We should count ourselves lucky.

Last summer I was extremely lucky to have the opportunity to visit Harvard School of Dental Medicine for my elective. I now return to my final year of dental school in Manchester with a renewed sense of appreciation for the education system I have entered in to. I was shocked at the price dental students in America pay to receive an education, and at some of their unusual practices along the way.

Outcomes and predictors of response from an optimised, multidisciplinary intervention for chronic fatigue states.

BACKGROUND: Medically unexplained chronic fatigue states are prevalent and challenging to manage. Cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are effective in clinical trials. The evaluation of delivery in a standard healthcare setting is rare. An integrated treatment programme with individualised allocation of resources to patients' needs was developed and implemented through an academic outpatient clinic. It was hypothesised that the programme would result in similar responses to those observed in the clinical trials. AIM: To evaluate the outcomes of an integrated, 12-week CBT and GET programme delivered by exercise physiologists and clinical psychologists. METHODS: Consecutive eligible patients (n = 264) who met the diagnostic criteria for chronic fatigue syndrome or post-cancer fatigue were evaluated with self-report measures of fatigue, functional capacity and mood disturbance at baseline, end-of-treatment (12 weeks) and follow-up (24 weeks). A semi-structured interview recording the same parameters was conducted pre- and post-treatment by an independent clinician. Primary outcome was analysed by repeated measures analysis of variance and predictors of response were analysed by logistic regression. RESULTS: The intervention produced sustained improvements in symptom severity and functional capacity. A substantial minority of patients (35%) gained significant improvement, with male gender and higher pain scores at baseline predicting non-response. A small minority of patients (3%) worsened. CONCLUSION: The manualised protocol of integrated CBT and GET was successfully implemented, confirming the generally positive findings of clinical trials. Assessment and treatment protocols are available for dissemination to allow standardised management. The beneficial effects described here provide the basis for ongoing studies to optimise the intervention further and better identify those most likely to respond.

Ethanol induces apoptosis in human mast cells.

AIMS: Alcohol abuse is associated with increased frequency of infections attributed to ethanol-induced immune suppression. The precise mechanism of immune suppression is however not known. Mast cells (MC) belong to the innate immune system and they have been implicated in the first line of immune defence against bacteria and parasites. Therefore we studied the effects of ethanol and its first metabolite acetaldehyde on mast cell viability, proliferation and apoptosis. MAIN METHODS: Human mast cell line (HMC)-1 cells, mouse bone marrow derived mast cells (mBMMC) and human peripheral blood derived mast cells (HuMC) were used. Effects of ethanol and acetaldehyde on mast cell proliferation were determined by assessing incorporation of [(3)H]thymidine into cellular DNA and by trypan blue exclusion. Apoptosis was assessed by measuring apoptotic nucleosomes and caspase-3, -8 and -9 activities using ELISA and by using Tunel assay. The expression of anti- and proapoptotic proteins Bcl-2 and Bax was analyzed by RT-PCR and western blot, respectively. KEY FINDINGS: Ethanol, but not acetaldehyde inhibited dose-dependently the proliferation and viability HMC-1 and mBMMC cells. The decreased viability was caused by apoptotic cell death of the MC. Significant apoptosis of HMC-1 cells was observed in the presence of 43mM (2.5 per thousand) ethanol. Induction of apoptosis was associated with clearly increased caspase-3 activity and moderately increased caspase-8 and 9 activities. Ethanol also shifted the Bcl-2/Bax balance towards apoptosis. SIGNIFICANCE: The ethanol-induced reduction of MC viability could contribute to immunosuppression associated with ethanol abuse.

Selective activation of mast cells in rheumatoid synovial tissue results in production of TNF-alpha, IL-1beta and IL-1Ra.

OBJECTIVES AND DESIGN: To study the consequences of mast cell activation in human synovial tissue. METHODS: Synovial tissue was obtained from 18 RA patients and mast cells was selectively activated in synovial tissue explant cultures. Expression of TNF-alpha, IL-1beta and IL-1Ra were determined and tissue distribution of IL-1beta was studied. RESULTS: Compared to untreated synovia, selective activation of synovial mast cells increased significantly the production of TNF-alpha (0.49 +/- 0.88 vs. 4.56 +/- 3.18 pg/mg wet tissue, p < 0.001) and IL-1beta (0.058 +/- 0.032 vs. 2.55 +/- 1.98 pg/mg wet tissue, p = 0.013). The expression of TNF-alpha and IL-1beta mRNA increased significantly (19-fold (p = 0.009) and 13-fold (p = 0.031), respectively). Mast cell activation induced IL-1beta expression in particular in nearby CD68 positive synovial macrophages. Secretion of IL-1Ra was also increased but to a lesser degree than that of IL-1beta. CONCLUSIONS: Synovial mast cells produce proinflammmatory cytokines and may thus contribute to the inflammation in RA.

Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C.

OBJECTIVE: To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells. METHODS AND RESULTS: In the presence of 25 microM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 +/- 7.3% of control. Similarly, the activation-induced secretion of TNF-alpha and IL-8 by HMC-1 cells were decreased in the presence of 25 microM CMT-3 to 13.5 +/- 4.1% and 9.7 +/- 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-alpha but instead it reduced the expression of TNF-alpha mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC(50) value of 31 microM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity. CONCLUSIONS: Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.

Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovia: a potential approach to the treatment of arthritis.

BACKGROUND: Mast cells have been implicated in the pathogenesis of arthritis, but elucidation of their precise role has been hampered by a lack of efficient and selective inhibitors of their function. OBJECTIVE: To elucidate the role of mast cells in the pathogenesis of rheumatoid arthritis (RA) and to assess whether apoptosis of cultured and synovial tissue mast cells can be induced by inhibiting mast cell growth factor receptor, c-kit tyrosine kinase. METHODS AND RESULTS: Double staining with tumour necrosis factor (TNF) alpha and tryptase antibodies showed the presence of TNFalpha positive mast cells in human rheumatoid synovial tissue. Selective activation of mast cells by anti-IgE resulted in production of TNFalpha in synovial tissue cultures. Inhibition of the c-kit tyrosine kinase with imatinib mesylate (1.0-10 micromol/l) induced profound apoptosis in cultured mast cells as judged by typical apoptotic morphology, increased number of apoptotic nucleosomes, and activation of caspases 8 and 9. Importantly, imatinib also induced apoptosis of mast cells in explant cultures of synovial tissue obtained from patients with RA as judged by a TUNEL assay. Inhibition of c-kit tyrosine kinase was accompanied by significant reduction of TNFalpha production in synovial tissue cultures. CONCLUSION: Mast cells may have a role in the pathogenesis of RA, and inhibition of c-kit may be a new means of inhibiting mast cell activity and of abrogating the contribution of mast cells to synovial inflammation in RA.

Imaging evaluation of posttraumatic renal injuries.

Computed tomography plays an important role for the evaluation of most patients with suspected renal injury after trauma. Intravenous urography is used for gross assessment of renal function in hemodynamically unstable patients. Renal injuries can be classified into four large groups: (1) minor renal contusion, lacerations, subcapsular hematoma, and small cortical infarcts; (2) major renal lacerations extending to the medulla with or without involvement of the collecting system; (3) catastrophic renal injuries including fragmentation of the kidney and renal pedicle vascular injuries; and (4) ureteropelvic junction injuries. Integration of the imaging findings of renal injury with clinical information is important to developing a treatment plan.

Imaging of renal trauma: a comprehensive review.

Computed tomography (CT) is the modality of choice in the evaluation of blunt renal injury. Intravenous urography is used primarily for gross assessment of renal function in hemodynamically unstable patients. Selective renal arteriography or venography can provide detailed information regarding vascular injury. Retrograde pyelography is valuable in assessing ureteral and renal pelvic integrity in suspected ureteropelvic junction injury. Ultrasonography is useful in detecting hemoperitoneum in patients with suspected intraperitoneal injury but has limited value in evaluating those with suspected extraperitoneal injury. Occasionally, radionuclide renal scintigraphy or magnetic resonance imaging may prove helpful. Renal injuries can be classified into four large categories based on imaging findings. Category I renal injuries include minor cortical contusion, subcapsular hematoma, minor laceration with limited perinephric hematoma, and small cortical infarct. Category II lesions include major renal lacerations extending to the medulla with or without involvement of the collecting system and segmental renal infarct. Category III lesions are catastrophic renal injuries and include multiple renal lacerations and vascular injury involving the renal pedicle. Category IV injuries are ureteropelvic junction injuries. CT is particularly useful in evaluating traumatic injuries to kidneys with preexisting abnormalities and can help assess the extent of penetrating injuries in selected patients with limited posterior stab wounds. Integration of the imaging findings in renal injury with clinical information is critical in developing a treatment plan.