UK).

Conclusions

The decline in autopsy rates has several causes: diagnostic overconfidence, physician reluctance to pursue consent for autopsy, lack of regulatory requirements, public resistance, and budgetary constraints. Part of the problem is that doctors are short on time and motivating the family to agree to autopsy requires tact, time, and dedication. Reluctance to embark on the additional paper work may also contribute. Autopsy remains the gold standard for determining the cause of death [13], and although revitalizing it seems unrealistic, I feel a need to alert younger generations what they are missing, in rheumatology as in other specialties.

Box 1. About Frank Wollheim

Frank Wollheim is Emeritus Professor at the Department of Rheumatology, University of Lund. He was its chairman from 1982 to 1998 and started its programs in scleroderma, systemic lupus erythematosus, early rheumatoid arthritis, and biomarkers of arthritis. He trained in internal medicine with Jan Waldenström in Malmö and rheumatology with Ralph C Williams in Minneapolis before starting the first rheumatology unit in Malmö in 1972. He has served as Secretary General and board member of Osteoarthritis Research Society International and is a master member of the American College of Radiology.

Abbreviations

CT: Computed tomography; MRI: Magnetic resonance imaging; RA: Rheumatoid arthritis

Competing interests

The author declares that he has no competing interests.     

Accuracy of clinical diagnosis in a Canadian teaching hospital.

Two hundred autopsies were investigated to determine the correlation between the clinical and pathological diagnoses in three categories--major underlying disease, cause of death and significant incidental pulmonary findings. There was concurrence in diagnosis of the major underlying disease in 76% of cases, with 12% of disagreements being considered minor and 12% major. In only three cases might different management have affected the outcome had the correct diagnosis of the major underlying disease been made during life. There was concurrence of the diagnosis of the cause of death (which was often different from the underlying disease) in 64% of cases, and in 10% of cases the outcome might have been different had the clinical diagnosis been accurate. The clinical opinion that lung disease was the cause of death was confirmed at autopsy in 54% of cases, and 45% of the pulmonary causes of death as determined at autopsy had been recognized clinically. Major incidental pulmonary findings diagnosed clinically were confirmed in 76% of cases, and major pulmonary findings diagnosed at autopsy had been recognized clinically in 83%. The major sources of these discrepancies were pulmonary embolism and pneumonia. If autopsies are to play a role in patient management, clinicians will have to be made aware of discrepancies between clinical and autopsy diagnosis. The real test of efficacy would be modification of patient management for the good.     

Administration of monoclonal anti-T cell antibodies retards murine lupus in BXSB mice

Murine lupus in BXSB mice is associated with B cell hyperactivity, monocyte proliferation, and impaired T cell function. However, the significance of these abnormalities, and the relationship among them, has not been clearly established. To examine the role of T cells in the pathogenesis of autoimmune disease in BXSB mice, we depleted specific T cell subsets from BXSB males by using rat IgG2b monoclonal antibodies (MAb) to either Thy-1.2 (on all T cells) or L3T4 (on "helper/inducer" T cells). A single injection of anti-Thy-1.2 (6 mg i.v.) at age 3 mo produced a sustained 40 to 50% reduction in circulating T cells for 6 mo. Treatment prevented monocytosis, reduced anti-DNA antibody concentration, and retarded renal disease, but it did not prolong life. Repeated injections of rat MAb to Thy-1.2 were precluded by the development of a host immune response to rat immunoglobulin (Ig) that can cause anaphylaxis in BXSB mice. In contrast, rat MAb to L3T4 stimulated little or no immune response to rat Ig. We therefore were able to treat BXSB mice weekly with anti-L3T4 (2 mg i.p.) from age 3 to 12 mo. Treatment reduced circulating L3T4+ cells beneath the level of detection by fluorescence analysis. It also significantly reduced monocytosis, anti-DNA antibody production, renal disease, and mortality. These findings establish that monocytosis and autoimmunity in BXSB mice are promoted by T cells. They extend our previous observation that MAb to L3T4 retard autoimmunity in NZB/NZW F1 mice. Our finding that treatment with MAb to L3T4 is effective in two strains of lupus-prone mice suggests that treatment with MAb to Leu-3/T4, the human homologue for L3T4, may be effective in people with systemic lupus erythematosus.     

积分系统参与MDS诊断的可行性研究

目的:骨髓增生异常综合征(MDS)是一种起源于造血干细胞,以高风险向急性髓系白血病转化为特点的难治性血细胞质、量异常的异质性疾病。对不明原因血细胞减少或者有巨幼红细胞血症的老年人,如果得不到明确的诊断就不会获得有效的治疗。探讨对伴有不明原因血细胞减少或大红细胞血症患者采用一种积分系统来预测诊断为骨髓增生异常综合征(MDS)的可行性。方法:应用四个因子即年龄≥65,红细胞平均体积(MCV),红细胞分布宽度(RDW),和乳酸脱氢酶(LDH)的一个积分系统来计算诊断MDS的概率。结果:调查了303个病人,他们都因为不明原因的血细胞减少或者大红细胞血症在过去三年(2010~2012)进行了骨髓检查,最终三分之二患者被诊断为MDS,9%为疑似MDS,采用积分系统前后的MDS诊断率分别为12%和48%。结论:此四个因子的积分系统可以用于指导MDS患者的诊断。提高MDS的诊断率,减少不必要的骨髓穿刺,减轻病人的疼痛和医疗费用。     

Circulating Concentrations of Vitamin B6 and Kidney Cancer Prognosis: A Prospective Case-Cohort Study

Prospective cohort studies have found that prediagnostic circulating vitamin B6 is inversely associated with both risk of kidney cancer and kidney cancer prognosis. We investigated whether circulating concentrations of vitamin B6 at kidney cancer diagnosis are associated with risk of death using a case-cohort study of 630 renal cell carcinoma (RCC) patients. Blood was collected at the time of diagnosis, and vitamin B6 concentrations were quantified using LC-MS/MS. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models. After adjusting for stage, age, and sex, the hazard was 3 times lower among those in the highest compared to the lowest fourth of B6 concentration (HR_4vs1 0.33, 95% CI [0.18, 0.60]). This inverse association was solely driven by death from RCC (HR_4vs1 0.22, 95% CI [0.11, 0.46]), and not death from other causes (HR_4vs1 0.89, 95% CI [0.35, 2.28], p-interaction = 0.008). These results suggest that circulating vitamin B6 could provide additional prognostic information for kidney cancer patients beyond that afforded by tumour stage.     

Fine needle aspiration of extramedullary myeloid cell tumor in myelodysplastic syndrome. A report of three cases.

BACKGROUND: Soft tissue tumors are rare in myelodysplastic syndrome (MDS), and the role of fine needle aspiration (FNA) cytology in their diagnosis has not been explored. CASES: Two patients with refractory anemia with excess blasts in transformation (RAEB-t) developed soft tissue swellings during the course of the illness. In a third patient, soft tissue swelling was a presenting feature. The swellings in all three cases were diagnosed as extramedullary myeloid cell tumor (EMT) on FNA and showed increased blasts (10-14%), dyspoietic changes, Auer rods and monocytosis. CONCLUSION: Soft tissue tumors appearing in MDS are likely to be EMTs. FNA is therefore particularly valuable in their diagnosis as morphology, cytochemistry, immunophenotyping and flow cytometric analysis of hematopoietic cells are best studied on aspirated material. We suggest that FNA be preferred over excisional biopsy for the diagnosis of soft tissue swellings in MDS.     

Evaluation of the autopsy report before releasing musculoskeletal tissue donors; what is the benefit?

EU directive 2006/17/EC requires that all available medical information, including the autopsy report, is evaluated before releasing tissues for transplantation. The study objective was to investigate whether evaluation of autopsy results of musculoskeletal tissue donors contributes to safety and availability of transplantable tissues. The files of all donors of whom musculoskeletal tissues were retrieved by BIS in 2006 were reviewed for death cause and autopsy results. Of 84 donors musculoskeletal tissues were retrieved. In 47 donors autopsy was performed (56.0%). The groups with and without autopsy were similar in sex, age, length, and weight. In one donor no autopsy results were evaluated, since the donor was already rejected because of positive blood tests. In 13 donors (28.1%) death causes before autopsy were unknown. In 12 of these donors a death cause could be established after autopsy. In nine of the donors with a clear suspected death cause (27.3%), the death cause after autopsy differed from the suspected death cause. Four donors with autopsy (8.7%) had a general contraindication for donation, a (possible) sepsis in three and a persisting unknown death cause in one. Eight donors (17.4%) had musculoskeletal-specific contraindications, i.e. local infections. In conclusion, in 26.1% of the donors with autopsy, general or musculoskeletal-specific contraindications for donation were found. Furthermore, performance of autopsies enlarges the potential donor pool, since death causes can be established in almost all autopsies done in case of an unknown death cause. Therefore, evaluation of autopsy results improves the safety and quantity of tissues for transplantation.     

The effect of thymic substances on T circulating cells of patients treated for Hodgkin's disease

Forty-one patients with Hodgkin's disease staged as IA(4), IIA/B(4/6) IIIA/B(6/9) and IVA/B(3/9) who had had radiotherapy (subtotal nodal irradiation (STNI) or total nodal irradiation (TNI), or combined one (STNI/TNI plus chemotherapy MOPP or MOPP/ABVD) have been enrolled consequently and randomized to receive thymic hormone (17 patients) or pentapeptide treatment (14 patients) for 3-6 months at the end of the therapeutic regimens. In all patients severe immunodeficiency evaluated either as leukopenia (WBC less than 4000/mm3) or lymphocytopenia (lymphocytes less than 1500/mm3) or CD3 and CD2 cell reduction, or imbalance of helper/suppressor (H/S) ratio have been documented before starting thymic therapy. Different results by immunorestorative therapy have been registered according to the entity of immunodeficiency. In fact in the group of 15 patients with severe lymphopenia (lymphocytes less than 1000/mm3) either the thymic hormone or the synthetic drug produced a significant increase of all subsets examined: CD3-CD2-CD4-CD8 without or with minimal influence on H/S ratio, due to the increase of absolute lymphocytes count. In the remaining patients with mild or no lymphopenia the two drugs resulted ineffective on T cells. Comparing the overall group of patients who received thymic therapy with a control group of patients who did not, an advantage in terms of recruitment of T cell compartment has been observed in the former group when mean values are compared. According to the clinical impact of the immunotherapy with thymic substances on these patients, a significant decrease in incidence of herpes virus infection (HVI) has been observed in patients who had had thymic therapy compared with the incidence of HVI in the control group (18% versus 53.8%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Leukostasis associated with blood transfusion in acute myeloid leukaemia.

Three patients with acute myeloblastic leukaemia and blast cell counts greater than 100 X 10(9)/1 (100 000/mm3) died unexpectedly soon after blood transfusion. In two cases postmortem examination disclosed cerebral leukostasis. Analysis of the records from the MRC''s fourth and fifth acute myeloid leukaemia trials showed that in the first week after diagnosis mortality was five times greater in patients with blast counts above 100 X 10(9)/1 than in patients with lower counts. Age and platelet count did not explain this excess. The mean haemoglobin concentration in the patients with high blast counts who died within the first week was 10.5 +/- 2.8 g/dl, which was significantly higher than that in the surviving group (7.6 +/- 2.4 g/dl). Only half the patients received chemotherapy within two days of diagnosis. Leukostasis is an important cause of early death in patients with high blast counts, and the increase in viscosity produced by transfusing to a haemoglobin concentration above 10 g/dl may lead to sudden deterioration. Transfusion to such concentrations should be avoided until the blast count has been reduced by early chemotherapy.     

Hypothesis test for causal explanations in human pathology: evaluation of pulmonary edema in 181 autopsied patients with leukemia

Symbolic logic, as used in the formal theory of scientific explanation proposed by Hempel and Oppenheim, has been suggested as the basis for automated medical diagnosis. In human autopsy pathology the determination of cause-and-effect relationships is a major area subject to logical analysis. We propose a modification of the Hempel-Oppenheim schema in which the logical relationships must only be satisfied “much” of the time, as determined by binomial significance tests. The analysis employs “certainty levels” logic with a more limited consistency requirement than classical logic. The analysis is applied to a series of 181 autopsied patients with leukemia in an attempt to determine a possible role of chemotherapeutic agents in the etiology of pulmonary edema. Among 51 patients who had received cytosine arabinoside (Ara-C) within 30 days of death, there was significantly more unexplained moderate or massive pulmonary edema than among patients with no or remote therapy (p<0.001). The results suggest that a symbolic logical analysis combined with a binomial significance test can elucidate cause-and-effect relationships observed at autopsy, especially when there are multiple possible explanations for the same effect.     

Combined use of111In-labeled pentetreotide and three-step immunoscintigraphy with antichromogranin a monoclonal antibody in the diagnosis of pituitary adenomas

For various pituitary adenomas, it has been demonstrated that somatostatin receptor can be present. Pilot studies have shown that radio-indium labeled pentetreotide allows very good scintigraphic localization of somatostatin receptor-bearing cell masses. Recently, the presence of CgA in pituitary adenomas has also been demonstrated. MAb A11, raised against CgA, has been successfully used with a three-step ISG for the diagnosis of neuroendocrine tumors. Therefore the combined use of three-step ISG with MAb A11 and radiolabeled somatostatin can be useful in the diagnosis of pituitary adenomas. Twelve patients, 5 secreting (group A) and 7 nonsecreting (group B) pituitary adenomas, were enrolled in the study. All patients underwent three-step ISG, and, 2 wk later, scintigraphy with¹¹¹In-labeled pentetreotide (Octreoscan). Three-step ISG consisted of iv injection of 1 mg of biotinylated MAb A11 (first step), followed by 10 mg of avidin (second step) and [^99mTc]PnAO-biotin (third step). Tomographic imaging were acquired for three-step ISG and Octreoscan at 2 and 4 h after radiotracer injection, respectively. The results are the following: 2 patients of group A (secreting tumors) had a positive three-step ISG, whereas all the patients but one of the same group had a positive pentetreotide study; all the patients of group B (nonsecreting tumors) had a positive three-step ISG and 4 had a positive pentetreotide scintigraphy. These data suggest the utility of the combined use of these techniques for a better diagnosis of pituitary adenomas.     

An autopsy study describing causes of death and comparing clinico-pathological findings among hospitalized patients in Kampala, Uganda

Background

Information on causes of death in HIV-infected patients in Sub-Saharan Africa is mainly derived from observational cohort and verbal autopsy studies. Autopsy is the gold standard to ascertain cause of death. We conducted an autopsy study to describe and compare the clinical and autopsy causes of death and contributory findings in hospitalized HIV-infected and HIV-uninfected patients in Uganda.

Methods

Between May and September 2009 a complete autopsy was performed on patients that died on a combined infectious diseases gastroenterology ward in Mulago Hospital in Kampala, Uganda. Autopsy cause of death and contributing findings were based on the macro- and microscopic post-mortem findings combined with clinical information. Clinical diagnoses were reported by the ward doctor and classified as confirmed, highly suspected, considered or not considered, based on information derived from the medical chart. Results are reported according to HIV serostatus.

Results

Fifty-three complete autopsies were performed in 66% HIV-positive, 21% HIV-negative and 13% patients with an unknown HIV serological status. Infectious diseases caused death in 83% of HIV-positive patients, with disseminated TB as the main diagnosis causing 37% of deaths. The spectrum of illness and causes of death were substantially different between HIV-positive and HIV-negative patients. In HIV-positive patients 12% of postmortem diagnoses were clinically confirmed, 27% highly suspected, 16% considered and 45% not considered. In HIV-negative patients 17% of postmortem diagnoses were clinically highly suspected, 42% considered and 42% not considered.

Conclusion

Autopsy examination remains an important tool to ascertain causes of death particularly in settings with limited access to diagnostic testing during life. HIV-positive patients continue to die from treatable and clinically undiagnosed infectious diseases. Until rapid-point of care testing is available to confirm common infections, empiric treatment should be further investigated.     

Autopsy analyses in acute exacerbation of idiopathic pulmonary fibrosis

Background

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. However, few studies have so far reviewed analyses of autopsy findings in patients with AE-IPF.

Methods

We retrospectively reviewed 52 consecutive patients with AE-IPF who underwent autopsies at five university hospitals and one municipal hospital between 1999 and 2013. The following variables were abstracted from the medical records: demographic and clinical data, autopsy findings and complications during the clinical course until death.

Results

The median age at autopsy was 71 years (range 47–86 years), and the subjects included 38 (73.1%) males. High-dose corticosteroid therapy was initiated in 45 (86.5%) patients after AE-IPF. The underling fibrotic lesion was classified as having the usual interstitial pneumonia (UIP) pattern in all cases. Furthermore, 41 (78.8%) patients had diffuse alveolar damage (DAD), 15 (28.8%) exhibited pulmonary hemorrhage, nine (17.3%) developed pulmonary thromboembolism and six (11.5%) were diagnosed with lung carcinoma. In addition, six (11.5%) patients developed pneumothorax prior to death and 26 (53.1%) developed diabetes that required insulin treatment after the administration of high-dose corticosteroid therapy. In addition, 15 (28.8%) patients presented with bronchopneumonia during their clinical course and/or until death, including fungal (seven, 13.5%), cytomegalovirus (six, 11.5%) and bacterial (five, 9.6%) infections.

Conclusions

The pathological findings in patients with AE-IPF represent not only DAD, but also a variety of pathological conditions. Therefore, making a diagnosis of AE-IPF is often difficult, and the use of cautious diagnostic approaches is required for appropriate treatment.     

Postmortem Diagnosis of Diabetic Ketoacidosis Presenting as the "Dead-in-Bed Syndrome"

Objective:To report a case of a young male with type 1 diabetes mellitus found dead in his bed, initially assumed to have died from hypoglycemia (i.e., the “dead in bed” syndrome). However, his autopsy findings revealed that diabetic ketoacidosis (DKA) was the cause of death.MethodsWe present the laboratory and autopsy findings of the patient, highlighting the importance of laboratory analyses of the vitreous humor and microscopy of kidney tissue when investigating the cause of sudden death in patients with type 1 diabetes.ResultsA 25-year-old healthy male with type 1 diabetes on continuous subcutaneous insulin infusion therapy was found dead in his undisturbed bed. An autopsy included vitreous humor analyses. His results were as follows: glucose of 755 mg/dL (reference range 70-105 mg/dL), anion gap > 36 mEq (reference range 4-12 mEq/L), elevated acetone at 66 mg/dL (reference range negative), which were consistent with DKA. Renal microscopy demonstrated subnuclear vacuoles in the proximal tubules, 1 of 2 lesions were described as an Armanni-Ebstein lesion, which is a postmortem finding in patients who die from diabetic coma.ConclusionThe most likely cause of death at home in young patients with type 1 diabetes is severe hypoglycemia. However, an autopsy of the present case confirmed DKA based on vitreous humor biochemistry and microscopic examination of the kidneys, which demonstrated the Armanni-Ebstein phenomenon. Analysis of the vitreous fluid and microscopic examination of the kidneys for the presence of Armanni-Ebstein lesion can be used to help determine the cause of death in patients with type 1 diabetes mellitus. (Endocr Pract. 2014;20:e123-e125)     

Tumor Necrosis Factor Inhibition and Head and Neck Cancer Recurrence and Death in Rheumatoid Arthritis

The objective of this retrospective cohort study was to determine the effect of tumor necrosis factor inhibitor (TNFi) therapy on the risk of head and neck cancer (HNC) recurrence or HNC-attributable death in patients with rheumatoid arthritis (RA). RA patients with HNC were assembled from the US national Veterans’ Affairs (VA) administrative databases, and diagnoses confirmed and data collected by electronic medical record review. The cohort was divided into those treated with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) versus TNF inhibitors (TNFi) after a diagnosis of HNC. Likelihood of a composite endpoint of recurrence or HNC-attributable death was determined by Cox proportional hazards regression. Of 180 patients with RA and HNC, 31 were treated with TNFi and 149 with nbDMARDs after the diagnosis of HNC. Recurrence or HNC-attributable death occurred in 5/31 (16.1%) patients in the TNFi group and 44/149 (29.5%) patients in the nbDMARD group (p = 0.17); it occurred in 2/16 (13%) patients who received TNFi in the year prior to HNC diagnosis but not after. Overall stage at diagnosis (p = 0.03) and stage 4 HNC (HR 2.49 [CI 1.06–5.89]; p = 0.04) were risk factors for recurrence or HNC-attributable death; treatment with radiation or surgery was associated with a lower risk (HR 0.35 [CI 0.17–0.74]; p = 0.01 and HR 0.39 [CI 0.20–0.76]; p = 0.01 respectively). Treatment with TNFi was not a risk factor for recurrence or HNC-attributable death (HR 0.75; CI 0.31–1.85; p = 0.54). We conclude that treatment with TNFi may be safe in patients with RA and HNC, especially as the time interval between HNC treatment and non-recurrence increases. In this study, TNF inhibition was not associated with an increase in recurrence or HNC-attributable death.     

Evolution du risque infectieux chez l'enfant atteint de leucémie.

Infection is the leading cause of illness and death in children with leukemia. The risk of infection may change over time as regimens of therapy are modified. A review of the hospital charts of 166 infants in whom leukemia had been diagnosed between 1976 and 1980 revealed an increased number of deep fungal infections (20 v. 3) during this period in comparison with the number between 1969 and 1976 in 164 patients treated at the same hospital whose leukemia was diagnosed between 1969 and 1975. The 20 severe fungal infections between 1976 and 1980 were characterized by difficulty of diagnosis (a definite diagnosis having been made three times out of four only at autopsy), an important role of Candida but also of Aspergillus (the latter having been isolated almost as often as the former) and a grave prognosis (the mortality being very high [75%] and much above that for gram-positive septicemia [6%] and that for gram-negative septicemia [31%]). This increase in frequency of fungal infections was concurrent with the introduction of phase-1 chemotherapy, which was often responsible for prolonged neutropenia. To reduce the risk of infection in children with leukemia it appears to be essential to improve diagnostic methods and approaches to therapy.     

Cystatin C as a potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease

The definite diagnosis of Creutzfeldt-Jakob disease (CJD), the most common form of human prion diseases, relies upon neuropathological data usually obtained at autopsy. In living patients, the diagnosis, based on suggestive clinical features and EEG abnormalities, can be aided by the detection of altered levels of isoforms of the 14-3-3 protein in the cerebrospinal fluid (CSF). However, the validity of this test has been recently challenged and the search for other, more reliable biomarkers for CJD remains highly desirable. The present study describes the identification of a new potential surrogate marker in the CSF of CJD-affected patients. A preliminary study employing surface-enhanced laser desorption/ionization-time of flight (SELDI-TOF) technology highlighted a protein at 13.4 kDa in a small group (n = 8) of CJD-affected patients. Further analysis aimed at identifying this protein using cationic exchange chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed it to be cystatin C. Additional immunoblot assays confirmed that the level of cystatin C was significantly increased (p 相似文献