Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Association of fibromyalgia characteristics in patients with non-metastatic breast cancer and the protective role of resilience.

Cancer patients often complain about weakness, fatigue, and pain. The aim of this study was to assess the features of the fibromyalgia syndrome (FMS) characteristics in patients with non-metastatic breast cancer. The study group included 40 women whose age ranged from 40 to 70 years with Stages 0-3 breast cancer. The control group included 40 healthy women matched by age. A diagnosis of FMS was established based on medical history, physical examination, and the Fibromyalgia Impact Questionnaire (FIQ). Pain measures and functional factors were evaluated by the Brief Pain Inventory and the Sheehan Questionnaire. Resilience was assessed by Antanovsky's Sense of Coherence Questionnaire. Psychiatric disturbances were tested by the MINI Questionnaire and Hamilton questionnaires for depression and anxiety. The prevalence of chronic pain was higher in the study group. Statistically significant differences were also found between the group regarding pain, fatigue, and functional measures. The prevalence of depressive or anxious mood, measured by the Hamilton questionnaires, was strongly related to FMS characteristics reflected by FIQ scores (r = 0.79 between FIQ and the Hamilton Depression Index and r = 0.75 between FIQ and the Hamilton Anxiety Scale). The sense of coherence measure for these patients demonstrated an inverse correlation with pain, fatigue, and functional capability. Women with breast cancer tend to develop chronic widespread pain syndromes more often than do healthy women.

Prolidase deficiency: it looks like systemic lupus erythematosus but it is not.

Three siblings with recalcitrant leg ulceration, splenomegaly, photosensitive rash, and autoantibodies were suspected of having prolidase deficiency. Urine was checked for iminodipeptiduria, fibroblasts were cultured and analyzed for prolidase activity, and DNA was extracted for identifying the causative mutation. Glycyl proline was found as the dominant dipeptide in the urine. The activity of proline dipeptidase in fibroblasts was 2.5% of control fibroblasts. Sequence analysis of the PEPD gene revealed a homozygous nonsense C-->G transition at nucleotide 768. In conclusion, prolidase deficiency was diagnosed in siblings with skin ulceration autoantibodies and a lupus-like disease. A novel nonsense mutation was found, associated with the severe outcome of our patients.

Impact of treatment with infliximab on serum cytokine profile of patients with rheumatoid and psoriatic arthritis.

This article analyzes the serum cytokine profile of a nonrandomized group of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who are destined to be treated with infliximab following failure after failure of different disease-modifiying antirheumatic drugs (DMARDs). Serial serum samples were collected from 11 patients with refractory RA, three with PsA and one with undifferentiated spondyloarthropathy. All were treated with the antitumor necrosis factor (TNF)alpha agent, infliximab, after failing to sustain a clinical remission with conventional DMARDs. Blood samples were obtained at different phases of their therapy. Serum levels of tumor necrosis factor (TNF)alpha, interferon (IFN)gamma, interleukin (IL)-1beta, IL-6, sIL-2R, IL-10, and IL-1 receptor antagonist (IL-1RA) were determined by commercial ELISA kits. Interestingly, only eight of the 11 patients with RA had elevated TNFalpha serum levels (at least once in their serial measurements). Only one was unresponsive to therapy and despite anti-TNFalpha therapy her serum TNFalpha levels remained extremely high. Two RA patients who responded to infliximab had normal TNFalpha serum levels prior to and following infliximab administration. One RA patient improved after infliximab therapy despite unrelenting high serum levels of TNFalpha, IL-6, and sIL-2R. Patients with active PsA who responded to infliximab therapy had sustained high serum TNFalpha levels. In an unselected population of RA and PsA patients, we noticed diverse patterns of serum cytokine profiles. These results imply that the cytokine profiles of RA and PsA are diverse and their pathogenesis is heterogeneous.

Posttraumatic stress disorder, tenderness, and fibromyalgia syndrome: are they different entities?

OBJECTIVES: Many features of fibromyalgia syndrome (FMS) resemble those of posttraumatic stress disorder (PTSD). The goal of this study was to investigate the comorbidity of FMS and PTSD in a cohort of men following an intensive, initial, defined traumatic event. METHODS: One hundred twenty-four males (55 patients with PTSD, 20 patients with major depression, and 49 controls) were evaluated for the presence of FMS. The major traumatic events in all PTSD patients were combat-related. Each individual completed questionnaires characterizing his disease, disabilities, and quality of life. RESULTS: Forty-nine percent of PTSD patients, compared to 5% of major depression patients and none of normal controls, fulfilled the American College of Rheumatology criteria for FMS (P<.0001). Significant correlations were detected between tender points and measured parameters in the PTSD group. CONCLUSIONS: In male patients, PTSD is highly associated with FMS. The degree and impact of these disorders are also highly related.

Preparedness for End of Life-a Survey of Jerusalem District Nursing Homes.

OBJECTIVES: To evaluate the quality of end-of-life (EOL) care in nursing homes. DESIGN: Survey and semistructured interviews. SETTING: Jerusalem district nursing homes. PARTICIPANTS: Staff members of 28 long-term care and skilled nursing facilities in the Jerusalem area in Israel of various ethnic, religious, and administrative affiliations (N = 207). MEASUREMENTS: Qualitative analysis of semistructured interviews and statistical analysis of questionnaires. RESULTS: Most staff members reported that EOL preferences were unknown for more than 90% of residents and that fewer than 10% had a healthcare proxy. Most staff members recalled conducting fewer than five EOL conversations over the past year with residents or family members and could recall fewer than five cases in which a resident was allowed to die in the nursing home. According to staff opinions the prevalence of tube feeding was estimated at greater than 10%, initiated because of aspiration, malnutrition, and understaffing, often against family's preferences. More than 25% of staff members believed that pain management was inadequate. Knowledge about management of chronic pain was poor in half of nurses and nearly one-third of physicians. Most staff would rather not receive the treatments they administered to residents. CONCLUSION: Nursing homes in Jerusalem lack competency for quality EOL care, and there are multiple psychological, training, and policy challenges to improvement.

Risk factors for cranial ischemic complications in giant cell arteritis.

Cranial ischemic complications (CICs) are among the presenting manifestations of giant cell arteritis (GCA). Yet patients with GCA may develop CICs at a later stage, despite steroid therapy. In the current report we delineate risk factors for CICs, both at presentation and during follow-up, and review the relevant literature. We reviewed charts of 175 patients with GCA. Follow-up data were available for 166 patients. CICs at presentation or developing within 2 weeks of GCA diagnosis were considered GCA related. CICs developing later were considered GCA related only when associated with other GCA-related manifestations or acute-phase reactions. Associations between CICs and other variables were tested by multivariate analysis. At presentation, 43 patients (24.6%) had CICs. Risk factors were transient cerebro-ophthalmic ischemic episodes (COIEs) (odds ratio [OR] 4.3) and male sex (OR 2.5), while the presence of systemic symptoms was "protective" (OR 0.3). During follow-up 8.4% of patients with GCA developed new CICs. Risk factors in these cases were previous CICs at presentation (OR 5.6) and transient COIEs developing during follow-up (OR 14.8). The use of low-dose aspirin was protective (OR 0.2). These data, together with data from the literature review, suggest that GCA patients with transient COIEs and without fever or other systemic symptoms are at increased risk of presenting with CICs. Risk factors for late-developing CICs were CICs at presentation and late-developing transient COIEs.

General medicine practitioners' attitudes towards "do not attempt resuscitation" orders.

OBJECTIVE: To examine whether "all-or-none" guidelines for cardiopulmonary resuscitation (CPR) are being applied by practitioners on general medical wards (GMWs). HYPOTHESIS: Do not attempt resuscitation (DNAR) orders are rarely related to patient preferences. Limited resuscitation efforts are being practiced to circumvent the need for DNAR orders. DESIGN: A surprise opinion survey (presented below), based on case vignette and practice description, and performed by remote control votes. SETTING: The multi-centre forum for practitioners on GMWs within the greater Jerusalem district. PARTICIPANTS: 79/85 clinicians practicing/training on GMWs in six teaching hospitals, who attended the forum and responded within 3 min to the survey. RESULTS: Fifty-eight practitioners (73%) assigned a DNAR order for a patient unable to express a preference and only 43 (55%) complied with the request of a competent patient for a DNAR order (P < 0.05]; 95% CI: 2-34). During the past year, only five practitioners (9% of respondents) had performed CPR solely when pathophysiological benefit was expected, 31 (59%) had performed limited CPR efforts and only 13 (28%) had discussed the subject of DNAR with patients and their next of kin >5 times. CONCLUSIONS: (1) DNAR orders are rarely discussed with patients and their next of kin in GMWs within the region examined; (2) even when DNAR is discussed, physicians tend to confer DNAR orders based on their personal value judgements rather than on patient preferences; (3) practitioners on GMWs perform CPR when no pathophysiological benefit is expected; (4) limited resuscitation efforts are performed frequently in GMWs.

Hypertrophic pulmonary osteoarthropathy: control of pain and symptoms with pamidronate.

This case presents a patient with hypertrophic osteoarthropathy of the lower extremities that developed secondary to congenital cyanotic heart disease. The major clinical manifestation was severe bilateral leg pain. The pain that was debilitating in nature completely resolved following a single administration of 60 mg pamidronate. Hypertrophic osteoarthropathy (HOA) is an acquired, uncommon disorder of obscure etiology. It has been described mainly in association with chronic suppurative pulmonary diseases, bronchogenic carcinoma and lung metastases, cystic fibrosis, and cyanotic congenital malformations of the heart.

Large vessel (Takayasu's) arteritis in a patient with myelodysplastic syndrome: is there a common pathogenesis?

Autoimmune phenomena may complicate the course of myelodysplastic syndromes (MDS) but large vessel arteritis is a rare event. We report a case of large vessel arteritis in a patient with MDS. A 62-year-old male presented with thrombocytopenia and was diagnosed with low-risk MDS, (<5% blasts in his bone marrow and a normal karyotype). Shortly thereafter he developed large vessel (Takayasu's) arteritis (TA) that responded well to oral corticosteroid and methotrexate therapy. Ten months later the MDS transformed into acute myeloid leukemia (AML). After a successful induction course with cytarabine and daunorubicin he underwent allogeneic transplantation from a matched unrelated donor with reduced-intensity conditioning. The transplantation was complicated by systemic cytomegalovirus (CMV) disease and he died 6 weeks post transplantation. Takayasu's arteritis is an uncommon form of vasculitis affecting primarily young women and is atypical for elderly males. Though autoimmune manifestations in MDS occur in 10%-18.5% of patients, usually large vessels are spared. In MDS, activated T cells are thought to mediate bone marrow failure via overproduction of proinflammatory cytokines that cause stem cell apoptosis. These T cells may also mediate the autoimmune phenomena in MDS. The prognostic significance of autoimmunity in the course of MDS is not yet determined. Some reports suggest worse prognosis. The case illustrates a possible association between MDS and large vessel vasculitis and suggests a possible relationship between the presence of autoimmune syndromes and the outcome of patients with MDS.

The premenstrual syndrome and fibromyalgia--similarities and common features.

The aim of the study was to assess the clinical similarities and common features of fibromyalgia syndrome (FM) and premenstrual dysphoric syndrome (PMDD). Thirty young patients who met the diagnostic criteria for PMDD were included in the study and compared to 26 women belonging to the medical staff of a general psychiatry department. All enrollees were interviewed and examined by a skilled physician. They completed the following nine survey items: demographic information, clinical health assessment questionnaire, fibromyalgia impact questionnaire, sleep and fatigue questionnaires, Sheehan disability scales, SF-36 assessment for quality of life, visual analog scale for pain, Mini International Neuropsychiatric Interview (MINI) questionnaire (assessment of coexistent psychiatric conditions), and the premenstrual severity scale. Additionally, each individual underwent a physical examination measuring the classical tender points and was asked to describe the distribution and continuum of her pain or tenderness. The PMDD group scored significantly higher in the measures pain and tenderness as well as in severity of premenstrual symptoms compared to the control group. Five patients in the PMDD group and none in the control group had FM. Quality of life measured by the SF-36 was higher in the control group than in the PMDD group and correlated with the degree of tenderness reported. Psychiatric comorbidity was significantly more common in the PMDD group, affecting 16 of the 30 PMDD patients compared to only three of the 26 control patients. In this study, patients with PMDD were found to have higher levels of tenderness, higher psychiatric comorbidity, greater level of physical disabilities, and a lower quality of life. These parameters were highly correlated with a lower pain threshold.

An open-label study adding creatine monohydrate to ongoing medical regimens in patients with the fibromyalgia syndrome.

Fibromyalgia is an ill-defined condition that causes pain and disability but still lacks effective treatment. The aim of this open-label study was to assess the efficacy of administering a food supplement, creatine monohydrate, in an "add on" to existing therapies in patients with fibromyalgia. This study included 30 patients with fibromyalgia. After 8 weeks of receiving creatine, we witnessed a significant improvement in parameters reflecting severity of fibromyalgia, quality of life and sleep, disability, and pain. These results deteriorated 4 weeks after stopping creatine therapy. The findings of this study are preliminary and limited due to the small sample and relatively high rate of dropouts.

Contradictions in end-of-life decisions for self and other, expressed by relatives of chronically ventilated patients.

OBJECTIVES: In certain populations, social, legal, and religious factors may influence end-of-life decisions in ventilator-dependent patients. This study aims to evaluate attitudes of first-degree relatives of chronically ventilated patients in Israel, toward end-of-life decisions regarding their loved ones, themselves, and unrelated others. MATERIALS AND METHODS: The study was conducted in a chronic ventilation unit. First-degree family members of chronically ventilated patients were interviewed about their end-of-life attitudes for patients with end-stage diseases. Distinctions were made between attitudes in the case of their ventilated relatives, themselves, and unrelated others; between conscious and unconscious patients; and between a variety of interventions. RESULTS: Thirty-one family members of 25 patients were interviewed. Median length of ventilation at the time of the interview was 13.4 months. Most interviewees wanted further interventions for their ventilated relatives, yet, for themselves, only 21% and 18% supported chronic ventilation and resuscitation, respectively, and 48% would want to be disconnected from the ventilator. Interventions were more likely to be endorsed for others (vs self), for the conscious self (vs unconscious self), and for artificial feeding (vs chronic ventilation and resuscitation). Interviewees were reluctant to disconnect patients from a ventilator. CONCLUSIONS: Family members often want escalation of treatment for their ventilated relatives; however, most would not wish to be chronically ventilated or resuscitated under similar circumstances. Advance directives may reconcile people's wishes at the end of their own lives with their reticence to make decisions regarding others.

Increased intracranial pressure related to systemic lupus erythematosus: a 26-year experience.

OBJECTIVE: To assess whether increased intracranial pressure (IIP) is associated or coincidental with systemic lupus erythematosus (SLE) and to characterize the patients with this condition, its commonly used treatment, and outcome. METHODS: A retrospective cohort study was conducted at the Hadassah Medical Center, Jerusalem, Israel. Files were retrieved from the hospital archives by screening records from 1980 to 2006 using the terms "SLE" and "pseudotumor cerebri" or "benign intracranial pressure." Medical records were screened for data regarding: (1) The prevalence of IIP among hospitalized patients; (2) the demographic, clinical, and laboratory characteristics of SLE patients reported to have at least 1 episode of IIP. RESULTS: Ten of 651 hospitalized SLE patients (prevalence, 1.5%) were found to have IIP, exceeding the prevalence of 1 to 19 per 100,000 reported in the general population. In 3 patients this was a presenting manifestation of SLE and the average time elapsed until IIP diagnosis was 10.7 months. Arabs were strikingly overrepresented among the 10 individuals, comprising 6 patients (versus 19% Arabs of all SLE patients). In 8 patients, other central nervous system (CNS) abnormalities were found either clinically or in laboratory tests. Two individuals had elevated antiphospholipid antibodies (aPL) and a history of thromboembolic events, compatible with antiphopholipid syndrome. The most commonly employed treatments were corticosteroids and acetazolamide, each in 9 patients with generally good clinical response. CONCLUSIONS: We propose that IIP is a manifestation of SLE and that corticosteroids should be considered as first-line treatment.