text:
Mixed cryoglobulinemia
- Clodoveo Ferri1Email author
© Ferri; licensee BioMed Central Ltd. 2008
Received: 26 February 2008
Accepted: 16 September 2008
Published: 16 September 2008
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© Ferri; licensee BioMed Central Ltd. 2008
Received: 26 February 2008
Accepted: 16 September 2008
Published: 16 September 2008
Mixed cryoglobulinemia (MC), type II and type III, refers to the presence of circulating cryoprecipitable immune complexes in the serum and manifests clinically by a classical triad of purpura, weakness and arthralgias. It is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of 'essential' MC is reported as approximately 1:100,000 (with a female-to-male ratio 3:1), but this term is now used to refer to a minority of MC patients only. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as a late complication. MC may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called 'essential' MC. The etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection is suggested to play a causative role, with the contribution of genetic and/or environmental factors. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjögren's syndrome. Diagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low C4 levels and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium- and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions. Differential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, Sjögren's syndrome, polyarthritis, and B-cell lymphomas. The first-line treatment of MC should focus on eradication of HCV by combined interferon-ribavirin treatment. Pathogenetic treatments (immunosuppressors, corticosteroids, and/or plasmapheresis) should be tailored to each patient according to the progression and severity of the clinical manifestations. Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies.
Mixed cryoglobulinemia (type II or type III), cryoglobulinemic vasculitis.
Classification and clinico-pathological characteristics of different cryoglobulinemias.
Pathological findings
Clinical associations
Type I cryoglobulinemia
monoclonal Ig, mainly IgG, or IgM, or IgA
self-aggregation through Fc fragment of Ig
tissue histological alterations of underlying disorder
-lymphoproliferative disorders: MM, WM, CLL, B-cell NHL
Type II
mixed cryoglobulinemia
monoclonal IgM (or IgG, or IgA) with RF activity (often cross-idiotype WA-mRF) and polyclonal Ig (mainly IgG)
-leukocytoclastic vasculitis
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV)
-autoimmune/lymphoproliferative disorders
-rarely 'essential'
Type II–III
mixed cryoglobulinemia
oligoclonal IgM RF or mixture of poly/monoclonal IgM
(often cross-idiotype WA-mRF)
-leukocytoclastic vasculitis
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV)
-autoimmune/lymphoproliferative disorders
-rarely 'essential'
Type III
mixed cryoglobulinemia
polyclonal mixed Ig (all isotypes) with RF activity of one polyclonal component (usually IgM)
-leukocytoclastic vasculitis
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV)
-more often autoimmune disorders
-rarely 'essential'
The leukocytoclastic vasculitis is the histopathological hallmark of MC (Fig. 2). It may involve small- and medium-sized vessels and may be responsible for multiple organ involvement. The term 'cryoglobulinemic vasculitis' is frequently used as synonym; it better focus on the typical histopathological alterations responsible for cutaneous and visceral organ involvement [3, 10].
For the same reasons, the clinical pattern of the MC syndrome may vary largely among patients series referred to different tertiary care facilities [3, 6, 8–14] (Fig. 3).
It has been estimated that low levels of circulating mixed cryoglobulins can be detected in over 50% of HCV-infected individuals, while overt cryoglobulinemic syndrome develops in about 5% [3, 15, 16]. Because of the wide diffusion of HCV infection worldwide, a growing incidence of HCV-related MC can be expected, especially in underdeveloped countries where HCV in the general population is rather prevalent [3, 17].
The prevalence of 'essential' MC is reported as approximately 1:100,000 but this term is now referred to a minority of MC patients. The female-to-male ratio is 3:1.
Demographic, clinico-serological and virological features of 250 mixed cryoglobulinemia (MC) patients*.
Clinical features
Age at disease onset, mean ± SD yrs (range)
54 ± 13 (29–72)
Female/Male ratio
Disease duration, mean ± SD years (range)
12 ± 10 (1–40)
Arthritis (non-erosive)
Raynaud's phenomenon
Sicca syndrome
Peripheral neuropathy
Renal involvement**
Liver involvement
B-cell non-Hodgkin's lymphoma
Hepatocellular carcinoma
Cryocrit, mean ± SD %
4.4 ± 12
Type II/type III mixed cryoglobulins
C3, mean ± SD mg/dl (normal 60–130)
93 ± 30
C4, mean ± SD mg/dl (normal 20–55)
10 ± 12
Antinuclear antibodies
Antimitochondrial antibodies
Anti-smooth muscle antibodies
Anti-extractable nuclear antigen antibodies
anti-HCV Ab ± HCV RNA, %
Anti-HBV antibodies
Skin lesions represent the most frequent manifestations of the MC [6–10, 14, 24, 25]. Orthostatic purpura is generally intermittent, the dimension and diffusion of purpuric lesions largely varied, from sporadic isolated petechias to severe vasculitic lesions, often complicated by torpid ulcers of the legs and malleolar areas (Fig. 2). In a significant proportion of patients, repeated episodes of purpura may lead to stable, often confluent areas of ochreous coloration on the legs (Fig. 2). Cutaneous manifestations, in particular orthostatic purpura and ulcers, are the direct consequence of vasculitic alterations with the possible contributions of various co-factors, in particular chronic venous insufficiency, physical stress, mainly the prolonged standing, and/or muggy weather. In addition, the contribution of hemorheological disturbances due to high cryocrit levels may also be taken in account [27]. In this respect, the purpuric outbreaks are frequently observed late in the afternoon when highest cryocrit levels are generally observed, often in concurrence with prolonged standing [24].
MC patients commonly report arthralgias, while clear clinical signs of arthritis (usually mild, non-erosive oligoarthritis) are relatively rare [11, 12, 25, 28]
Almost half MC patients complain of xerostomia and xerophthalmia, however, only a few cases meet the current criteria for the classification of primary Sjogren's syndrome (see 'differential diagnosis') [11, 12, 25].
Peripheral neuropathy may frequently complicate the clinical course of the MC, in the majority of cases as mild sensory neuritis [24, 25, 29, 30]. The common symptoms are paresthesias with painful and/or burning sensations in the lower limbs, often with nocturnal exacerbation. The patient quality of life may be severely compromised because of the chronicity of these symptoms along with their scarce sensibility to therapeutic attempts. In a minority of cases the peripheral neuropathy may be complicated by severe sensory-motor manifestations, which usually appeared abruptly, often as asymmetric mononeuritis; in some patients, it may complicate the alpha-interferon treatment, possibly in predisposed subjects [29–33]. Dysarthria and hemiplegia expression of central nervous system involvement are rarely reported [25, 34]; it is often difficult to distinguish these symptoms from the most common atherosclerotic manifestations.
Since HCV infection represents the underlying disorder of the MC in the vast majority of cases, overt chronic hepatitis, generally with mild-to-moderate clinical course, can be observed at any time during the natural history of the disease [24, 25]. Chronic hepatitis was found in a great number of patients (Table 2), evolving to cirrhosis in 1/4, while only 7 patients developed hepatocellular carcinoma. In few cases, especially in combination with renal involvement, liver involvement became a life-threatening complication. On the whole, the clinical course and the prognostic value of this manifestation seem to be less severe if compared to HCV-related chronic hepatitis without MC syndrome [24, 25]; similarly, hepatocellular carcinoma less frequently complicates MC syndrome compared to the whole population of HCV-positive individuals [24, 25]. These differences are quite intriguing, but very difficult to fully explain. It is possible that the light consumption of alcohol and/or the relatively low prevalence of HCV genotype 1b [24, 25] may explain, at least in part, the rather benign clinical course of liver involvement and its scarce prognostic relevance in MC series.
Membranoproliferative glomerulonephritis type 1 is another important organ involvement, which may severely affect the prognosis and survival of the disease [24, 25, 34–37]. MC-related nephropathy is a typical immune-complex-mediated glomerulonephritis, although other immunological mechanisms have also been hypothesized [24, 25, 38, 39].
Widespread vasculitis involving medium-small sized arteries, capillaries and venules with multiple organ involvement may develop in a small proportion of patients [3, 6, 10, 24, 25, 40]. This extremely severe complication may involve the skin, kidney, lungs, central nervous system, and gastrointestinal tract. In rare cases intestinal vasculitis may suddenly complicate the disease, often in patients with renal and/or liver involvement; pain simulating an acute abdomen is the presenting symptom of intestinal vasculitis. A timely diagnosis and aggressive steroid treatment are necessary for this life-threatening complication.
Interstitial lung involvement has been anecdotally observed in MC syndrome as well as in patients with isolated HCV infection [3, 25, 41–43]. Almost invariably, lung involvement in MC is characterized by subclinical alveolitis, as demonstrated by means of bronco-alveolar lavage in unselected patient series [44]; this condition may predispose to harmful infectious complications and, in rare cases, it may lead to clinically evident interstitial lung fibrosis. The hyperviscosity syndrome, due to high levels of serum cryoglobulins is another rare clinical manifestation of MC [27]. Generally, there was no relationship between the severity of clinical symptoms, such as glomerulonephritis, skin ulcers, or diffuse vasculitis and the serum levels of cryoglobulins and/or hemolytic complement [3, 24, 25]. Low complement activity is almost invariably detectable in MC, with the typical pattern of low or undetectable C4 and normal or relatively normal C3 serum levels, regardless the disease activity (Table 2). Moreover, in vitro consumption of complement can be also observed due to the anti-complement activity of some cryoimmunoglobulins [3]. Of interest, a sudden increase in C4, raised to abnormally high levels, can be observed in MC patients developing a B-cell lymphoma [45]. The lack of correlation between circulating cryoglobulin levels and the severity/activity of MC manifestations might be explained on the basis of different hypotheses: the pathogenic role of other non-cryoprecipitable immune-complexes, their intrinsic capacity to activate the complement, and/or the in situ formation of immune-complexes, with a relative concentration of HCV virions [3, 14, 24, 25].
Some endocrinological disorders are significantly more frequent in MC patients compared to the general population [3, 12, 13, 24, 25, 46–50]. The most common thyroid disorders are autoimmune thyroiditis, subclinical hypothyroidism, and thyroid cancer; while hyperthyroidism is less frequent, generally as reversible complication of interferon treatment [51–54]. Moreover, a statistically increased incidence of diabetes mellitus has been observed in HCV-positive patients with and without MC syndrome compared to the general population [55–57]. Finally, HCV-positive males with or without cryoglobulinemic vasculitis may develop erectile dysfunction, attributable to hormonal and/or neuro-vascular alterations [49].
B-cell lymphom a is the most frequent neoplastic manifestation complicating MC, often as late manifestation of the MC syndrome [58–65]. This complication may be related to peripheral B-lymphocyte expansion and to lymphoid infiltrates observed in the liver and bone marrow of MC patients [19, 39, 58, 59]. In particular, these infiltrates have been regarded by some authors as "early lymphomas", since they are sustained by lymphoid components indistinguishable from those of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL) and immunocytoma (Ic) [3, 12, 25, 59]. However, unlike frank malignant lymphomas, they tend to remain unmodified for years or even decades and are followed by overt lymphoid tumors in about 10% of cases [3]. These characteristics justify the proposed term of "monotypic lymphoproliferative disorder of undetermined significance (MLDUS)" [3, 12, 25, 59]. Interestingly enough, type II MC-related MLDUS has its highest incidence in the same geographic areas where about 30% of patients with 'idiopathic' B-cell lymphomas also display HCV-positivity, and where an increased prevalence of HCV genotype 2a/c has been observed in both MC and lymphomas [3, 12, 25, 59]. The type II MC-associated MLDUS presents two main pathological patterns; namely, the B-CLL-like and the Ic-like [3, 12, 25, 59]. In the clinical practice, it is not rare to observe the appearance of malignant B-cell lymphomas in patients with mild MC clinical course, sometimes unexpectedly during a routine evaluation. It is possible to observe a sudden decrease or disappearance of serum cryoglobulins and RF, sometimes associated with abnormally high levels of C4, as presenting symptom of complicating B-cell malignancy [40].
Other neoplastic manifestations, i.e. hepatocellular carcinoma or papillary thyroid cancer, are less frequently observed [3, 11, 24, 50, 59]. In this light, the MC can be regarded as a pre-neoplastic disorder [61]; consequently, a careful clinical monitoring is recommendable, even in the presence of mild MC syndrome [3, 11].
Soon after the discovery of hepatitis C virus (HCV) as the major etiologic agent of non-A-non-B chronic hepatitis [67], a possible role of HCV infection in MC was proposed independently by two pioneering reports [68, 69] showing a significantly higher prevalence of serum anti-HCV antibodies compared to the general population. This hypothesis was definitely demonstrated in 1991, when the presence of HCV RNA was detected by means of polymerase chain reaction (PCR) in 86% of Italian MC patients [70]. Successively, an increasingly number of studies including clinico-epidemiological observations, as well as both histopathological and virological investigations (HCV RNA detection by PCR and/or in situ hybridization) have been definitely established the preeminent role of HCV in the pathogenesis of MC [8–14, 21, 25, 59, 71–76]. The prevalence of serum anti-HCV antibodies and/or HCV RNA in MC patients ranged from 70% to almost 100% among different patient populations [3, 11–13, 25]. Given the striking association between MC and HCV infection, the term 'essential' is now referred to a minority of MC patients (in Italy <5%, Fig. 5) [3, 11–13, 25].
Another important pathogenetic factor is the interaction between HCV E2 protein and CD81 molecule, a quite ubiquitary tetraspannin present on B-cells surface [78]; the consequence may be the strong and sustained polyclonal stimulation of B-cell compartment (Fig. 6). A following pathogenetic step of HCV-related autoimmune-lymphoproliferative disorders may be the t [14, 18] translocation observed in B-cells of HCV-infected individuals [63, 79]. Even if not definitely confirmed [80, 81], the t [14, 18] translocation might lead to abnormally elevated expression of Bcl-2 protein with consequent inhibition of apoptosis and abnormal B-cell survival. Interestingly, the relevant prevalence of t [14, 18] translocation in patients with only type C hepatitis (about 37–38%), become particularly high in patients with HCV-related cryoglobulinemic syndrome, ranging 85% in type II MC [63]. It is possible to hypothesize that during chronic HCV infection, several factors (including the interaction between HCV E2 protein and CD81 molecule, the high viral variability, and the persistent infection of both hepatic and lymphatic cells) may favor a sustained and strong B-cell activation (Fig. 6). This latter may in turn favors the apparition of t [14, 18] translocation and Bcl-2 overexpression; the consequent B-lymphocyte expansion is responsible for autoantibody production, including the cryoglobulins [3, 11, 12, 63, 77–79]. In addition, the prolonged B cell survival may represent a predisposing condition for further genetic aberrations, which may lead to frank B-cell malignancy as late complication of MC syndrome [11, 20, 24, 82].
Of interest, HCV-driven lymphoproliferation may explain the pathogenetic role of HCV infection also in 'idiopathic' B-cell lymphomas [11, 59, 64, 65, 80]. This association was firstly described in unselected Italian patients with 'idiopathic' B-cell lymphomas [64] and successively confirmed by different epidemiological and laboratory studies, mainly in the same geographical areas where HCV-associated MC is commonly found [65].
Given its biological characteristics, HCV may be involved in a wide number of autoimmune and lymphoproliferative disorders [3, 11, 12, 63, 77–79]. Fig. 6 summarizes the main causative factors -infectious, toxic, genetic, and/or environmental- that are potentially involved in the pathogenesis of MC [11, 12, 79, 82–84]. These factors, alone or in combination, may trigger two multistep pathogenetic processes, not mutually exclusive, responsible for MC and other HCV-related disorders. The first one produces a 'benign' poly-olygoclonal B-lymphocyte proliferation responsible for organ- and non-organ-specific autoimmune disorders, including the immune-complex-mediated cryoglobulinemic vasculitis; the second one is characterized by different oncogenetic alterations, which ultimately may lead to malignant complications [11, 82]. Comparable pathogenetic mechanisms could be also hypothesized for HCV-negative MC, this intriguing clinical subset might be correlated to other infectious agents or associated to some well-known autoimmune/rheumatic or lymphoproliferetive disorders (Fig. 5, 6) [13]. Th1-mediated tissue alterations are probably responsible for some endocrine disorders, i.e. diabetes type 2 and thyroid dysfunction, in HCV-associated MC patients [57]. Our preliminary data suggest that HCV infection of thyrocytes, as well as of beta cells, may upregulate CXCL10 gene expression and secretion (as shown in human hepatocytes); the consequent recruitment of Th1 lymphocytes that secrete IFN-γ and TNF-α may in turn induce CXCL10 secretion by infected cells, thus perpetuating the immune cascade responsible for these endocrine disorders. All the above pathogenetic mechanisms could be also hypothesized for HCV-negative MC, this intriguing clinical subset might be correlated to other infectious agents or associated to some well-known autoimmune/rheumatic or lymphoproliferetive disorders (Fig. 5, 6) [13].
MC with or without overt clinical syndrome has been reported in patients with a great number of infectious agents, usually as anecdotally observations [9]. A significant prevalence of MC has been observed in patients with human immunodeficiency virus (HIV) infection, with and without HCV co-infection [85]. HIV alone may exert a continuous antigenic stimulation of B-lymphocytes; these latter may be responsible for type III MC production earlier in the course of HIV infection. In some patients the B-cell disorder may evolve to monoclonal MC with typical clinical syndrome. As observed for HCV infection, the prevalence of other virus-related MC seems to show a variable prevalence among patient's series from different geographical areas [86]. Moreover, a number of clinico-epidemiological studies revealed a heterogeneous distribution of different HCV-related extra hepatic manifestations, including some autoimmune disorders such as 'primary' Sjogren's syndrome [87–98].
Proposed criteria for the classification of mixed cryoglobulinemia (MC) patients.
mixed cryoglobulins
low C4
leukocytoclastic vasculitis
rheumatoid factor +
clonal B-cell infiltrates
(liver and/or bone marrow)
chronic hepatitis
peripheral neuropathy
skin ulcers
definite mixed cryoglobulinemia syndrome:
a) serum mixed cryoglobulins (± low C4) + purpura + leukocytoclastic vasculitis
b) serum mixed cryoglobulins (± low C4)+ 2 minor clinical symptoms
+ 2 minor serological/pathological findings
essential or secondary mixed cryoglobulinemia:
absence or presence of well-known disorders (infectious, immunological or neoplastic)
The detection of serum mixed (IgG-IgM) cryoglobulins is necessary for a correct classification of MC syndrome (Table 3, Fig. 1). Unfortunately, there are no universally accepted methodologies for cryoglobulin measurements, but simple standardized indications are often sufficient for testing cryoglobulinemia [3, 9, 23]. Since cryoglobulins present a high thermal instability, the measurement of Ig cryoprecipitate should be performed immediately in the same place where the blood is sampled. For a correct evaluation of serum cryoglobulins, it is necessary to avoid false-negative results due to Ig cold precipitation also at room temperature. For this purpose, the first steps (blood sampling, clotting, and serum separation by centrifugation) should be always carried out at 37°C and the cryocrit determination and cryoglobulin characterization at 4°C (after 7 days). The serum with cryoglobulins should be tested for reversibility of the cryoprecipitate by rewarming an aliquot at 37°C for 24 hours. Moreover, cryocrit determinations (percentage of packed cryoglobulins referred to total serum after centrifugation at +4°C; Fig. 1) should be done on blood samples without anticoagulation to avoid false-positive results due to cryofibrinogen or heparin-precipitable proteins. Without the above relatively simple precautions, not only will the quantities of cryoglobulins measured be incorrect, but the test may completely fail to even detect cryoglobulins.
After isolating and washing the cryoprecipitate, the identity of cryoglobulin components can be determined by immunoelectrophoresis or immunofixation. These analysis must be performed at 37°C to avoid precipitation and hence loss of the cryoglobulin during the procedures. More sophisticated methodologies, such immunoblotting or two-dimensional polyacrylamide gel electrophoresis, can be proposed for laboratory investigations [102–104]. While the detection of serum cryoglobulins is fundamental for the diagnosis of MC, the levels of serum cryoglobulins usually do not correlate with the severity and prognosis of the disease [3, 11, 12, 24, 25]. Very low levels of cryocrit, often difficult to quantify, can be associated with severe and/or active cryoglobulinemic syndrome; on the contrary, high cryocrit values may characterize a mild or asymptomatic disease course. In rare cases, very high cryocrit levels, possibly associated to cryogel phenomenon, can be associated to classical hyperviscosity syndrome [24, 25, 27]. On the contrary, a sudden decrease or disappearance of serum mixed cryoglobulins, with or without abnormally high levels of C4, can be regarded as alarming signal of complicating B-cell malignancy [45].
Clinico-diagnostic assessment of mixed cryoglobulinemia (MC) syndrome
Clinical and serological work-up at patient's first evaluation
• past clinical history, physical examination
• chest x-ray, EKG, abdominal US, blood chemistry & urinalysis
• cryoglobulin detection and characterization (see Tab. 1)
• RF, C3–C4, ANA, anti-ENA, ANCA, ASMA, AMA, anti-LKM1, others auto-Ab
• virological markers: HCV (genotyping), HBV, others
• evaluate possible comorbidities (cardiovascular, endocrine/metabolic, etc.)
• MC classification (definite, essential, secondary): see Tab. 3
Diagnosis & monitoring of major MC complications
• chronic hepatitis, cirrhosis, hepatocellular carcinoma: monitoring (every 6–12 month) of ALT, AP & liver US (biopsy, CT scan)
• glomerulonephritis: monitoring of urinalysis & serum creatinine (kidney US, biopsy)
• peripheral neuropathy: clinical monitoring; EMG
• skin ulcers: exclusion of vascular comorbidities (A-V Doppler evaluation)
• sicca syndrome: differential diagnosis with primary SS (see Fig. 7)
• arthritis: differential diagnosis with RA (see Fig. 7)
• thyroid involvement: hormones, auto-Ab, neck US, fine-needle aspiration
• B-cell lymphoma: clinical monitoring; bone marrow/lymph node biopsies, total body CT scan
The term 'essential' MC was originally referred to autonomous disease when other well known systemic, infectious or neoplastic disorders have been ruled out by means of a wide clinico-serological work-up [5]. However, in some patients a definite diagnosis may be difficult because of the clinical polymorphism of the disease. Moreover, the association of MC with HCV infection may further complicate the differential diagnosis with other immunological HCV-related disorders: there is a frequent clinico-pathological overlapping among different HCV-related disorders. Cryoglobulinemic syndrome can represent a crossroads between some autoimmune diseases (autoimmune hepatitis, Sjögren's syndrome, polyarthritis, glomerulonephritis, thyroiditis, type 2 diabetes, etc.) and malignancies (B-cell lymphomas, hepatocellular carcinoma) [3, 11, 12, 25, 28, 87–98]. It is possible to observe in the same patient a slow progression from mild HCV-associated hepatitis to various extrahepatic manifestations (arthralgias, sicca syndrome, Raynaud's phenomenon, RF positivity, etc.), and ultimately to overt MC syndrome with typical clinico-serological manifestations. In only a minority of MC patients a malignancy may develop, generally after a long lasting follow-up period [3, 11, 12, 24, 25]. Therefore, a careful patient evaluation is necessary for a correct diagnosis of MC syndrome, particularly with regards to other RF-positive, systemic rheumatic disorders such as rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS) (Fig. 7).
While arthralgias are one of the most frequent symptoms, clear signs of sinovitis are quite rare. Generally, patients develop mild, non-erosive oligoarthritis [28, 90], often sensitive to low doses of corticosteroids with or without hydroxychloroquine. In contrast, a rheumatoid-like polyarthritis is more frequent in patients with HCV-related hepatitis without MC syndrome [28]. In patients with HCV-associated MC and symmetrical, erosive polyarthritis the diagnosis of overlapping MC/RA syndrome can be suspected. In these cases, the detection of serum anti- cyclic citrullinated peptide antibodies, markers of classical RA, may represent a useful diagnostic tool [91, 92].
Almost half MC patients complain of sicca syndrome; however, only a few cases meet the current criteria for the classification of pSS. MC and pSS may share various symptoms: xerostomia and/or xerophthalmia, arthralgias, purpura, RF and serum cryoglobulins, and the possible complication with B-cell lymphoma [3, 11, 12, 25, 87, 93–98]. However, a careful patient clinical assessment is usually sufficient for a correct diagnosis in the large majority of cases by considering some important findings: histopathological alterations of salivary glands and specific autoantibody pattern (anti-RoSSA/LaSSB) of pSS are rarely found in MC patients; conversely, HCV infection, cutaneous leukocytoclastic vasculitis, and visceral organ involvement (renal, liver) are seldom recorded in primary Sjögren's syndrome (Fig. 7). Given the above considerations, it has been recently proposed that the presence of HCV infection per se should be considered exclusion criteria for the classification of pSS [99, 100]. In rare cases in which the differential diagnosis may result very difficult, particularly in HCV-negative individuals, it might be correct to classify the disorder as overlap syndrome. However, patients with MC/pSS overlap syndrome are often characterized by more severe clinico-prognostic evolution; they show a significant low rate of anti-RoSSA/LaSSB along with a high prevalence of mixed cryoglobulinemia, hypocomplementemia, systemic autoimmune manifestations, and complicating lymphomas (94, 97, 98). In the clinical practice, this particular condition could be better regarded as vasculitic syndrome with relevant implications on the patient monitoring and treatment [11, 24, 25].
Finally, autoimmune hepatitis, the old 'lupoid' hepatitis, may be associated to HCV infection, mainly in the same countries where HCV-associated MC is more frequently found [88]. Moreover, it may share with MC syndrome a number of extrahepatic symptoms, including serum mixed cryoglobulins [89]. The differential diagnosis between these two conditions may be problematic: some typical features of MC (leukocytoclastic vasculitis, hypocomplementemia, glomerulonephritis), as well as the presence of serum autoantibodies commonly found in autoimmune hepatitis (anti-smooth muscle antibodies) can be taken into account.
In patients with 'essential' MC the immunosuppressive treatment, i.e. cyclophosphamide or rituximab, is still the first-line intervention (Fig. 9, 10). For HCV-associated MC, immunomodulating/immunosuppressive treatments should be considered, especially in patients with more severe complications. These treatments include steroids, low-antigen-content (LAC) diet, plasma exchange, and immunosuppressors [3, 11, 12, 24, 116–122]. In particular, both traditional plasma exchange and double-filtration plasma exchange are able to markedly reduce the levels of circulating immune-complex, especially the cryoglobulins [24, 121, 122]. Oral cyclophosphamide (50–100 mg/day for 2–6 weeks) during the tapering of apheretic sessions can reinforce the beneficial effect of plasma exchange; moreover, it can prevent the rebound phenomenon that may be observed after the aphaeresis discontinuation [24]. Plasma exchange is particularly useful in severe MC complications such as active membranoproliferative glomerulonephritis (Fig. 8, 9, 10).
LAC-diet is a particular dietetic treatment that can improve the clearance circulating immune-complexes by restoring the activity of the reticulo-endothelial system, overloaded by large amounts of circulating cryoglobulins [122, 123]. LAC-diet has been designed to reduce the input of alimentary macromolecules crossing the mucosal barrier of the gut; some foods, particularly dairy products and eggs, present a potential antigenic activity, and consequently might be involved in the pathogenesis of some diseases in humans. The reduction of the alimentary input of macromolecules directed to mononuclear phagocytic system may improve its function in those conditions characterized by abnormal endogenous production of immune-complexes responsible for organ damage, i.e. mixed cryoglobulinemia and other immune-complex mediated diseases. An impaired function of mononuclear phagocytic system has been also demonstrated in patients with IgA nephropathy [123]. Given the above pathogenetic considerations, LAC-diet has been usefully employed in patients with clinically mild MC symptoms and IgA nephropathy (reduction of 24-hour proteinuria). Usually, LAC-diet and/or low dosage of steroids (6-methyl-prednisolone 2–4 mg/day) may be sufficient to improve mild manifestations (arthralgias, sporadic purpura, etc.) of the MC (Fig. 8, 9, 10); patients with mild-moderate symptoms, such as palpable purpura, are particularly sensitive to the smallest variations of daily steroid dosage (1–2 mg).
In clinical practice, MC treatment should be tailored for the single patient according to the severity of clinical symptoms (Fig. 9, 10). Therefore, patients with severe vasculitic manifestations must be promptly treated with high doses of steroids and/or plasma exchange and/or cyclophosphamide or rituximab. Some recent clinical studies suggested that sequential or combined antiviral/immunosuppressive treatment could represent a rather useful therapeutic strategy [124, 125]. The rationale of such aggressive therapies could be particularly indicated in MC patients with major clinical manifestations and partial/transitory remission after standard treatments [25, 124, 125]. On the contrary, clinically asymptomatic patients usually do not need any treatment, even in the presence of high levels of cryocrit. In all cases, a careful clinical monitoring of the disease is mandatory, with particular attention to neoplastic complications. Preliminary studies suggested the synergic affect of some therapies in association with antiviral treatment, namely the cyclosporine A or tumor necrosis factor inhibitors, in the setting of chronic hepatitis type C [126–128]. These agents may contribute to viral clearance and/or to improve the immune-mediated hepatic and extrahepatic inflammatory manifestations; future clinical trials might evaluate their potential usefulness even in MC, possibly in selected patient subsets.
The natural history of MC is not predictable and strongly depends on concomitant diseases and complications and response to treatment. Morbidity due specifically to cryoglobulinemia may also be significant (infections, cardiovascular diseases, progressive renal failure, advanced neuropathy). The overall prognosis is worse in patients with renal disease, liver failure, lymphoproliferative disease, and malignancies. Mean survival is estimated to be approximately 50–60% at 10 years after diagnosis [24]. Careful monitoring of life-threatening MC complications (mainly nephropathy, widespread vasculitis, and B-cell lymphoma or other malignancies) should be carried out in all MC patients.
MC was first described as distinct disorder in 1966 [5]; 25 years later the discovery of the strong association between MC and HCV infection [3, 11, 12, 25, 70] represented a decisive contribute for a better understanding of the etiopathogenetic mechanisms responsible for the disease, and consequently for an adequate therapeutic strategy.
However, the following points remain still to be clarified:
1- Since the etiopathogenesis of HCV-associated MC syndrome is a multifactorial and multistep process, two important aspects need further investigations: a) HCV may represent the simple triggering factor or it could also contribute to self-perpetuating mechanism of the disease: b) nature and role of other etiopathogenetic co-factors;
2- The etiopathogenesis of 'essential' MC syndrome;
3- The actual role of HCV eradication on the natural history of HCV-associated MC syndrome;
4- The usefulness of sequential or combined antiviral/immunesuppressive treatments compared to traditional therapeutic approach.
rheumatoid factor
mixed cryoglobulinemia
hepatitis C virus
membranoproliferative glomerulonephritis
B-cell chronic lymphocytic leukemia
monotypic lymphoproliferative disorder of undetermined significance
hepatitis B virus
polymerase chain reaction
very low-density lipoprotein
mucosa-associated lymphoid tissue
human immunodeficiency virus
rheumatoid arthritis
primary Sjögren's syndrome
low-antigen-content diet.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Food & Home
Gardening with Kids: Potted Flowers
An excellent way of honoring our earth is to let it help us grow things. It is remarkably easy to start flowers and plants and even vegetables from seed. This is an excellent project for parent and child.
Design Your Own Crib Bedding
The mom-run bedding company Javis Davis provides parents with a new easy-to-use design tool allowing them to become designers of their own made-to-order crib bedding.
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Ethan Allen's Manhattan Beach Set.
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Elmo Inflatable Bed.
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Select Local Merchants
Water 2 WineRead MoreAfter 22 years in the air force, Water 2 Wine–founder John McFadden established his first custom winery in San Antonio seven years ago. Already the business has spread as far as Milwaukee to the north and Denver to the west, bringing the country's vinophiles more than 100 wines, each of which are fermented on site and available for tastings every day. Those who want to get more involved in the crafting process may sign up to make their own wine and steep themselves in each step of the operation, from selecting the grape varieties, beginning the fermentation process, withstanding a wait of about 45 days, and finally christening their creation by smashing a tiny boat against the bottle. All custom-made wines are plastered with personalized labels made from one of Water 2 Wine's templates or images that customers design from the ground up.2000 S I-H 35, Ste. H1-2Round Rock, TX US
Inwood Estates VineyardsRead MoreDan Gatlin is a bona fide pioneer in the field of Texas winemaking. His father owned a chain of convenience and wine and spirits stores, which meant Dan was closely attuned to the rise of winemaking in California in the 1970s. In 1981, Dan took a shot at spurring the same type of enterprise in Texas, opening a small vineyard that would one day grow into the successful Inwood Estates Vineyards. Today the winery produces red and white wines that take advantage of Texas's distinctive terroir, or soil, to produce complex flavors.100 Via FrancescaFlorence, TX US
Lola Savannah CoffeeRead MoreJonesing for a cup of your favorite java? Lola Savannah Coffee's got you covered. Vegan diners will feel at home at Lola Savannah Coffee, a local favorite. Your large group can all sit together at Lola Savannah Coffee. Surf the web from your tablet or laptop on Lola Savannah Coffee's complimentary wifi. Dine out in the open during Lola Savannah Coffee's summer season when patio tables are available for use. Drift away from stuffy dress-code conventions and dine in comfort at Lola Savannah Coffee. At Lola Savannah Coffee, you can park quickly and safely in a lot next door. Bike parking is also available outside the coffee shop. Major credit cards are accepted as a form of payment, so patrons are advised to charge responsibly. You can stop by at practically any time, since Lola Savannah Coffee serves breakfast, lunch, and dinner. If you need a midday pick-me-up, you can count on the coffee from Lola Savannah Coffee to do the trick.6317 Bee Cave RoadAustin, TX US
Texas WinosRead MoreTexas Winos host events that showcase life's finer pleasures without the pretension. The staff organizes outings such as winery and brewery tours, music events, picnics, and fundraisers. Holiday-themed tours inject festive seasonal glee into tours, with special events on fetes such as Cinco de Mayo. But one of their true passions remains wine. Eager to share their vigor for vino, they take guests to the state's finest vineyards, allowing tour-goers a behind-the-scenes look at the winemaking process while meeting new friends. Hands-on experiences include primers on how to expertly taste wine as guides expound on the vagaries of the fermentation process and explain exactly where baby grapes come from.258 W. 2nd StreetAustin, TX US
Fall Creek VineyardsRead MoreYou'll love the professionals in Austin at Fall Creek Vineyards and their fantastic wines to pair with any of your meals. At Fall Creek Vineyards, you can browse a selection of wines and expand your taste palette. With the many parking choices near Fall Creek Vineyards, finding parking within walking distance is a breeze. When you need to start your weekend early, head on over to Fall Creek Vineyards and pick up a few bottles of wine.1402 San Antonio StreetAustin, TX US
Austin Custom WineryRead MoreYou can find great parking in the surrounding area. Austin Custom Winery provides ample space for bikers to store their bikes.5207 Brodie LaneAustin, TX US


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The gorgeous days the region has seen this week will soon turn into heavy rains and uncomfortable moisture.
News 12 New Jersey Meteorologist Dave Curren says overnight lows will be in the 60s.
This weekend, parts of central and southern New Jersey will receive some lingering showers as a storm moves up the coast.
Highs will be in the high 70s and low 80s.
The dew point temperatures...
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Script Debugger's ability to explore a scripting dictionary is nothing short of amazing. You can get a quick overview or scrutinize the tiniest details of any application's syntax. Best of all, you can view an application's current settings and document properties in the terminology of its own scripting dictionary.
- Stan Cleveland, Professional Scripter, Portland, Oregon
This is an outstanding upgrade to an already outstanding application. The new dictionary viewer is simply stunning, but the whole UI has been refreshed with an eye to helping the scripter be more productive. In a word: indispensable.
- Shane Stanley, AppleScript Trainer and author of 'AppleScriptObjC Explored'
Script Debugger 5 is a tremendous leap for what has long been an indispensable tool for any AppleScript developer. Its much-improved interface allows easier access to multiple scripts and its superb dictionary view options. But this is also a feature-rich update.
- Ray Robertson, Developer and AppleScript Trainer


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Half the storySeptember 17,2013
Half the story
The recent Times Argus headline Shumlin eyes payroll tax hike on the front page unfortunately tells only half the story of funding for single payer. It isnt until the last paragraph on Page 3 of the Peter Hirschfeld article that we read about the biggest health care premium reduction in American history that should more than offset the payroll tax in dollars for all Vermonters.
To emphasize in a headline only one aspect of the plan without the other is not even-handed reporting. Unfortunately, to many casual readers, the tax, not the premium reduction is what they will end up remembering.
Jerry Kilcourse
MontpelierMORE IN LettersAn open mind and job options; an interesting jobs program idea Art Edelstein came up with in his... Full Story
The life of the Titanic came to an abrupt, catastrophic end on its maiden... Full StoryAs most people know, a trace of marijuana can remain in a persons system long after the high... Full Story
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Town Square
First 8 PM or Later Menlo Park Sunset Occurs Tonight
Original post made by Hank Lawrence, Menlo Park: Sharon Heights, on May 2, 2013
Comments (1)
a resident of Menlo Park: Sharon Heights
on May 2, 2013 at 11:23 am
Thank you, Hank. To you and yours as well.
First post in awhile, glad to see you back.
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Teaspoon adds new location inside Mervyn's in Mountain View
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Archived Story
Lent should be a season of giving back, not giving upPublished 9:03am Friday, February 28, 2014
By the Rev. Don Rose, Mansfield and United Lutheran Churches
"Are you giving anything up for Lent this year?" With Ash Wednesday and the beginning of Lent just a few days away, this question is being asked in many Christian circles these days. It has long been a tradition for many to see Lent as a time to exercise discipline and self-control by denying themselves something in their lives, i.e. chocolate, dessert, etc. Though the season is only 40 days long, it is not often any easier to keep these Lenten disciplines than it is to keep New Year's resolutions. What starts with great zeal and dedication often runs out of steam very quickly.
As good as these acts of self-denial might be for the individual and his or her health, perhaps God's people would be better served to look outside of themselves for the season of Lent and to discover others who are in need and to work on direct, concrete ways in which those persons might be assisted. The classic Lenten disciplines of prayer, fasting and the giving of alms or assistance were not just intended to improve one's relationship with God. In addition, they were to improve one's relationship with people and the whole of God's creation. As a result, caring for others then becomes not just an act of charity but rather, more importantly, a witness to faith in the midst of a world that is self-focused to say the least.
Rather than a season for giving up, Lent can become a season of taking up ways in which God's people can be of service to others by offering themselves through the gifts of time, talents and treasure to improve the lives of others. Lent is a good season for engaging in these opportunities as such acts reflect the self-sacrificing love of God as revealed in Jesus the Christ as well as it's being a season that is short enough to make such commitments realistic, and yet long enough to make such practices habits of everyday life as children of God.
God's people are encouraged to see Lent as an opportunity rather than a burden. It is a season of witness and service for the sake of the one who gave himself to be the redemption of the whole world. Use this season as a time to take up something new that will be a help to others. Trust God that it may change your life forever.


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DIRECTV And Viacom Reach Agreement To Renew Carriage Of Viacom's Networks
NEW YORK, July 20, 2012 /PRNewswire/ -- Viacom (NASDAQ: VIA, VIAB) today announced that the company has reached a long-term agreement to renew carriage with DIRECTV. (Logo: http://photos.prnewswire.com/prnh/20110811/NY51392LOGO )All 26 Viacom networks, including Nickelodeon, Comedy Central, MTV, BET, CMT, Logo, Spike, TV Land, MTV2, VH1, VH1 Classic, Palladia, Nick Jr., Nicktoons, TeenNick, Tr3s and Centric, will return to DIRECTV's channel lineup immediately. As part of the overall carriage agreement, DIRECTV has an option to add the EPIX service to its entertainment offerings. Viacom is extremely pleased to bring its programming back to DIRECTV subscribers, and thanks everyone affected by the disruption for their patience and understanding during this challenging period. SOURCE Viacom Inc.
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- Mann Ki Baat PM Modi discussed issues like Education to Drought(1255)
- To Complete Financial Business, Parliament Session set to start from April 25(1140)
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Latest Pictures
Resul Pukootty is ecstatic as he shows off his Oscar trophy to Amitabh Bachchan at an award ceremony.
Resul Pukootty is ecstatic as he hugs Amitabh Bachchan who later gave him an award for his contribution to sound industry on behalf of Western India Motion Pictures & TV sound engineers association in Mumbai.
Resul Pukootty is ecstatic as he displays his Oscar and Bafta awards after recieving an award from Amitabh Bachchan for his contribution to sound industry.
Resul Pukootty is ecstatic as he hugs Amitabh Bachchan who later gave him an award for his contribution to sound industry on behalf of Western India Motion Pictures & TV sound engineers association in Mumbai.
Resul Pukootty is ecstatic as he displays his Oscar and Bafta awards after recieving an award from Amitabh Bachchan for his contribution to sound industry.
Singer Rageshwari at the launch of music album "Dancing Flute" in Mumbai.
Film Star Pran
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Displaying 1 - 10 of about 129 for Pran.
Hot news for Pran.
President condoles Pran's death
- 13 Jul 2013
New Delhi, July 13 (IANS) President Pranab Mukherjee Saturday condoled the death of Bollywood actor Pran.In a condolence message to Pran's wife Shukla Sikand... of your husband, Shri Pran Krishan Sikand (Pran). Shri Pran was a highly talented
Dadasaheb Phalke award for Pran
- 12 Apr 2013
New Delhi, April 12 (IANS) The arch villain of Bollywood, Pran Krishan Sikand - or Pran as he is popularly known - was Friday named for the Dadasaheb Phalke... the Information & Broadcasting Ministry told IANS: "Yes, he (Pran
Pran's immortal songs
- 13 Jul 2013
Mumbai, July 13 (IANS) Not too many people know this, but Pran has a hugely... at Pran's chartbusters.* Kasme vaade pyar wafa: "Upkar" (sung by Manna Dey...: "Adhikar". This evergreen qawaalli sung by Mohd Rafi and filmed on Pran embodies
Veteran actor Pran dead
- 12 Jul 2013
Mumbai, July 12 (IANS) Legendary actor Pran Kishan Sikand, popular as Pran... six decades, Pran acted in over 400 movies.Pran was chosen to receive the 44th..., Pran got a break in Bombay Talkies' film "Ziddi", in which Dev Anand played
Veteran actor Pran in hospital
- 19 Nov 2012
Mumbai, Nov 19 (IANS) Veteran actor Pran, 92, is in hospital but there is no cause for worry, a spokesperson of the Lilavati Hospital here said Monday."Pran is hospitalised here. He was admitted on Friday. He is here for just a routine
Pran alright, says doctor
- 23 Nov 2012
Mumbai, Nov 23 (IANS) It is a week since veteran actor Pran, 92, is admitted...."Pran is hospitalised here. He is alright and is absolutely fine," Suhir... is fine."Pran established his image as Bollywood's quintessential villain in movies
Bollywood reacts to Pran's death
- 13 Jul 2013
Mumbai, July 13 (IANS) Bollywood stars who worked with Pran in films speak... and Pran saheb sharing screen space. It was one of my most fun-filled shootings. Pran saheb was full of anecdotes and stories about the industry. He kept me
Pran recovering fast at hospital
- 20 Nov 2012
in Bollywood when news of the 92?year?old veteran actor Pran's hospitalisation filtered... Raza Murad who visited Pran Saab Monday afternoon, the ailing actor is well.... They are all hopeful of taking Pran Saab home in a day or two. It was nothing
Pran's body taken to crematorium
- 13 Jul 2013
Mumbai, July 13 (IANS) Legendary actor Pran's body, adorned with flowers... overnight at the Lilavati Hospital, where Pran, Bollywood's most loved villain... and prolific career, Pran was marked for his roles as a villain, hero and even
Pran still in hospital, but better
- 19 Jan 2013
Mumbai, Jan 19 (IANS) Veteran actor Pran, who has been in hospital now for almost a month, has shown signs of improvement, the actor's son said."My father... is doing fine, and is much better now," Pran's son Sunil told IANS.The 92-year


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Rachmaninov: Symphony No. 2 / Dortmunder PO, Gabriel Feltz
1 Super Audio CD / Dreyer-Gaido / 2015-11-13Works: Sergey Rachmaninov: Symphony no 2 in E minor, Op. 27
Conductors: Feltz, Gabriel
Ensemble: Dortmunder Philharmonic
The legacy of Sergei Rachmaninov encompasses a staggering plethora of musical styles and sensibilities and a fascinating bridge between the Romantic and modern musical eras....continue...
Recording information: Konzerthaus Dortmund (10/21/2014/10/22/2014)....continue...
Mahler: Symphony No. 1 "Titan" / Stuttgart PO, Feltz
1 CD / Dreyer-Gaido / 2014-04-29Works: Gustav Mahler: Symphony no 1 in D major "Titan"
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The Gustav Mahler symphony cycle project, began in 2007, from conductor Gabriel Feltz and the Stuttgart Philharmonic continues with the release of the First Symphony....continue...
Recording information: Beethovensaal, Liederhalle, Stuttgart, Germany (02/24/2012)....continue...
Mahler: Symphony No. 4 / Jeannette Wernecke, soprano; Gabriel Feltz
1 CD / Dreyer-Gaido / 2012-06-26Works: Gustav Mahler: Symphony no 4 in G major
Performers: Wernecke, Jeannette [Soprano Vocal]
Conductors: Feltz, Gabriel
Ensemble: Stuttgartt Philharmonic
Dreyer Gaido, based in Münster and founded in 2001 by Michael Dreyer and Hugo Germán Gaido, has acquired an outstanding reputation in the classic scene...continue...
Recording information: Beethovensaal, Stuttgarter Liederhalle (01/25/2011)....continue...


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Whenever a new innovation hits the world of food claiming to make you healthier, it's always smart to err on the side of caution. The infomercial duds are rampant, and after this weekend's CES Unveiled event in Las Vegas, a new one has just joined their ranks. It's a vibrating utensil: "The fork vibrates if you take a bite less than 10 seconds after the last mouthful," CNET reports. "That will teach you to slow down, enjoy each morsel, and allow your brain to rein in your appetite." For my part, I can't imagine any scenario in which you'd want to be interrupted from a delicious dinner by an acute buzzing in your mouth. And in any case, most readily "boltable" foods tend to be fast food — pizza, sandwiches, burritos, and other things people generally eat without forks. Even CNET points out flaws: "They haven't proven effective at helping people lose weight yet." There's no question that bolting your food down in five minutes like a wild animal is both unhealthy and unseemly, but let's not pretend the solution is to spend $99 on something that could short-circuit in your dishwasher. Try this more sensible approach, instead.
The Hapifork: An Annoying Utensil That You Will Never Buy
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There's a strong case for making restaurant work mandatory.
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Chipotle Has a New Plan to Win You Back, and It, Too, Might Upset Your Stomach
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There's More Than One Right Way to Get Sticky Gunk off Your Fancy Cookware
Our resident clean person breaks down a few different methods.
This Naked Restaurant Is Definitely Taking the Paleo Diet Too Far
Today in things that shouldn't exist.
Let's Make Sense of Ray Kurzweil's Batshit Breakfast
Or what to eat if you want to live "forever."
The Real Reason McDonald's Ditched the McWrap
Hint: It's everyone's favorite scapegoat.
Bernie Sanders Would Be Pissed About What Third-Class Titanic Passengers Were Eating
The 1% got veal, camembert, and salmon mayo.
Say a Prayer That McDonald's All-You-Can-Eat Fries Pilot Becomes Official
Or make a blood sacrifice to the Golden Arches.
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Inspired by a map featured on twhl.info
My first multiplayer map that I've released in all it's glory.
(Try to) Have fun.
Made with Jackhammer.
bast map 10/10
the hell is that?
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Second Sister Dies Following Fitchburg FireA second woman has died a day after being pulled from an early morning Fitchburg fire that also killed her sister.
Woman Dies, 2 Rescued From Fitchburg House FireOne woman was found dead but her sister and brother were rescued from a burning house in Fitchburg early Wednesday morning.
Jeremiah Oliver's Death Officially Ruled A HomicideThe Fitchburg boy's remains were found in April 2014 on Interstate 190 in Sterling after he was missing for months.
Man Wanted In Virginia Killing Dies After Shooting Self In FitchburgAuthorities say a man who shot himself as police closed in on him in connection with a killing in Virginia has died.
Man Loses Leg, 2 Boys Severely Hurt In Fitchburg ATV CrashA man's leg was cut off and two little boys were seriously hurt when two all-terrain vehicles crashed on New Year's Eve in Fitchburg.
3 People Injured In ATV Accident In FitchburgThree people were injured when two ATVs crashed in Fitchburg.
Fitchburg Man Saves Life Just Days After Learning How To Use NarcanA Fitchburg library worker saved a woman's life just days after learning how to use Narcan.
22 Displaced By Fitchburg Triple-Decker FireNearly two dozen people were displaced by a triple-decker fire in Fitchburg on Saturday afternoon.
Firefighters Battle 3-Alarm Fitchburg House FireFirefighters battled a three-alarm house fire in Fitchburg on Saturday afternoon.
Father Fights For Justice After Daughter Was Killed By Snow Plow In FitchburgNo charges have ever been filed, but her family is hoping a new lawsuit will shed light on the case.
String Of Suspicious Fitchburg Fires Have Residents Living In FearA string of suspicious fires have Fitchburg residents living in fear following one that broke out on Monday morning.
Man Arrested After Firing Shots Near Fitchburg State, Police SayA 29-year-old Fitchburg man is facing multiple charges after allegedly firing two shots into the air near Fitchburg State University on Thursday.


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Rubenstein School Alumni and Friends
Welcome Back!
Thanks for checking in with the Rubenstein School of Environment and Natural Resources! As alumni and friends of the School, you are an integral part of the Rubenstein School community. Your support and involvement help ensure excellence in our academic programming as well as opportunities for our current students.
Stay Connected!
As a School, we are proud of our alumni and the incredible work that you are doing around the world. Please stay connected. Use the Alumni Update form to update your email address and to let us know what you are up to. Explore the School website to find out about ways that you can be involved. It is an exciting time in our School's history as we help lead UVM toward becoming a premier environmental university in the country. Join us in this extraordinary effort.
If you are an alum and would like to receive our quarterly School enewsletter, please send your email address to firstname.lastname@example.com.
2016 Rubenstein School Alumni Survey
As part of our 10-year program review, we have reached out to you, our 4,281 alumni, to help us assess the impact and value of the learning opportunities you experienced while a student. Thanks to all our alumni who completed the survey. It's not too late if you haven't completed yours – simply email email@example.com for your email invitation..
We value your reflections and appreciate your time spent completing the 12-minute survey. Your anonymous responses will be used to:
- Better understand how your education prepared you for your career.
- Learn what you valued most and how we might improve our programs.
- Connect you to the Rubenstein School Alumni Network (as desired).
Hardcopy surveys were mailed at the end of January to alum we had not heard back from. Help us reduce our paper use by completing your survey online today. Thank you for helping us continue to strengthen the Rubenstein School as one of the leading schools of natural resources in the nation.
Opportunities and Information
- Help RSENR with its 10-year program review. Please complete the survey sent to you via email or postal mail. Email email@example.com to request the survey.
- Submit an alumni note for our School enewsletter.
- Read the Rubenstein School Enewsletter.
- Learn about ways to Give to the School.
- Explore the UVM Alumni Site.
- Help collect group summer camp photos for this website. Scan and email pics to Joanna Birbeck (FOR '84).


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B&Bs in Cotahuasi, Peru
Choose from our range of B&B's in Cotahuasi. View photos of B&B's in Cotahuasi and read bed and breakfast reviews. To find a B&B in Cotahuasi in the right location for you, view all of the Cotahuasi B&B's on the map and book online.
NOTESorry, there is no online availability for the destination and dates you selected.
Possible reasons for this are:
- You have searched too far ahead.
- There is limited availability for the dates you chose.
- The destination you are searching for has limited properties.
Using the search panel on the left, please select different dates or choose a nearby destination.


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Principles by Ben de Lisi Designer dark grey sketched panel top
Item No.0380101433
Item No.0380101433
50% Off - Save a total of £16.25
From the designer Principles range by Ben de Lisi, this dark grey jersey top has a woven front panel with a sketched design and gathered effect on the hem. It has three quarter sleeves and a keyhole detail to the back.
Sunday to Friday - order by 9pm
Saturday - order by 6pm
Monday to Sunday - order by midnight
Next day collection in-store
Show full delivery details
Subject to exceptions, Debenhams is happy to exchange or refund your purchase within 28 days of delivery. Please check here for more details on our returns policy and exceptions.
Open a Debenhams MasterCard today and receive:
Please note: if the amount you pay on your card is less than £500 after the 10% discount is applied, the offer will not be available.
Credit available from NewDay Ltd to over 18's only. *Terms &Conditions applyFind out more & apply now


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District Sales Manager - Heavy Equipment Sales
Drake International - Edmonton, AB
This job posting is no longer available on Indeed. Find similar jobs:District Sales Manager jobs - Drake International jobs
About this company
Drake International Canada specializes in recruitment solutions for an array of industries. Visit our website for a list of job openings...


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The process of buying a new Hyundai car or truck can seem overwhelming if you don't know where to begin. Edmunds.com can get you started on the right track with a convenient directory of Hyundai car dealerships in and around Dover Plains, New York. Compare online price quotes on the new or used car, truck, SUV, minivan, or wagon of your choice to locate the best deals. Edmunds.com makes it easy to find trusted Hyundai car dealers in Dover Plains, saving car buyers time and money on what will be an important purchase.
Non Display Review Name "To be honest my husband and I went to multiple dealers and sat with many sales people. I had in mind what I wanted and so did Bill. At Brass City they"... Read more Review by: Waterbury_1959
Non Display Review Name "I came there on 10/17/15 not really knowing what to expect due to my credit not being all that great. However, I still went out and saw the car that I"... Read more Review by: ConswellaS


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2014 Dodge Durango to get Charger "race track" tail lights
There have long been rumors that the Dodge Durango will be killed off for the 2015 model year but according to attendees at the recent Chrysler Group national dealer convention; one of the vehicles on display was a refreshed Durango that will come for the 2014 model year. The most significant feature of the 2014 […] More »
New Dodge Challenger "Shaker" hood shown at Vegas dealer show
Since the modern Dodge Challenger debuted alongside the Dodge Magnum Dodge Charger, Mopar lovers have been cutting holes in their hood to make room for a modern take on the vintage "Shaker" hood design. The Shaker hood has appeared in the aftermarket on just about every modern Mopar – from the Dakota to the Neon […] More »
2013 SRT Viper pricing announced starting at $97,395
Last night, the Chrysler Group announced the first bits of pricing information for the 2013 SRT Viper and SRT Viper GTS – with the "base model" Viper starting at $97,395 while the higher performance Viper GTS starts at $120,395. This pricing information will allow dealerships to offer a 640 horsepower supercar for less than the […] More »
BangShift: This is the Craziest Street-Legal Monster Dually We've Ever Seen
Yes, this is apparently a street legal truck in Ohio. We need to move to Ohio. This nearly 11′ tall 2003 Dodge Ram dually sports an astounding six 54″ Mickey Thompson Baja Claw tires and a pretty unbelievable 28″ of lift to make it all happen. No, you're not calling up Skyjacker or any other […] More »
SRT Barracuda to replace Dodge Challenger SRT8 in 2014?
There have long been rumors that, at some point in the future, the Dodge Challenger would be discontinued as the Chrysler Group reincarnated the Barracuda name. New information has been offered up to suggest that the Dodge Challenger will continue on alongside the SRT Barracuda but the Challenger will likely go on without the SRT […] More »


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It's a must. If u ever coming to Sidney BC. They have amazing sushi, the vegetarian choice, the best ones I tried. And tea is free. Just delicious!!!
Foursquare © 2016 Lovingly made in NYC & SF
Victoria Sushi Restaurants
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Created by Matt B49 items • 2 followers
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Student Resources
As a student, you have many resources on campus. Consider these resources when you need help. Click the links below to find out more information about the opportunities available for you on campus.
Allen Student Help Center
Located on the 4th floor of Baker.
Campus Involvement Center
Located on the 3rd floor of Baker.
Career and Leadership Development Center
Located on the 5th floor of Baker.
Student Accessibility Services
Located on the 3rd floor of Baker.
Ohio University Military and Veterans Services
Located on the 1st floor of Chubb Hall.
The Patton College Military & Veterans Information
Lindley Hall 052, Student Affairs
Academic Advancement Center
Located on the 1st floor of Alden Library.
Student Writing Center
Located on the 2nd floor of Alden Library.


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The United States is widely recognized as a world leader in climate change research. US academic and government research scientists are responsible for much of the data documenting climate change, and for establishing the link between human activities and global warming.
Avoiding the most severe climate impacts requires keeping the vast majority of fossil fuels in the ground and replacing coal, oil and natural gas with low-carbon energy sources. An energy transition not only protects communities from the threat of climate disruption, it opens the door to new jobs in the clean energy sector. While the economy and jobs consistently rank as higher priorities for most individuals than climate disruption, the issues are intimately linked.
The Cherry Blossom Festival is held each year in Vancouver from March 24th to April 17th, and starts with a concert at Burrard Station downtown in the park surrounded by cherry blossoms. In full bloom, the blossoms are so thick they block the sky from underneath the trees.
Earlier this year, members of the Climate Access team partnered with the Toronto Environmental Alliance (TEA) to identify and evaluate climate engagement models that could help advance municipal climate action in Canada's largest city. TEA's Dusha Sritharan shares insights from the project, including a tip sheet on best practices in climate engagement.
Want more access? Find out how you can join our growing network of practitioners and get the most out of Climate Access.
Sign up today
Tweets by @climateaccess
Climate Access is an initiative of The Resource Innovation Group's Social Capital Project. We are grateful to our founding partners, the Stonehouse Standing Circle and the Rutgers Initiative on Climate and Society.


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Peoria's history, population, vision/mission statements, sustainability efforts, redistricting, and construction projects. Info on the P83 district, schools, the Peoria Leadership Institute seminar, and diversity.
Information on the City Council including agendas , the Mayor, the Municipal Court, City Manager and ADA along with the city's various initiatives.
News from the city of Peoria, press releases from the Office of Communications, links to RSS feeds and E-News signup. View programming on Channel 11, PeoriaTV.
Information on the employment process, a listing of current open jobs, how to apply on-line and a list of all jobs and salaries at the city.
A listing of links to directories of city services, including all online e-services.
The city of Peoria Municipal Complex is home to City Hall, the Council Chambers, the Main Library, the Development and Community Services Building, the Public Safety Administration Building, and the Municipal Court.
A listing of links to maps available on the city of Peoria Website.
The City of Peoria budget is managed by the Management and Budget Division. Find copies of the latest Program Budget and the CIP here.
The City Code and Zoning Ordinace, with updates are located here. Also, find the City Charter, and legal statements related to the website, including our Privacy Notice.
City Manager's Message on Diversity and Inclusion
How to pay bills you may have with the city, including water, sewer and trash collection fees, recreation program and class fees, traffic fines and more. Setup water and sewer service.
Home and Property Resources includes information on trash pickup,water conservation, swimming pool issues and recycling, along with other relevant information for homeowners.
Neighborhood Resources includes information on dealing with graffiti removal, block parties, animal control, street repairs, odors and other neighborhood related quality of life issues.
Helpful services provided by the fire and police departments. Report criminal activity, locate crime information, register alarms, and learn about crime prevention.
Search for scheduled events and meetings in the city including documents relating to city council meetings and other meetings.
This section contains information and links to the Peoria Public Library's website, the Arts Commission, the Center for Performing Arts, and Annual Arts festivals and Celebrations.
Information on recreation programs and classes, afterschool and preschool programs, sports leagues and locations and amenities of city parks.
Information on bus routes, park and ride, dial a ride and bicycle paths. Also, road closures and lane restrictions.
Use this page to find information on the city of Peoria website of interest to builders and developers.Included are inspections, zoning and zoning ordinance, the city code, general plan, permitting, and impact fees.
How to get a business license, tax license, sales tax schedules/forms, register to use the online eTax system, pay taxes and fees. Bidding on contracts with the city and auctions, trash collection, recycling, traffic counts.
Links to the Building Development Division and the Site Development Division of the Engineering Department
Information on Building Permits. Find out about permits for signs, temporary use of property, filming, and alarms. Download forms and track applications for development, building, planning and engineering permits.
The city's main document portal for development related documents including planning and zoning, building, engineering and fire prevention.
Economic Development Services offers Business and Real Estate Development, and other assistance for businesses and developers, on the website PeoriaAZSmart.com.
The Seattle Mariners and the San Diego Padres conduct spring training at the Peoria Sports Complex each February and March. Everything you need to know is at PeoriaSpringTraining.com.
A listing of area hotels, motels and RV Parks, listed by distance from the Peoria Sports Complex.
The city of Peoria, Arizona is proud to be the "Gateway to Lake Pleasant," one of the finest water recreation areas in Arizona.
Links to Items of interest to tourists, including VisitPeoriaaz.com, our official tourism website.
The Peoria Center for the Performing Arts consists of a 280 seat main stage auditorium and an 80+ seat black box theater, designed to bring award winning community theater to downtown Peoria.
City of Peoria hiking trails information, directions and maps.
Special Events, sponsored and hosted by the city, held throughout the year at the Peoria Sports Complex, Oldtown Peoria and other areas.
The Peoria Sports Complex is home to the San Diego Padres and Seattle Mariners during spring training, and many other events throughout the year.
PEORIA, Ariz. (June
15, 2010) – City of Peoria invites the
community out to enjoy their 27th Annual July 4th All- American Festival on
Sunday, July 4th, 2010. There will be plenty of kid-friendly activities
including the Haydon Building Corp. Water Zone, Kids Zone, bounce houses,
carnival games, crafts and more. Enjoy great music in the Country Zone starring
Disney recording artist Bucky Covington as well as Chad Freeman and Redline, the
Rock n Roll Zone featuring Vintage Rock Group, and the all-new Fiesta zone
featuring Havana Soul! Don't forget to sign up at local Sonic locations by June
20th to participate in the Sonic Hot Dog Eating contest, held at the event.
Check out the F-16 flyover at approximately 7:00 p.m. and watch one of the
valley's best fireworks extravaganzas at 9:15 p.m.
Gates open at 5pm at Peoria Sports Complex, located at 16101 N. 83rd Ave just
south of Bell Rd. Admission is $5 and kids 12 and under are free. Concessions
and beer will be available for purchase. Lawn chairs, blankets, coolers with
food and non-alcoholic beverages are permitted. No alcohol, glass containers,
portable canopies, or bicycles are permitted into the event. All music and
activities are free with admission. To purchase tickets online and for more
information visit us on the web at
www.peoriasportscomplex.com or call 623-773-8700.
City of Peoria would like to give special thanks to our corporate and media
partners Haydon Building Corp, Hunter Contracting Co., Seattle Mariners, San
Diego Padres, KMLE Country, Entravision Communications, KDKB, Radio Disney and
MEGA/The Beat.
City of Peoria8401 W. Monroe StreetPeoria, Arizona 85345


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Police to close Strongs Avenue today for accident reconstruction teamSTAFF REPORT | April 23,2013Strongs Avenue will be closed between City Hall and Madison Street from 1 to 3 p.m. today as part of the investigation into the death of Mary Jane Outslay. Rutland City Police said a crash reconstruction team is being brought in to work on the scene of the fatal hit-and-run. Motorists are asked to plan to take alternative routes.MORE IN This Just InNEW YORK His defiant protests helped shape Americans opposition to the Vietnam War. Full StoryWhen Rutland City Mayor Christopher Louras told those gathered in the citys aldermanic chambers... Full Story
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