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The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient's conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjögren's syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient's evaluation, including hepatic, virological, and immunological findings.
Following the discovery of hepatitis C virus (HCV) in 1989 as the major etiological agent of non-A-non-B chronic hepatitis [1], some epidemiological studies suggested its possible role in the pathogenesis of mixed cryoglobulinemia syndrome (MCs), which now represents the prototype of HCV-associated autoimmune-lymphoproliferative disorders [1-4]. Since the disease may mimic numerous immunological and neoplastic disorders, the discovery of its association with HCV infection prompted further clinical investigations into the possible pathogenetic role of HCV in other auto-immune diseases [2,3]. In 2007, we proposed the term 'HCV syndrome', which encompasses the wide spectrum of both hepatic and extrahepatic HCV-associated autoimmune diseases, including some malignancies [4]. Figure 1 shows the variable strength of association between HCV and different diseases in the context of HCV syndrome.
Figure 1. Strength of association between hepatitis C virus and different diseases in the context of hepatitis C virus syndrome. The spectrum of different hepatitis C virus (HCV)-associated immunological and neoplastic disorders may be classified on the basis of clinico-epidemiological, histopathological, and molecular biology studies in three different levels. High: the association with HCV infection characterizes the large majority of patients; HCV infection is one of the major triggering agents of the disease. Medium: patients with the disease show a significantly higher prevalence of HCV infection compared to controls; the putative pathogenetic role of HCV is also supported by pathogenetic studies and it may identify at least a specific disease subset. Low: the possible association is suggested by limited clinico-epidemiological observations; a pathogenetic link in at least a specific disease subset from some geographical areas is probable, but needs to be definitely demonstrated. Other possible associations have been suggested (see text) on the basis of anecdotal observations. B-cell NHL, B-cell non-Hodgkin's lymphoma; HCC, hepatocellular carcinoma.
The pathogenesis of various HCV-associated disorders is quite complex and still not completely understood. HCV infection is the underlying condition that generally precedes by a long time interval the clinical appearance of extrahepatic diseases. The development of different clinical phenotypes is probably the consequence of multifactorial and multistep processes together with decisive contributions by both genetic and environmental co-factors [1-4]. This hypothesis is in keeping with the strong geographical heterogeneity in the prevalence of different HCV-associated diseases [1,3]. HCV lymphotropism [5] is responsible for the B-lymphocyte expansion responsible for the production of large amounts of circulating immune complexes, mainly mixed cryoglobulins with rheumatoid factor activity, as well as various organ- and non-organ-specific autoantibodies [1]. Interestingly, the same immunological alterations may also be observed in a significant percentage of individuals with isolated HCV infection [1,6].
HCV is a positive, single-stranded RNA virus without a DNA intermediate in its replicative cycle, so that viral genomic sequences cannot be integrated into the host genome. Much evidence indicates that HCV infection results in chronic stimulation of the immune system, which facilitates the clonal B-lymphocyte expansion [1,2,7]. Figure 2 (left side) summarizes both virus- and host-related co-factors, together with the main biological alterations, of the pathogenetic cascade. The result may be classical MCs or other autoimmune disorders, as well as some malignancies, mainly B-cell non-Hodgkin's lymphoma (B-NHL) [1]. Besides MCs, other rheumatic diseases can be related to this virus with variable strength of association [1,3,8,9]. The present review focuses on the clinical-serological assessment and therapeutic approach to the main HCV-associated rheumatic disorders.
Figure 2. The treatment of mixed cryoglobulinemic syndrome must be decided on the basis of the etiopathogenetic cascade that leads from hepatitis C virus infection to multiple immune-system alterations, mainly B-cell proliferation, and lastly to immune complex-mediated small vessel vasculitis. The vasculitic syndrome may be complicated by malignancies, mainly B-cell lymphoma. Accordingly, we can treat mixed cryoglobulinemic syndrome (MCs) at three different levels by means of etiological, pathogenetic, and symptomatic therapies. The use of antivirals, namely peg-interferon-alpha (peg-IFNα) plus ribavirin (RIBA), aims to eradicate the hepatitis C virus (HCV); it represents the etiological treatment of HCV-associated MCs. The anti-CD20 monoclonal antibody rituximab is considered the most useful and safe pathogenetic treatment of MCs. In selected patients with severe, active clinical manifestations, sequential or combined therapy with antivirals and rituximab has been usefully employed (see also Figure 3). CIC, circulating immune complexes; CPX, cyclophosphamide; HLA, human leukocyte antigen; LAC, low antigen-content; LDL, low-density lipoprotein; RF, rheumatoid factor.
Mixed cryoglobulinemia (cryoglobulinemic vasculitis)
The pathological hallmark of MCs is the leukocytoclastic vasculitis of small arteries, capillaries, and venules; therefore, the disease is currently classified among systemic vasculitides, in the setting of small-vessel vasculitides, and the terms MCs and cryoglobulinemic vasculitis should thus be related to the same clinico-pathological condition [1]. MCs represents the cross-road between classical rheumatic diseases, such as rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS), and other autoimmune lymphoproliferative disorders [1] (Figure 1). It is characterized by the typical clinical triad of purpura, weakness, and arthralgias and by multisystem organ involvement [1,2]. The typical cutaneous and visceral organ involvements, such as purpura, skin ulcers, and glomerulonephritis, are the consequence of the vessel deposition of circulating immune complexes, mainly mixed cryoglobulins and complement [1]. Liver involvement, generally a mild to moderate chronic hepatitis, may evolve to frank cirrhosis in a minority of patients, and is rarely complicated by hepatocellular carcinoma [4]. Renal involvement is often responsible for membranoproliferative glomerulonephritis type I; it may severely affect the overall prognosis of patients with MCs, often in combination with liver damage [4]. Peripheral neuropathy and skin ulcers are quite frequent manifestations of MCs; they are barely responsive to treatments and consequently may compromise the patient's quality of life [4]. Finally, B-NHL and widespread vasculitis may complicate a minority of cases; they represent the most harmful manifestations of the disease [1,2,4]. Besides mixed cryoglobulins in serum, marked reduction of hemolytic complement activity, with the typical pattern of low, often undetectable complement C4, is another hallmark of the disease and is particularly useful for disease classification [1,10,11]. However, both complement levels and cryocrit rarely correlate with the activity/severity of MCs; consequently, they are not very useful for clinical monitoring of patients and therapeutic decision-making. In contrast, the correct evaluation of B-cell expansion, which represents the biological substrate of MCs, is mandatory because of the possible complication of overt lymphoma [1,2,7]. This latter event should be suspected in the presence of rapid increases of cryocrit and serum levels of monoclonal rheumatoid factor and/or complement C4 [1].
The treatment of HCV-associated MCs is particularly challenging due to the complex etiopathogenesis and clinical polymorphism of the disease. In fact, we can treat MCs at three different levels (Figure 2): the chronic HCV infection; the immune-pathological alterations, mainly B-lymphocyte proliferation; and the immune complex-mediated cryoglobulinemic vasculitis [1,3]. Moreover, the correct evaluation of different clinical phenotypes, varying from mild purpuric lesions, arthralgias, and/or weakness to severe organ involvement (renal, liver, diffuse vasculitis) or malignancies (B-NHL), should direct our therapeutic interventions (Figure 3).
Figure 3. The therapeutic strategy for mixed cryoglobulinemic syndrome may be modulated according to the clinical status of individual patients. We can consider at least four clinical conditions. Mixed cryoglobulinemic syndrome (MCs) may be completely asymptomatic or it may sporadically show very mild manifestations, such as fleeting purpuric lesions on the legs; in these cases monitoring may be sufficient, while an attempt at HCV eradication may be considered. On the opposite side are patients with severe, rapidly progressive cryoglobulinemic vasculitis that must be treated with aggressive combined treatment similar to that used for other systemic vasculitides. Sequential or combined treatment with antivirals and rituximab may be usefully employed in selected patients with severe manifestations. The order of sequential treatment may be decided on the basis of prevalent organ manifestation(s), even if the combined therapy seems to be comparable for efficacy and safety. CPX, cyclophosphamide; CS, corticosteroid; LAC, low antigen-content; peg-IFN, peg-interferon; RIBA, ribavirin; RTX, rituximab.
HCV infection results in chronic stimulation of the immune-system [7], and it may also be responsible for either liver damage or neoplastic complications; in theory, HCV eradication using alpha-interferon and ribavirin should be attempted in all cases [1,3,12,13]. However, a beneficial effect of antivirals may be recorded in less than half of treated patients and they are often associated with important immune-mediated side effects, such as peripheral sensory-motor neuropathy, thyroiditis, and rheumatoid-like polyarthritis [1,3,14]. It is plausible that alpha-interferon, which is both an antiviral and immunomodulating agent, can foster or exacerbate these symptoms, possibly in predisposed subjects.
In the near future, a vaccine-based therapy [15] might be able to prevent the progression of HCV infection and possibly to interrupt the self-perpetuating autoimmune mechanism underlying MCs.
Preliminary studies suggested that some immunomodulating therapies in association with antiviral treatment, namely cyclosporine A or TNF inhibitors, have synergistic effects in the setting of chronic hepatitis type C [16,17].
Besides etiological treatments, immunomodulating/immuno suppressive drugs represent the most useful therapies able to affect the main pathogenetic mechanisms of MCs, including T- and B-cell proliferation and autoantibody production. These treatments include cyclophosphamide and an anti-CD20 monoclonal antibody (rituximab) [1,3]. During the past decade, rituximab has been increasingly employed for both cutaneous and visceral organ involvement of MCs; it can be regarded as a useful and safe pathogenetic treatment of cryoglobulinemic vasculitis [18]. Its safety was also confirmed in patients with liver damage; interestingly, in patients with HCV-associated MCs and advanced cirrhosis, treatment with rituximab was able to improve both the cryoglobulinemic vasculitis and liver function [19]. A comprehensive analysis of the literature regarding the use of rituximab and its role in the therapeutic strategy of MCs patients has been recently published [18]. Very recently, the results of a randomized controlled trial demonstrated that anti-CD20 monotherapy also represents a useful and safe option for patients with severe MCs [20].
Among symptomatic/pathogenetic treatments, a low antigen-content diet can improve the clearance of circulating immune complexes by restoring the activity of the reticulo-endothelial system, which becomes overloaded by large amounts of circulating cryoglobulins [1]. This reduction in the alimentary input of macromolecules with potential antigenic activity may improve the function of the mononuclear phagocytic system, which is normally impaired in MCs [21]. A low antigen-content diet can be usefully employed in patients with clinically mild MCs symptoms (arthralgias, weakness, sporadic purpura, and/or mild sensory peripheral neuropathy), often in association with low doses of steroids (6-methylprednisolone 2 to 4 mg/day) and/or colchicine. Most patients show only mild symptoms for a long time period, and are particularly sensitive to symptomatic treatments and to small doses of daily steroid (1 to 2 mg). Clinically asymptomatic patients do not usually need any treatment, even in the presence of high levels of cryocrit, but patients with severe vasculitic manifestations must be promptly treated with high doses of steroids and/or plasma exchange and/or immunosuppressors; this combination therapy is often able to improve the most harmful disease complications (Figure 3) [1,4,22].
The treatment of cryoglobulinemic skin ulcers is particularly challenging. These lesions are prevalent in the lower limbs, where other pathogenetic co-factors may be associated - namely, venous insufficiency and/or arteriosclerotic alterations, which are not rare in older patients with comorbidities and/or who have received long-term steroid treatment. The skin ulcers are painful, non-healing, and often complicated by local infection and they may severely affect patients' quality of life [4]. Figure 4 summarizes the therapeutic strategy for treating cryoglobulinemic skin ulcers, including both systemic and local treatments at a wound care clinic [23]. The long-term administration of analgesics is often necessary to improve the patient's chronic pain and their compliance with local wound care. A team of operators with specific experience should carry out this integrated therapeutic approach [18,23,24].
Figure 4. Therapeutic strategy for treating cryoglobulinemic cutaneous ulcers should be based on both systemic and local treatments. After clinical work-up considering the entire MCs, including possible comorbidities (venous insufficiency and/or arteriosclerotic alterations, diabetes, and so on), and careful examination of the ulcer characteristics, the systemic treatment may be based on etiological, pathogenetic, and/ or symptomatic therapies. More aggressive combined treatments (immunosuppressors, steroids, and plasmapheresis) may be necessary in the presence of very severe, non-healing skin ulcers. Long-term administration of analgesics is often necessary to improve the patient's chronic pain and compliance with local treatment, which should be carried out at a wound care clinic. Wound bed preparation, with particular regard to the prevention and treatment of infections, is crucial for the healing of cryoglobulinemic skin ulcers. CPX, cyclophosphamide; peg-IFN, peg-interferon; RIBA, ribavirin; RTX, rituximab.
More recently, some studies have suggested that sequential or combined antiviral and immunosuppressive therapy could represent a rather useful therapeutic strategy for treating MCs [18,25,26]. This more aggressive treatment could be particularly indicated in patients with major clinical manifestations and/or inadequate remission after standard treatments.
On the whole, careful monitoring of a patient's clinical status is mandatory in clinical practice, with particular attention paid to neoplastic complications; in all instances the treatment should be tailored to the individual patient according to the severity of their MCs symptoms (Figure 3) [1].
Given the rarity of the disease and the difficulties of recruiting clinically homogeneous series of patients, there are few controlled randomized trials evaluating the usefulness of proposed treatments for MCs. The results of a consensus conference based on the available published studies and expert opinions have been summarized in a preliminary core set of therapeutic recommendations [27].
Sicca syndrome/Sjögren's syndrome
A possible pathogenetic role of HCV in pSS has been reported in anecdotal clinical observations [28]. In contrast, the frequent association between sicca syndrome and HCV infection has been demonstrated by both experimental and epidemiological studies focusing on the presence of chronic lymphocytic sialadenitis in patients with HCV infection [29]. HCV can replicate within epithelial cells of the salivary gland of patients with sicca syndrome and HCV infection [30].
In clinical practice, the correct differential diagnosis between some HCV-associated rheumatic disorders and classical rheumatic diseases is still under debate, in particular between MCs and pSS; this probably reflects the lack of standard classification of these diseases in different referral centers.
Figure 5 shows the main clinico-pathological and immunological differences between MCs and other possible HCV-associated diseases. Patients with MCs may develop a mild sicca syndrome in the absence of typical histopathological and/or serological alterations [1]. On the other hand, the detection of mixed cryoglobulins in the serum of a minority of pSS cases seems to identify a particular clinical subset characterized by worse prognosis and frequent evolution to malignant B-NHL [31]. In individual cases the differential diagnosis between pSS and MCs may be very difficult, mainly in patients with overt sicca syndrome, cryoglobulinemia, and HCV infection [1]. Therefore, it is correct to classify these patients as overlapping MCs/pSS [1], and the therapeutic approach should consequently be decided after careful evaluation of the main clinical manifestation(s), including the presence/severity of type C hepatitis.
Figure 5. Differential diagnosis between some important hepatitis C virus-associated rheumatic manifestations and classical diseases such as primary Sjögren's syndrome and rheumatoid arthritis is possible on the basis of clinico-serological and pathological features. Some important findings may be usefully employed for a correct diagnosis: the histopathological characteristics and severity of salivary gland involvement and specific autoantibodies (anti-SSA/SSB) are rarely found in hepatitis C virus (HCV)-associated sicca syndrome or mixed cryoglobulinemia syndrome (MCs) patients. Conversely, cutaneous leukocytoclastic vasculitis, visceral organ involvement (hepatitis, membranoproliferative- glomerulonephritis), abnormally low complement C4, and HCV infection, typically found in MCs, are very uncommon in primary Sjögren's syndrome (pSS). Both MCs and pSS may be complicated by B-cell non-Hodgkin's lymphoma (B-cell NHL), and less frequently also rheumatoid arthritis patients. Finally, erosive symmetrical polyarthritis and serum anti-cyclic citrullinated peptide (anti-CCP) antibodies are specific diagnostic findings of classical rheumatoid arthritis, but generally absent in HCV-associated arthritis. However, there is a gray area of clinical overlap between different disorders. RF, rheumatoid factor.
Antiviral treatment with IFNα and ribavirin seems to improve sicca syndrome in HCV-positive patients, even if serious immune-mediated adverse events have been observed [32]. Besides topical treatments that may partially improve patients' quality of life, there is no specific systemic treatment for HCV-associated sicca syndrome. As for classical MCs or pSS, the possible complication with malignant lymphomas must also be taken into account in these patients [28,31].
While arthralgias are one of the most common extrahepatic manifestations of HCV infection, chronic arthritis is significantly less common [4,8,9]. When present, it is often a less aggressive oligo-polyarthritis compared to classical RA. Patients with HCV-associated MCs present with arthralgias, while inflammatory joint involvement is quite rare and generally characterized by mild oligoarthritis [4]. A symmetrical rheumatoid-like polyarthritis may complicate IFN treatment in HCV-positive patients [9]. Because of the relatively high prevalence of the two diseases, it is not rare to observe a simple association between classical RA and HCV infection. Figure 5 summarizes the main clinico-serological parameters for differential diagnosis between classical RA and other HCV-associated disorders [1,3,4,8,28,31,33,34]. In patients presenting with chronic arthritis, the presence of hepatotropic virus infection (that is, HCV and hepatitis B virus) must be ruled out because of the possible severe, often life-threatening side effects of disease-modifying antirheumatic drugs (DMARDs) and biologics [35]. Several different viral infections may trigger symmetrical arthritis mimicking classical RA and clinical work-up including virological investigations should therefore be done at the patient's first assessment (Figure 6).
Figure 6. Differential diagnosis among patients with arthritis and concomitant hepatitis C virus infection, and therapeutic strategies. Clinico-serological and virological work-up is mandatory in patients presenting with chronic arthritis. Patients with polyarthritis and hepatitis C virus (HCV) infection can be classified as either having simple comorbidity, that is, HCV infection and rheumatoid arthritis (RA) or other forms of chronic arthritis, or having HCV-associated arthritis. This latter may represent one extrahepatic manifestation of HCV infection or it can be a symptom of MCs. The comorbidity may be treated with the standard therapeutic strategies for RA, with some precautions because of concomitant viral infection, in particular for methotrexate and leflunomide. On the contrary, biologics (anti-TNFα and anti-CD20 rituximab) have been usefully employed without significant side effects in HCV-positive RA patients. The antiviral therapy of IFNα plus ribavirin (RIBA) can also be employed after careful hepatologic evaluation of patients. Interestingly, anti-TNFα, rituximab, and cyclosporine A seem to have a potential synergistic effect if associated with antiviral treatment (IFNα + RIBA). Usually, HCV-associated arthritis is poorly aggressive and may respond to low doses of steroids and hydroxychloroquine (HCQ). The use of other disease-modifying anti-rheumatic drugs (DMARDs) presents the above-mentioned limitations, while rituximab may be usefully employed, especially in patients with more aggressive arthritis. Finally, rituximab may represent the first-choice treatment in patients with arthritis in the setting of MCs. Ab, antibody; CCP, cyclic citrullinated peptide; RF, rheumatoid factor.
Patients who present with both HCV infection and arthritis can either have a simple comorbidity of RA and HCV infection or HCV-associated arthritis, with or without MCs. The first may be treated with standard strategies used for RA with some precautions in consideration of the concomitant viral infection and possible liver involvement. Some DMARDs, in particular methotrexate and leflunomide, may be employed after carefully evaluating and monitoring liver involvement, while biologics such as anti-TNFα and rituximab have been usefully employed without significant side effects in HCV-positive RA patients [36]. Interestingly, these biologic therapies, as well as cyclosporine A, seem to have a potential synergistic effect with antiviral treatments for hepatitis C [16,17]. Therefore, careful hepatologic evaluation of these patients is always mandatory, taking into account the opportunity for antiviral treatment [35].
On the whole, patients with concomitant RA and HCV infection require the same clinical assessment and monitoring as patients with HCV-associated arthritis with or without MCs; they may have an increased risk to develop some HCV-associated complications, such as B-cell NHL, even as a consequence of immunomodulating therapies.
Usually, HCV-associated arthritis is poorly aggressive and the patients may respond to low doses of steroids and hydroxychloroquine. The use of other DMARDs presents the above-mentioned limitations. On the contrary, rituximab may be usefully employed, mainly in patients with more aggressive disease, and may represent the first-choice treatment in patients with arthritis in the setting of MCs [18].
Other possible HCV-related rheumatic diseases
Besides the HCV-related conditions described above, other rheumatic diseases have been suggested to be associated with HCV infection; namely, osteosclerosis, myalgia, fibromyalgia, poly/dermatomyositis, polyarteritis nodosa, Beçhet's syndrome, systemic lupus erythematosus, and antiphospholipid syndrome [1,8,9,29].
Osteosclerosis is a very uncommon condition described in adults infected with HCV and can be defined as an acquired, painful skeletal disorder characterized by a marked increase of bone mass [37-40]. Clinically, osteosclerosis is characterized by nonspecific, often diffuse bony pain and tenderness over involved bones due to periosteal stretching, in the absence of joint swelling or motion limitation. Radiographic examination shows bony sclerosis and thickening of the long-bone cortices, mainly diaphyseal cortical bone. Laboratory investigations frequently reveal abnormally increased markers of bone formation (alkaline phosphatase, bone-specific alkaline phosphatase, and osteocalcin); these alterations were mirrored by the marked increase of bone mass (bone mineral density) and enhanced radionuclide uptake at scintigraphy (99mTc-MDP). Bone biopsy shows increased numbers and thickness of trabeculae with parallel reduction of bone marrow [37-40]. The pathogenesis of this rare syndrome is still unknown. It has been suggested that HCV alone or in combination with other unknown agent(s) may infect and alter bone cells or their precursors in predisposed subjects. These alterations might be mediated by the production of bone growth factors, such as insulin-like growth factors or osteoprotegerin. The pathogenetic role of this latter factor seems to be relevant as an imbalance in the osteoprotegerin/RANKL (receptor activator of nuclear factor kappa-B ligand) system leading to a pre dominance of osteoprotegerin has been documented [38]. With regards to therapeutic approaches to osteosclerosis, attempts to treat with antiresorptive agents in at least seven patients was ineffective, while symptomatic treatments may provide some benefit. In some cases a partial or complete spontaneous remission of symptoms and/or bone sclerosis was observed during follow-up [37-40]. Anecdotally, in a recently published case report the antiviral therapy was followed by a recovery of skeletal sclerosis [40].
Myalgia has been recorded in a significant number (15%) of patients from a large series of HCV-infected individuals [29]. The pathogenesis of this symptom remains difficult to explain, although the detection of viral genomic sequences within muscle fibers suggested a direct involvement of HCV in the pathogenesis of diffuse muscle pain [41]. Fibromyalgia has also been reported by some studies in a significant percentage of patients with chronic HCV infection [42], but other studies in series of patients with typical fibromyalgia have not confirmed this association [9,43]. On the other hand, the differential diagnosis between fibromyalgia and muscle pain, frequently associated with weakness and arthralgias, may be very difficult in the setting of HCV-positive patients. With regard to sicca syndrome and pSS, some authors prefer to maintain HCV-associated myalgia and classical fibromyalgia as distinct entities [9,43].
Several case reports in the literature have documented an association between poly-dermatomyositis and HCV infection [1,8,9,29,44]. Generally, these disorders appear in patients with long-lasting viral infection or may complicate IFNα treatment [45]. Similarly, cases of vasculitis involving medium-sized arteries suggesting the diagnosis of polyarteritis nodosa have been associated with HCV infection [29,46]. In addition, HCV seropositivity has been reported in a significant percentage of patients with polyarteritis nodosa [46]. This possible association is not surprising considering the well-known relationship between polyarteritis nodosa and another hepatotropic virus, hepatitis B virus, which is responsible for a significant number of patients with this vasculitis [47]. Polyarteritis nodosa may share numerous clinical symptoms with MCs; thus, patients with suspected HCV-associated polyarteritis nodosa should be correctly classified by means of wide clinico-serological and pathological work-up.
With regard to other possible HCV-associated disorders, namely Beçhet's syndrome, systemic lupus erythematosus, and antiphospholipid syndrome, data reported in the literature are generally anecdotal [8,9,29,48,49]. Even if a possible causative role of HCV in these autoimmune diseases cannot be totally excluded, these patients might be better classified as having a simple comorbidity. However, they invariably represent a troublesome clinical condition, mainly with regards to therapeutic approach.
As for HCV-associated MCs, patients with concomitant autoimmune systemic disorders, such as poly/ dermatomyositis, polyarteritis nodosa, systemic lupus erythematosus, and HCV infection may be usefully treated with immunesuppressors (for example, cyclophosphamide and rituximab) with some important pre cautions and limitations due to viral infection. In all instances, a preliminary clinical evaluation of liver condition and viral replication is necessary before any therapeutic decisions are made. These latter may be based on standard immunosuppressive treatments, possibly integrated by sequential/combined antiviral treatment.
HCV-associated disorders include a spectrum of different immunological and neoplastic manifestations, among which are some rheumatic diseases. On the basis of clinico-epidemiological, histopathological, and molecular biology studies, the strength of association between HCV and a given disease varies largely among different diseases and, more interestingly, for each disease among patient series from different countries.
Autoimmune systemic diseases often represent a clinical syndrome, which may include different clinicoserological subsets. These latter are the resulting phenotypes of multiple genetic, environmental, and infectious pathogenetic cofactors. MCs represents an important example of these multifactorial and clinically multifaceted disorders, potentially triggered by HCV infection in a variable percentage of cases. Considering the wide range of clinical phenotypes, some HCV-associated diseases may present important classificatory/diagnostic difficulties, and may constitute a real therapeutic dilemma because of the coexistence of autoimmune manifestations and viral infection.
B-NHL: B-cell non-Hodgkin's lymphoma; DMARD: disease-modifying anti-rheumatic drug; HCV: hepatitis C virus; IFN: interferon; MCs: mixed cryoglobulinemia syndrome; pSS: primary Sjögren's syndrome; RA: rheumatoid arthritis; TNF: tumor necrosis factor.
Competing interests
The authors declare that they have no competing interests.
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Ferri C, Cacoub P, Mazzaro C, Roccatello D, Scaini P, Sebastiani M, Tavoni A, Zignego AL, De Vita S: Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: Results of multicenter cohort study and review of the literature.
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De Vita S, Quartuccio L, Isola M, Mazzaro C, Scaini P, Lenzi M, Campanini M, Naclerio C, Tavoni A, Pietrogrande M, Ferri C, Mascia MT, Masolini P, Zabotti A, Maset M, Roccatello D, Zignego AL, Pioltelli P, Gabrielli A, Filippini D, Perrella O, Migliaresi S, Galli M, Bombardieri S, Monti G: A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis.
Arthritis Rheum 2012, 64:843-853. PubMed Abstract | Publisher Full Text
Ferri C, Pietrogrande M, Cecchetti C, Tavoni A, Cefalo A, Buzzetti G, Vitali C, Bombardieri S: Low-antigen-content diet in the treatment of mixed cryoglobulinemia patients.
Am J Med 1989, 87:519-524. PubMed Abstract | Publisher Full Text
Stefanutti C, Di Giacomo S, Mareri M, De Lorenzo F, D'Alessandri G, Angelico F, Bucci A, Musca A, Mammarella A: Immunoadsorption apheresis (Selesorb) in the treatment of chronic hepatitis C virus-related type 2 mixed cryoglobulinemia.
Transfus Apher Sci 2003, 28:207-214. PubMed Abstract | Publisher Full Text
Falanga V: Wound bed preparation: future approaches.
Ostomy Wound Manage 2003, (49 Suppl 5):30-33. PubMed Abstract | Publisher Full Text
Frykberg RG, Driver VR, Carman D, Lucero B, Borris-Hale C, Fylling CP, Rappl LM, Clausen PA: Chronic wounds treated with a physiologically relevant concentration of platelet-rich plasma gel: a prospective case series.
Ostomy Wound Manage 2010, 56:36-44. PubMed Abstract
Saadoun D, Resche Rigon M, Sene D, Terrier B, Karras A, Perard L, Schoindre Y, Coppere B, Blanc F, Musset L, Piette JC, Rosenzwajg M, Cacoub P: Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia.
Blood 2010, 116:326-334. PubMed Abstract | Publisher Full Text
Dammacco F, Tucci FA, Lauletta G, Gatti P, De Re V, Conteduca V, Sansonno S, Russi S, Mariggio MA, Chironna M, Sansonno D: Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: a long-term study.
Blood 2010, 116:343-353. PubMed Abstract | Publisher Full Text
Pietrogrande M, De Vita S, Zignego AL, Pioltelli P, Sansonno D, Sollima S, Atzeni F, Saccardo F, Quartuccio L, Bruno S, Bruno R, Campanini M, Candela M, Castelnovo L, Gabrielli A, Gaeta GB, Marson P, Mascia MT, Mazzaro C, Mazzotta F, Meroni P, Montecucco C, Ossi E, Piccinino F, Prati D, Puoti M, Riboldi P, Riva A, Roccatello D, Sagnelli E, et al.: Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virusinfected patients.
Autoimmun Rev 2011, 10:444-454. PubMed Abstract | Publisher Full Text
Vitali C: Immunopathologic differences of Sjögren's syndrome versus sicca syndrome in HCV and HIV infection.
Arthritis Res Ther 2011, 13:233. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette JC, Opolon P: Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group.
Arthritis Rheum 1999, 42:2204-2212. PubMed Abstract | Publisher Full Text
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J Rheumatol 2002, 29:2382-2385. PubMed Abstract | Publisher Full Text
Ioannidis JPA, Vassiliou VA, Moutsopoulos HM: Long term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren's syndrome.
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Doffoël-Hantz V, Loustaud-Ratti V, Ramos-Casals M, Alain S, Bezanahary H, Liozon E, Fauchais AL, Vidal E: Evolution of Sjögren syndrome associated with hepatitis C virus when chronic hepatitis C is treated by interferon or the association of interferon and ribavirin.
Rev Med Interne 2005, 26:88-94. PubMed Abstract | Publisher Full Text
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Clin Exp Rheumatol 2005, 23:2-6. PubMed Abstract
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The first step towards empowering your people begins with you.
First, you have to exhibit the behaviour that shows your team that you believe in, and are committed to, their increased participation in the decision-making process.
For leaders who have been used to performing all the organizational work themselves, this is a tough behavioral shift to make. The process of sharing the planning, scheduling, task assignment, etc., can be painful for leaders who have previously prided themselves on their solo performance in these areas. The key to altering your attitude is to view the changes as a way to develop your role and not as sacrificing your authority.
Your people skills will be stretched as never before, your creative processes will be accelerated as you learn to develop and encourage the ideas of others. Additionally, your calibre as a trainer and coach will be tested as you blend the individual human elements into a cohesive whole.
Recommended for YouWebcast: Sales and Marketing Alignment: 7 Steps To Implement Effective Sales Enablement
However, if you are questioning your ability or desire to empower your people, here is an overview of areas to consider to ease your way into this evolving role:
Ego. A team that believes that the ultimate solutions to problems and the most important assessment of their performance flow from their ultra-confident leader will find it difficult to begin relying on their own strengths. You cannot allow your ego to restrict your people's abilities.
Behaviour. Don't just talk about empowerment. You have to show your people, by your actions, that you are committed to their development.
Restrain yourself from micro-managing, intruding when you are not needed (nor wanted) and over-monitoring their progress. The early part of the empowerment learning curve can be painful, but true growth always involves some pain.
Attitude. Don't position yourself in competition with the team. If they suggest doing something differently from how you would have proceeded, don't take it as an attack on your abilities. Suppress such defensiveness. If this proves impossible, stay silent until you can consider the idea calmly and objectively.
Feedback. If you thought feedback was important before empowerment, now it is crucial. Now, feedback should be as frequent as possible – between you and your team and, just as importantly, between team members. You have to get them talking to each other – exchanging ideas, sharing praise and learning how to dispense constructive criticism.
Conflict. If a problem arises, or if there is work-related friction, you – as well as your team – must concentrate on the "why" not the "who." Teach them, through your example, that the sole objective is to progress towards the goal, not to detour into assigning blame or personal agendas.
To do this you have to have your priorities crystallized and have shared them with the team. They, as well as you, must elevate their thinking beyond personalities and onto what is best for the team, the department, the company.
As you can see, empowerment creates dramatic changes for everyone. Often these changes challenge deep-rooted behavioural and attitudinal patterns that have taken years to form. This evolution does not happen overnight, nor without resistance. To minimize the discomfort these changes can bring, be patient, be positive and be prepared. The results are truly worth the growing pains.

subset: commoncrawl


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What does KMPH stand for?
What does KMPH mean? This page is about the various possible meanings of the acronym, abbreviation, shorthand or slang term: KMPH.
We've found a total of 1 definition for KMPH:
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KiloMeter Per Hour
What does KMPH mean?
- KMPH 840 AM is a radio station licensed to and serving the Modesto, California area. The station is owned by Pappas Telecasting, and is running a Spanish language format.
Still can't find the acronym definition you were looking for? Use our Power Search technology to look for more unique definitions from across the web!
"KMPH." Abbreviations.com. STANDS4 LLC, 2015. Web. 1 Dec. 2015. <http://www.abbreviations.com/KMPH>.


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Klingon Bird of Prey (whichever class)
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October 6 2012, 09:42 PM
Re: Klingon Bird of Prey (whichever class)
We could always argue that the ability to raise the wings is crucial for giving the ship the ability to land - and the very reason this ship exists in the first place is that it is a landing-capable addition to the Klingon fighting arsenal. Up is necessary for landing; let's assume down (rather than horizontal) is necessary for flying in an atmosphere (because a bit of anhedral in the wings is a valid aerodynamics trick for creating stability in certain cases). The skippers can then choose whatever position they wish for spaceflight, where all positions are equal - and some prefer horizontal while others like down, perhaps because they have different ideas about whether to take the fight down to an atmosphere if one happens to present itself during the fight.
It would also make sense for the Klingons to have at least two sizes of ships that can operate in an atmosphere and land and take off. Perhaps it
a good idea to build both designs to the exact same shape? That is, in space, shape is irrelevant - but in atmospheric flight, the engineers would have to do new calculations for a new shape, and they decide not to.
Timo Saloniemi
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Blue Microphones S2 Shockmount BL PackItem #: HL.00754520
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If you go
Event info: Darius Rucker, 7 p.m. March 9, Budweiser Events Center, 5290 Arena Circle, Loveland.
Cost: Tickets are $26.50 to $49.50 and go on sale at 10 a.m. Nov. 15. Tickets will be available at www.comcasttix.com, (877) 544-8499 or at the Budweiser Events Center box office.
Former Hootie & the Blowfish member turned country singer Darius Rucker will bring his True Believers Tour to Northern Colorado on March 9 for a show at the Budweiser Events Center.
Its been a record year for Rucker, whose single Wagon Wheel helped earn him multiple CMA and ACA nominations. Rucker has released three country albums since going solo.
Opening acts for his Loveland show include the Eli Young Band and special guest David Nail.


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Maumelle Middle School
Maumelle, AR 72113
About This School
In 2011, Maumelle Middle School had 14 students for every full-time equivalent teacher. The Arkansas average is 14 students per full-time equivalent teacher.
Student Ethnicity (2011)
Students (2011)
Students Per Teacher (2011)
Female/Male (2011)
Subsidized Lunch (2011)
District Spending (2010)
All Grades Algebra I Performance
Maumelle Middle School Reviews
I hate this school. The teachers are always rude and mean. And I am tired of my child coming home crying because of the bad teacher yelling at her for not being "good enough" to go to All Region. And also if you aren't good enough, they don't even take time to teach you anymore. I am very disappointed in this school.
I think Maumelle Middle School is a great school. I really want my child to go there, but I don't know when the school stops let people go to their school.
We have only had one year at Maumelle Middle School, but I have been very pleased with the interest the teachers take in their students and the quick response time in receiving a call back when leaving a message. The principal seems to be hands on, and is seen quite often out and about around the students, which I think is a very good thing. The only frustration I have had is with edline and emails. I was not successful in getting a response from any teachers when I sent an email through the edline email addresses. This may be a problem with the email system, because telephone messages were always promptly returned. The teachers have been very willing and able to help my child to grow his character as well as his mind.


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Validity of the international physical activity questionnaire short form (IPAQ-SF): A systematic review
1 FAMILY: A Jockey Club Initiative for a Harmonious Society, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong
2 Institute of Human Performance, University of Hong Kong, 111-113 Pokfulam Road, Hong Kong
3 Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
International Journal of Behavioral Nutrition and Physical Activity 2011, 8:115 doi:10.1186/1479-5868-8-115Published: 21 October 2011
The International Physical Activity Questionnaire - Short Form (IPAQ-SF) has been recommended as a cost-effective method to assess physical activity. Several studies validating the IPAQ-SF have been conducted with differing results, but no systematic review of these studies has been reported.
The keywords "IPAQ", "validation", and "validity" were searched in PubMed and Scopus. Studies published in English that validated the IPAQ-SF against an objective physical activity measuring device, doubly labeled water, or an objective fitness measure were included.
Twenty-three validation studies were included in this review. There was a great deal of variability in the methods used across studies, but the results were largely similar. Correlations between the total physical activity level measured by the IPAQ-SF and objective standards ranged from 0.09 to 0.39; none reached the minimal acceptable standard in the literature (0.50 for objective activity measuring devices, 0.40 for fitness measures). Correlations between sections of the IPAQ-SF for vigorous activity or moderate activity level/walking and an objective standard showed even greater variability (-0.18 to 0.76), yet several reached the minimal acceptable standard. Only six studies provided comparisons between physical activity levels derived from the IPAQ-SF and those obtained from objective criterion. In most studies the IPAQ-SF overestimated physical activity level by 36 to 173 percent; one study underestimated by 28 percent.
The correlation between the IPAQ-SF and objective measures of activity or fitness in the large majority of studies was lower than the acceptable standard. Furthermore, the IPAQ-SF typically overestimated physical activity as measured by objective criterion by an average of 84 percent. Hence, the evidence to support the use of the IPAQ-SF as an indicator of relative or absolute physical activity is weak.


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Artistic Nativity Crèche in Saint Peter's Square
Italian Region of Basilicata Offers Artistic Work to the Holy Father
| 2270 hits
VATICAN CITY, DEC. 6, 2012 (Zenit.org).- The traditional nativity crèche mounted every Christmas in St. Peter's Square will this year be offered to the Holy Father by the Italian region of Basilicata.
The massive nativity scene, which includes one hundred terracotta figures, is the work of Francesco Artese, one of the most famous exponents of the southern school of traditional nativity sculpture. The most striking characteristic of Artese's work is his recreation of landscapes of the Stones of Matera and his reproduction of scenes of rural life. Indeed, the nativity of St. Peter's Square is reminiscent of locations in the Holy Land.
According to communique published yesterday, "The Lucanian landscape has been enriched by the work of religious people who have chosen to live there, transforming these places into a human settlement rich in holiness, building 154 rupestrian churches, monasteries and sanctuaries which, from the high Middle Ages until the nineteenth century, have shaped the identity of a vast area which is now a UNESCO World Heritage Site."
The communique goes on to say that the nativity crèche, though inspired by traditional iconographic style, will also be unique by incorporating "elements reproducing locations and architecture typical of the Lucanian landscape."
"Artese has chosen to dress the Holy Family with costumes in the classic tradition," the communique stated.
The Technical Services of the Governorate of Vatican City State will be entrusted with the installation of the crèche.


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- Filed Under
Plans are again in the works for a waste-to-energy plant to be built in Santa Rita.
Dave Sablan, program coordinator for the Guam Resource Recovery Partners, recently presented the plan to the Guam Economic Development Authority at the last board meeting, pitching his idea for a longer-lasting landfill in Layon and the utilization of excess trash.
Sablan made the case for the company's plan to open a municipal landfill in the Guåtali area of Santa Rita that would temporarily house trash before being transported to an incinerator. ...


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As an addition to the recently launched Peli ProGear Urban Backpack collection,
this new light-weight sports line brings added colors and styles to the range
(Barcelona – October 2012) Peli Products, the global leader in the design and manufacture of advanced lighting systems and high-performance protective case solutions, today announced the introduction of its Peli ProGear™ Sport Backpacks as the newest additions to its consumer products line, Peli ProGear (www.PeliProGear.com).
"All Peli ProGear products are built especially for the digital protection and extreme performance needs of everyone from the average consumer to the adventure-seekers, and the new Sport Backpacks are no exception," said Lyndon Faulkner, President and CEO of Peli Products. "Each backpack is created with the same Peli-tough DNA as found in our products used by professionals, such as firemen and other rescue services. We are incorporating this professional protection into our consumer goods."
Following the success of its initial backpack line – the Peli ProGear Urban Backpacks – under the new consumer brand, the new Peli ProGear Sport Backpacks also encompass either a Peli hard case or rigid compartment to fit and protect personal electronics and belongings.
The integrated crushproof Peli cases in the Elite models of this additional range, feature the same professional-grade attributes as Peli's classic case products (including a watertight o-ring seal with automatic pressure equalization valve), and is designed to safeguard laptops, MacBook® computers, netbooks, e-readers, tablets, keyboards and other accessories. Also included with Elite models is a set of four adhesive, memory foam buffers, which secure the laptop or tablet for safe travel.
The new Peli ProGear Sport Backpacks are offered to consumers in black and light weight styles. The collection appeals to an active demographic with light rip-stop nylon and a slimmer case design that favors Ultrabooks. Peli ProGear Sport Backpack models include:
• S140 Elite Tablet Backpack: An integrated watertight and crushproof Peli case safeguards tablets, notebooks and small netbooks, while also fitting most tablet keyboards. It also features a rigid front plate, ergonomic ventilated back panel and SureGrip soft rubber handle. Additional features include top-loading TSA-ready main storage compartment as well as a padded lumbar storage cavity - MSRP: € 247.95.
• S105 Laptop Backpack: Shielding 15-inch and 17-inch laptops and Apple® products, the impact-protective frame provides 360-degree protection – allowing the S105 to be light-weight, yet still provide superior performance. Additional features include a rigid front plate, integrated laptop sleeve and ergonomic design with deep-ventilated channel back panel – MSRP: € 144.95.
• S145 Tablet Backpack: Includes an impact-protected tablet sleeve with rigid front plate offering an additional storage option to the 21-liter main storage unit. The S145 also features an ergonomic, fast-access/top-load design with deep-ventilated channel back panel – MSRP: € 112.95.
Lear more about the S140 Elite Tablet Backpack, S105 Laptop Backpack and S145 Tablet Backpack at www.PeliProGear.com. Additional available product lines include the Peli ProGear Urban Backpacks, Peli ProGear Digital Protection (Micro Case Series™ and Hardback™ Series), Peli ProGear 9420 LED Work Light / 9420 XL and Peli ProGear Lighting.
The Peli ProGear brand includes new, rugged, protective consumer products designed to allow users to transport and protect all that they value, regardless of environmental conditions. Learn more at www.PeliProGear.com.


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Brad Biggs on the end of Urlacher era for Bears
Chicago Tribune Bears reporter Brad Biggs discusses if the team really wanted to bring back linebacker Brian Urlacher and what's next for the Bears defense.
bears need urlacher for one more season!!!
Urlacher doesn't deserve this from the bears but hey look at the bright side maybe the "Green Bay Packers" should take him and teach the bears a lesson.


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I have been slacking a little in manifest textual updates on the blog; Facebook currently has the audience of friends who care about my existence, and it is easy to just dump an update onto my wall and forget about it. Generally, I'm in good form. I've started to change my food intake, reduce my dependence on sweet things, and exercise more. I have had great advice on this from friends such as Nicole and Ciaran from the hackerspace, and I've had it beat into me that I shouldn't look at this as some kind of dieting fad with set goals. Rather, I should just make those changes I want to that will improve my health, and everything else will come in time. I already feel better, just by walking by someone lugging a pizza and bottle of soda from the supermarket.
I've started to cultivate a taste for beer, if only to get myself away from chugging Coca Cola and Red Bull around the clock. It's 4am and my current sidebar beverage is a glass of low-fat milk.
The biggest bind on me right now is college. To cut a long story short, this is my situation:
- I cannot apply for a grant renewal with the Galway V.E.C. until I have a letter from I.T. Sligo saying I will be accepted back as a repeat student for the academic year 2013-2014.
- The staff of I.T. Sligo are on holidays or otherwise unavailable until mid-September 2013.
- I would like to make plans for either Galway or Sligo now, and not in five weeks.
- If I cannot return to college this year, then I'd like to plan for it now. I'll add my relevant Facebook update here, verbatim:
August 5:
A big question in my life recently has been whether I go back to Sligo and repeat second year, or do something else, whatever that something else might be. I had a breakdown that started at the end of last September, dropped out of college, life, sight, and sound for more than six months. I tried to hang myself. I self-harmed, and I subjected myself to ever flavour and form of self-hatred that you can conceive.
I've improved since then. It isn't noticeable day-to-day, but I can look back at the month before and say that I've changed, but I'm still not healed. My temper is as bad: I was assaulted in Galway during the week gone, I snapped, and I left the idiot who attacked me in a heap on the ground; there are still days when I hate myself to the point that all I want to do is take a long walk off a high bridge; I've had to walk away from sharp implements more than once in the recent past; and, you know, the rule of thumb is that my self-esteem is nonexistent.
Don't get me wrong! I'm better than I used to be. Having spoken to Caira, and that she forgave me, was one of the balms I needed, and it's helped me let go of a lot of the crap I was carrying.
But, Sligo. I've cleared hurdles with the Galway VEC about my grant, although I need paperwork from I.T. Sligo for them (who in turn have been like a black hole that swallows all emails and phone calls). Despite this, I simply do not relish going back in September. I know how fragile things are, and I suspect that with a lack of activities in Sligo to catch my interest, I'd just wind back at square one and waste another year staring at a wall.
All this said, I'm going to settle my outstanding debts (~€360), find somewhere to live in the city or county, look for web/programming work, and see if I can get into NUIG or GMIT for September 2014. TL;DR: Galway, not Sligo.
I can't really put serious pressure on the admissions department of I.T. Sligo, or anyone else, because I'm one student of (I'm sure) several who are in the same boat, but that hasn't stopped me from giving them puppy eyes over the weekend.
Things have really warmed with Mariah, although there are moments where I feel struck through with the pain of how far we've come and how much we've separated. Honestly? I'm jealous of the fact that she has her own life with friends, where she can meet strangers, while I still hide in out of sight and sound, bury my nose in work (or play) and avoid everyone. Yeah, go me, that's crazy cat fella Mark for you.
I am proud of the children Garrett and Caira have become. Garrett's turned into this wonderful little clone of his mum and I. He's full of energy, picks up everything, is (like his sister) scarily intelligent, and he's hugely social. He remembers Ireland, remembers me, and still talks about it non-stop. Caira is…Caira; a bastard hybrid of Billy, Mariah, and I, a little girl full of energy and fun, and intelligence, even if she's troubled. She has to repeat the first grade at school, and a recluse who wants to do her own thing at all times. Caira has amazing perception, even if you practically have to pull out her fingernails will a pliers before she will demonstrate it.
I'm worried about her performance at school. If you do anything with her, you have to do it on her schedule, in her time, or you may as well go and bang your head off the wall. This isn't compatible with standardized testing, standardized schedules, and standardized school. I'm hopeful that either the counsellors at school or someone in her family will find the key that unlocks her mystery.
I spoke to Caira on Friday gone, and she seemed pretty happy when she finally stood still and said hey. She wants a photograph of me, and Garrett wants a toy robot.
I've finally started to give coding serious attention for the sake of experience, learning, work, and eventually money too. I find coding is 20% cool brainstorming, 50% writing, 15% debugging, and 15% crying into my beer because the fucking thing doesn't work. I've moved from C# into PHP, (better formatted) CSS and HTML, a brush of JavaScript, and a lot more shell scripting. Self-directed learning without peer review is awful-and it's a good deal of why I want to return to college-because I don't know if my work is good or bad, if it is good but I have bad habits, or actually, genuinely not-bad.
I think I've picked up a few valuable lessons to date (that the available documentation will always be awful is a good one), and struggled through a lot of self-dissuasion about handling larger projects. I've already had one offer for effectively an internship with a developer in Galway that I want to pursue if I stay here for the winter.
I am also in the final stages of wrapping up a large project for a group at NUIG-the final handoff is this week, and I will hopefully share screenshots, and thoughts on the project after that point.
That's it for now. For the lack of anything else to close on, here is Killer:


text:
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