Effects of Chronic, Low-Dose Cannabinoids, Cannabidiol, Delta-9-Tetrahydrocannabinol and a Combination of Both, on Amyloid Pathology in the 5xFAD Mouse Model of Alzheimer's Disease.

Background: There is an urgent need for novel therapies to treat Alzheimer's disease. Among others, the use of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been proposed as a putative approach based on their anti-inflammatory effects. Methods: The present work was designed to explore the effects of chronic (28 days) treatment with low doses of cannabinoids: CBD (0.273 mg/kg), THC (0.205 mg/kg) or a combination of both (CBD:THC; 0.273 mg/kg:0.205 mg/kg) in the 5xFAD mouse model of AD. Results: Our data revealed that THC-treated 5xFAD mice (but not other treatment groups) exhibited anxiogenic and depressant-like behavior. A significant improvement in spatial memory was observed only in the CBD:THC-treated group. Interestingly, all cannabinoid-treated groups showed significantly increased cortical levels of the insoluble form of beta amyloid 1-42. These effects were not accompanied by changes in molecular parameters of inflammation at the mRNA or protein level. Conclusions: These data reveal differential effects of chronic, low-dose cannabinoids and point to a role of these cannabinoids in the processing of amyloid peptides in the brains of 5xFAD mice.

Interferon-alpha as a treatment modality for colchicine- resistant familial Mediterranean fever.

OBJECTIVE: Previous reports on interferon-alpha (IFN-alpha) were conflicting with respect to its efficacy in familial Mediterranean fever (FMF) refractory to colchicine treatment. We investigated the effect of IFN-alpha in patients with colchicine-resistant FMF. METHODS: In a prospective, patient self-controlled, open-label study evaluating the safety and efficacy of IFN-alpha in patients with FMF with a severe phenotype, refractory to intensified (oral plus intravenous) colchicine therapy, we advised patients to subcutaneously inject IFN-alpha, 3 million international units, at the onset of the FMF attack. Attacks not treated with IFN-alpha of the same patients and in the same sites served as control attacks. Features of each attack were recorded in a questionnaire, eventually used to compare between IFN-alpha-treated and non-treated attacks. RESULTS: Ten patients with a total of 80 attacks were recruited. Compared to 22 untreated attacks, a > 20% and > 50% reduction in the duration of the attacks was noted in 100% and 90% of the 58 IFN-alpha-treated attacks, respectively (p < 0.001 for both). The severity (degree of pain) of the IFN-alpha-treated attacks was attenuated by > 20% and > 50% in 88% and 49% of these attacks, respectively (p < 0.001 for both). The most common drug-related adverse events were chills and fatigue. CONCLUSION: Early intervention with IFN-alpha injections was associated with reduced attack length and/or severity in a substantial number of bouts, with an acceptable cost of adverse events.

Familial Mediterranean fever and cryptogenic cirrhosis.

Familial Mediterranean fever (FMF) is a febrile disease characterized by acute, spontaneously resolving episodes of fever and pain caused by serosal inflammation and associated with mutations in the FMF gene, MEFV. Prophylaxis is maintained with colchicine. To our knowledge, no study has yet shown an association between FMF and cirrhosis of the liver. We conducted the current study to describe cryptogenic cirrhosis in FMF and to examine the possible relationship between the 2 entities. Patients with chronic liver disease were retrospectively identified through a computer search of a registry of 6000 patients with FMF followed in the clinics of the National Center for FMF. Data pertaining to FMF phenotype and genotype and characteristics of the liver disease were abstracted from patients' charts. Cryptogenic cause of cirrhosis was determined by exclusion of known causes of liver disease. Nine patients with cryptogenic cirrhosis were identified, comprising 0.15% of the FMF patient population, a rate significantly higher than the rate of 0.015% of cirrhosis of all types expected in the total population of Israel (p < 0.000). Most patients had typical FMF, with a normal severity score distribution. The mean daily dose of colchicine was 1.4 +/- 0.4 mg, not different from the usual dose. All 7 patients who underwent mutation analysis had 2 mutations. Five of them were homozygous for M694V. Child-Pugh classification was determined in 6 patients at the time of cirrhosis diagnosis, and was classified as A in 4 of them. These findings suggest that MEFV may serve as a modifier gene in cryptogenic cirrhosis. Genetic analysis in patients with cryptogenic cirrhosis unrelated to FMF, particularly patients of a Mediterranean origin, may be warranted in future studies.

A long-term follow-up after cardiac transplantation in a lupus patient: case report and review of the literature.

Heart or heart-lung transplantations have only rarely been performed in patients with systemic lupus erythematosus (SLE), who like other patients with multi-system autoimmune diseases are traditionally excluded from consideration for such transplantations. In view of the limited experience with heart transplantation in these patients, we report the successful transplantation outcome in a lupus patient and review the literature in relation to graft and recipient conditions.

A novel overlap syndrome: systemic sclerosis associated with antiphospholipid syndrome--a case series.

Antiphospholipid syndrome (APS) can be either primary or secondary to autoimmune diseases, malignancies, infectious diseases, or drug-induced conditions. The aim of this study was to describe a novel overlap syndrome of APS and systemic sclerosis (SSc) in a case series. A retrospective review of medical files of hospitalized patients who were followed in two rheumatology clinics in Israel for the diagnosis of SSc and APS was sought. A MEDLINE search was performed for reports of APS/SSc overlap syndrome. Five patients with the overlap syndrome of APS and SSc were retrieved. The diagnosis of both diseases was confirmed by the American College of Rheumatology classification criteria. Four patients were women and of an older age group (42-68 years old). Three patients had primary APS, and in two patients APS was secondary to SSc. Two of the five patients died. The interval between APS and SSc was < 1-18 years. APS/SSc overlap syndrome is described for the first time as a case series. The patients may be older, with an interval of up to 18 years between diseases. The APS patients did not suffer from SLE. The overlap syndrome was characterized in certain instances with severe disease and two patients died. With relevant clinical manifestations, APS should be sought in SSc patients and treated appropriately.

A single testing of serum amyloid a levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever.

OBJECTIVES: In a significant proportion of patients with familial Mediterranean fever (FMF), serum amyloid A (SAA) remains elevated during attack-free periods, thereby increasing the risk of developing amyloidosis. The aim of the study was to determine various correlates of elevated SAA and evaluate the role of SAA measurement in the diagnosis and management of FMF. METHODS: We reviewed the medical files of all 204 patients from our FMF center in whom SAA measurements were performed. SAA levels and the resulting diagnostic and therapeutic decisions were analyzed in relation to the reasons of SAA testing and to several clinical and genetic parameters. RESULTS: SAA measurements were made for diagnostic purposes in 29% of the patients. In the remainder, SAA measurements were used for adjustment of colchicine dose. Elevated SAA levels are found in a third of FMF patients during an attack-free period. The highest rate of elevated SAA levels was found in patients with proteinuria (60% of this patient group), followed by noncompliant (40%) and genetically positive asymptomatic patients (38%). Elevated SAA levels during remission were associated with family history of FMF, M694V homozygosity, and elevated C-reactive protein (CRP) (P<0.05 for each). Patients homozygous for the M694V mutation had the highest level of SAA. SAA measurement led to a change in colchicine dose in 30% of the patients, predominantly in noncompliant patients and patients with proteinuria or with atypical manifestations. CONCLUSIONS: Measurement of SAA level may help in the diagnosis of FMF and in adjustment of the colchicine dose.

Severe gastrointestinal inflammation in adult dermatomyositis: characterization of a novel clinical association.

OBJECT: Gastrointestinal involvement in adult dermatomyositis (DM) and polymyositis (PM) is usually mild, resulting from myoenteric dismotility. Severe inflammation of the alimentary tract in cases of adult DM and PM is rare. The purpose of this study was to examine the prevalence and clinical characteristics of inflammatory gastrointestinal involvement in patients with DM. METHODS: The charts of all cases with polymyositis or dermatomyositis, registered in our rheumatology clinic between 1984 and 2004, were reviewed retrospectively for documentation of severe gastrointestinal involvement. The clinical course and the histopathologic findings in all the patients were noted, and the prevalence of this disorder was computed. RESULTS: Among 48 patients with DM or PM, 3 patients with DM and severe gastrointestinal tract manifestations were identified (6% of the study population). Edematous hyperemic bowel wall, with multiple erosions and ulcerous lesions were the prominent endoscopic findings, whereas diffuse mucosal inflammation and multiple vascular ectasias without vasculitis dominated the histologic picture. The resulting clinical course was notable for recurrent abdominal pain and bloody diarrhea, ending catastrophically in two patients with fatal gastrointestinal perforations, despite aggressive immunosuppressive therapy. CONCLUSIONS: Severe inflammatory gastrointestinal tract disease should be recognized as a grave, albeit rare, manifestation of adult DM that portends a poor prognosis and carries a high rate of fatal complications. The role of vasculopathy in the pathogenesis of this syndrome remains to be determined.

The prodrome: a prominent yet overlooked pre-attack manifestation of familial Mediterranean fever.

OBJECTIVE: To identify and characterize pre-attack symptoms (prodrome) in patients with familial Mediterranean fever (FMF). METHODS: Forty-eight patients with FMF whose attacks are preceded by a prodromal period composed the study population. Clinical, demographic, and genetic characteristics of the study group were compared to those of a control group of 48 patients with FMF whose attacks begin without a premonitory phase. Patients of both groups were recruited consecutively, during their routine followup visit to the FMF clinic. RESULTS: A prodrome was found to be a common manifestation of FMF, experienced by about 50% of the patients. Overall, demographic, clinical, and genetic variables were comparable between study and control groups. In affected patients prodrome recurs in most attacks, lasts a mean of 20 hours, and manifests with either a mildly unpleasant sensation at the site of the forthcoming spell (discomfort prodrome), or with a spectrum of physical, emotional, and neuropsychological complaints (variant prodrome). The 2 types of prodromata are frequently accompanied by a host of constitutional symptoms. CONCLUSIONS: A prodromal period heralding attacks is a newly defined and reliable FMF manifestation that reproducibly predicts attacks and may help prevent attacks and elucidate the pathogenesis of the disease.

New therapeutic strategies for systemic sclerosis--a critical analysis of the literature.

Systemic sclerosis (SSc) is a multi-system disease characterized by skin fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In this review, we describe novel strategies in the treatment of SSc. Utilizing the MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma, systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension, methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg, calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan, cyclophosphamide, lung transplantation, ACE inhibitors, anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were omitted. Methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, and IVIg may be beneficial in improving the skin tightness in SSc. Calcium channel blockers, the angiotensin II receptor type 1 antagonist losartan, prazocin, the prostacyclin analogue iloprost, N-acetylcysteine and the dual endothelin-receptor antagonist bosentan may be beneficial for Raynaud's phenomenon. Epoprostenol and bosentan are approved for therapy of pulmonary hypertension (PAH). Other options under investigation include intravenous or aerolized iloprost. Cyclophosphamide (CYC) pulse therapy is effective in suppressing active alveolitis. Stem cell and lung transplantation is a viable option for carefully selected patients. Renal crisis can be effectively managed when hypertension is aggressively controlled with angiotensin converting enzyme (ACE) inhibitors. Patients should continue taking ACE inhibitors even after beginning dialysis in hope of discontinuing dialysis. Antithymocyte globulin and mycophenolate mofetil appear safe in SSc. The improvement in skin score and the apparent stability of systemic disease during the treatment period suggest that controlled studies of these agents are justified. Stem cell transplantation is under investigation for severe disease. Novel therapies are currently being tested in the treatment of SSc and have the potential of modifying the disease process and overall clinical outcome. The evaluation of these studies is still a difficult process.

Autoimmune phenomena following prostatectomy.

BACKGROUND: Benign prostatic hypertrophy is the most common benign tumor in males, resulting in prostatectomy in 20-30% of men who live to the age of 80. There are no data on the association of prostatectomy with autoimmune phenomena in the English-language medical literature. OBJECTIVES: To report our experience with three patients who developed autoimmune disease following prostatectomy. PATIENTS: Three patients presented awith autoimmune phenomenon soon after a prostectomy for BPH or prostatic carcinoma: one had clinically diagnosed temporal arteritis, one had leukocytoclastic vasculitis, and the third patient developed sensory Guillian-Barré syndrome following prostatectomy. CONCLUSIONS: In view of the temporal association between the removal of the prostate gland andthe autoimmune process, combined with previously known immunohistologic features of BPH, a cause-effect relationship probably exists.

Evaluation of disease severity in familial Mediterranean fever.

OBJECTIVE: To establish a new, objective, statistically based severity score for familial Mediterranean fever (FMF). METHODS: One hundred consecutive FMF patients were evaluated independently by 2 FMF experts for severity of their disease and were assigned to 1 of 3 severity levels: mild, intermediate, or severe. Nine candidate criteria, reflecting objective suffering and disability, were analyzed to determine their weight for patient placement in the 3 predefined severity groups. RESULTS: Candidate criteria best differentiating between the 3 patient categories were the frequency of attacks, the number of sites affected during an attack and during the course of the disease, and the duration of the attacks. These criteria were applied in a classification-tree model to establish a new FMF-severity score (F-SS). The first set of F-SS (F-SS-1) was highly sensitive and specific. Integrating F-SS-1 with clinical parameters strongly associated with disease severity resulted in a simplified score, the second set of F-SS (F-SS-2). CONCLUSIONS: New, useful, objective, and valid severity scores were established and found to distinguish between patients with mild, intermediate, and severe diseases with high sensitivity and specificity. RELEVANCE: The F-SS established may be important for treatment decisions, prognosis evaluation, and comparative analysis of patient populations.

Acute renal embolism. Forty-four cases of renal infarction in patients with atrial fibrillation.

Acute renal embolus is rarely reported in the medical literature; thus, accurate data regarding presentation, laboratory tests, diagnostic techniques, and treatment are lacking. To better define this condition, we examined the medical records of all patients admitted to Kaplan Medical Center and Sheba Medical Center in central Israel from 1984 to 2002 who had a diagnosis of renal infarction and atrial fibrillation. We noted demographic, clinical, and laboratory parameters; method of diagnosis; treatment received; and patient outcome. We identified 44 cases of renal embolus: 23 females and 21 males, with an average age of 69.5 +/- 12.6 years. Thirty (68%) patients had abdominal pain, and 6 (14%) had a previous embolic event. Nine patients were being treated with warfarin on admission, 6 (66%) of whom had an international normalized ratio (INR) < 1.8. Hematuria was present in 21/39 (54%), and 41 (93%) patients had a serum lactate dehydrogenase (LDH) level > 400 U/dL. The mean LDH was 1100 +/- 985 U/dL. Diagnostic techniques included renal isotope scan, which was abnormal in 36/37 cases (97%); contrast-enhanced computed tomography (CT) scan, which was diagnostic in 12/15 cases (80%); and ultrasound, which was positive in only 3/27 cases (11%). Angiography was positive in 10/10 cases (100%). Twenty-three (61%) of 38 patients had normal renal function on follow-up. The 30-day mortality was 11.4%. Renal embolus was diagnosed mainly in patients aged more than 60 years, some of whom had a previous embolic event. Most of those receiving anticoagulant therapy had a subtherapeutic INR. Abdominal pain was common, as well as hematuria and an elevated LDH. These patients are at risk of subsequent embolic events to other organs. The most sensitive diagnostic technique in this population is a renal isotope scan, but contrast-enhanced CT scan requires further assessment.

Destructive arthritis in a patient with Haim-munk syndrome.

Haim-Munk and Papillon-Lefèvre are 2 closely related syndromes, inherited in an autosomal recessive pattern, manifested by palmoplantar keratoderma and early, destructive periodontitis. Recently, mutations in the cathepsin C gene have been recognized in both syndromes. We describe a patient with Haim-Munk syndrome (palmar plantar keratosis and periodontitis) and destructive arthritis of the wrists and shoulder joints, an association that has not been previously described.

Analysis of the three most common MEFV mutations in 412 patients with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever is an autosomal recessive disease characterized by recurrent attacks of fever and serositis. The disease is caused by mutations in the MEFV gene, presumed to act as a down-regulator of inflammation within the polymorphonuclear cells. OBJECTIVES: To present the results of 412 FMF patients genotyped for three MEFV mutations, M694V, V726A and E148Q. RESULTS: The most frequent mutation, M694V, was detected in 47% of the carrier chromosomes. This mutation, especially common among North African Jewish FMF patients, was not found in any of the Ashkenazi (East European origin) patients. Overall, one of the three mutations was detected in 70% of the carrier chromosomes. M694V/M694V was the most common genotype (27%), followed by M694V/V726A (16%). The full genotype could be assessed in 57% of the patients, and one disease-causing mutation in an additional 26%. Only one patient with the E148Q/E148Q genotype was detected despite a high carrier rate for this mutation in the Jewish population, a finding consistent with a low penetrance of this genotype. The M694V/M694V genotype was observed in 15 patients with amyloidosis compared to 4 amyloidosis patients with other genotypes (P < 0.0001). CONCLUSIONS: Because of low penetrance and as yet other undetermined reasons, mutation analysis of the most common MEFV mutations supports a clinical diagnosis in only about 60% of patients with definite FMF.

Cholesterol crystal embolization to the digestive system: characterization of a common, yet overlooked presentation of atheroembolism.

In the 1359 published patients with multiorgan cholesterol crystal embolism (CCE), the digestive system seems to be the third most frequently affected system. Yet, this system received hitherto only little attention in the medical literature. Therefore, the aim of the present study was to clinically characterize the subset of patients with CCE involving the digestive system, based on our institutional experience and a review of the literature. Cases with CCE in a 7-yr period (1995-2001) were sought in the computerized records of our medical center. Of the CCE patients, those with digestive system involvement that could be related to CCE were included in this study. The clinical features of CCE were determined and compared with those found in published series. Fourteen cases with CCE were identified, giving an annual incidence of 0.8 per 10(5). Digestive system involvement was found in five (36%) of the 14 patients. All five patients had established atherosclerosis. Precipitating factors were vascular manipulations or anticoagulation treatment in four of these five patients. Two patterns of disease appeared: acute catastrophic multiorgan disorder with poor prognosis and chronic and more indolent GI disease. Abdominal pain, GI bleeding, fever, and diarrhea were the most common manifestations, resulting from bowel infarction, mucosal ulcerations, hepatocellular liver disorder, and/or pancreatitis. CCE is a systemic disorder with a frequent involvement of the digestive system and protean clinical manifestations. It should, therefore, be considered in any gastroenterological patient with atherosclerosis and recent vascular manipulations or systemic anticoagulation.

[Fever and chills following intravenous administration of NeyTumorin--an unconventional xenogenous derived peptides extract].

We report a 54 year old patient who was recently diagnosed with retroperitoneal recurrence of colon carcinoma, and who was admitted because of fever and chills. Extensive work-up yielded no source of infection, multiple blood cultures were sterile, and symptoms resolved within two days. During hospitalization, it was learned that her symptoms appeared an hour after a drug named NeyTumorin was administered to her intravenously by an alternative medicine practitioner. NeyTumorin is part of cell therapy, which is an alternative medicine therapy involving the administration of farm animals derived preparation of peptides from several organs, including the diencephalon and hypophysis. This case underscores the risk of invasive alternative medicine treatments, which are not subject to adequate scrutiny by the health authorities.