Fibromyalgia, chronic fatigue, and other iatrogenic diagnostic algorithms. Do some labels escalate illness in vulnerable patients?

Contemporary medicine has the sophistication to identify the clinical settings in which the hunt for a diagnosis can be harmful to a patient's health. Which patients are best served by a prolonged search for a cause? Why has the disease-illness paradigm backfired for so many patients? Dr Hadler challenges readers to look at the difficult questions linked with diagnostic labels that might teach patients to stay sick.     

Antinuclear antibody and HLA-B27 positive uveitis: combination of two diseases?

AIMS/BACKGROUND: Anterior uveitis associated with juvenile chronic arthritis concerns two different clinical entities: firstly, antinuclear antibody (ANA) positive patients who have a chronic anterior uveitis with severe complications and often a poor visual prognosis; secondly, usually HLA-B27 positive children, predominantly boys, with unilateral recurrent anterior uveitis. Three patients are described who had a combination of clinical and laboratory features of both diseases. METHODS: Retrospective clinical and laboratory analysis of three patients. RESULTS: Ocular features in the three patients combined the clinical picture of ANA positive chronic anterior uveitis during early childhood with the clinical features of HLA-B27 unilateral acute anterior uveitis during adolescence. The patients fulfilled the diagnostic criteria of juvenile chronic arthritis, and they had no ankylosing spondylitis. All three patients had the HLA-B*2705 subtype. CONCLUSIONS: Whether the association of ANA positive chronic anterior uveitis and HLA-B27 unilateral acute anterior uveitis is a coincidence or represents a distinct clinical entity is not yet clear.     

Conventional and hypobaric activation of an ultrasound contrast agent

Hypobaric activation is a new injection technique for use with the contrast agent EchoGen and, in this study, the agent's ability to produce parenchymal enhancement in vivo, with and without prior hypobaric activation, was investigated. Injections, ranging in dose from 0.05 to 0.5 mL/kg, were administrated through a peripheral vein to eight woodchucks with multiple hepatomas. At the 0.10 mL/kg dose level, seven of eight injections following hypobaric activation (88%) resulted in definite parenchymal enhancement. Conversely, dosages of 0.10 mL/kg without prior hypobaric activation produced no grey-scale changes. Only at the 0.4 and 0.5 mL/kg dosage level did the conventional administration technique obtain similar results (4 of 5 injections increased the echogenicity for a 0.4 mL/kg dose). These differences were statistically significant (p = 0.031). In vitro experiments were conducted to establish the physical mechanisms behind hypobaric activation. Relative measurements of contrast microbubble sizes were performed with a phase Doppler particle analyzer after hypobaric and after conventional (bolus) activation. Hypobaric activation produced approximately 20 times more microbubbles per unit volume than the conventional method. In conclusion, this investigation has demonstrated the benefits of prior hypobaric activation when performing in vivo contrast studies with EchoGen and determined the physical mechanisms behind this new injection technique. Hypobaric activation of EchoGen increases contrast enhancement and reduces dose size.     

Antibiotic therapy for seminal infection. Effect on antioxidant activity and T-helper cytokines

OBJECTIVE: To investigate the effect of antibiotic therapy on seminal infection. STUDY DESIGN: The seminal plasma of 50 men was evaluated in three groups: (1) men with seminal infection (20), (2) men with leukocytospermia only (18), and (3) men of proven fertility (12). The evaluation protocol included semen analysis, culture and antibiotic sensitivity test, total antioxidant activity, alpha-tocopherol and retinol, T-helper cytokines, IL-2, IL-8, IL-4 and antisperm antibodies. RESULTS: Sperm parameters were worse with seminal infection: 25 versus 84 million per milliliter for fertile men. Antioxidant activity, total alpha-tocopherol and retinol were reduced in leukocytospermia (P < .02, .01) and seminal infection (P < .01, .05) as compared to controls. Antisperm antibodies IL-2 and IL-8 were highly expressed, while IL-4 was low in men with leukocytospermia and bacteriospermia. Gram-negative organisms were more associated with expression of T-helper 1 cytokines than T-helper 2 cytokines. Antibiotic therapy significantly improved the sperm parameters, antioxidant activity and IL-4 but reduced IL-2 and IL-8 and had no effect on antisperm antibody titer. CONCLUSION: Antibiotic therapy improves sperm parameters by increasing antioxidant activity and IL-4 and by reducing IL-2 and IL-8.     

Macrophage migration inhibitory factor expression in human renal allograft rejection

BACKGROUND: Macrophage migration inhibitory factor (MIF) plays a pivotal role in immune-mediated diseases. Despite the long-standing association of MIF with the delayed-type hypersensitivity response, the potential role of MIF in allograft rejection is unknown. METHODS: MIF expression was assessed by in situ hybridization and immunohistochemistry staining in 62 biopsies of human renal allograft rejection and in normal human kidney. RESULTS: MIF mRNA and protein is constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells, some glomerular epithelial cells, and vascular smooth muscle cells. In both acute and chronic renal allograft rejection, there was marked up-regulation of MIF mRNA and protein expression by intrinsic kidney cells such as tubular epithelial cells and vascular endothelial and smooth muscle cells. There was also MIF expression by infiltrating macrophages and T cells. Of note, macrophage and T cell infiltrates were largely restricted to areas with marked up-regulation of MIF expression, potentially contributing to the development of severe tubulitis and intimal or transmural arteritis. Quantitative analysis found that increased MIF expression in allograft rejection gave a highly significant correlation with macrophage and T cell accumulation in both the glomerulus and interstitium (P<0.001). In addition, the number of MIF+ tubules and interstitial MIF+ cells correlated significantly with the severity of allograft rejection (P<0.01), and the loss of renal function (P<0.01). In contrast, no up-regulation of renal MIF expression and no leukocyte accumulation was seen in allograft biopsies without evidence of rejection. CONCLUSIONS: This is the first study to demonstrate that local MIF expression is up-regulated during allograft rejection. The association between up-regulation of MIF expression, macrophage and T cell infiltration and the severity of renal allograft rejection suggests that MIF may be an important mediator in the process of allograft rejection.     

Randomised trial of educational visits to enhance use of systematic reviews in 25 obstetric units

OBJECTIVE: To evaluate the effectiveness of an educational visit to help obstetricians and midwives select and use evidence from a Cochrane database containing 600 systematic reviews. DESIGN: Randomised single blind controlled trial with obstetric units allocated to an educational visit or control group. SETTING: 25 of the 26 district general obstetric units in two former NHS regions. SUBJECTS: The senior obstetrician and midwife from each intervention unit participated in educational visits. Clinical practices of all staff were assessed in 4508 pregnancies. INTERVENTION: Single informal educational visit by a respected obstetrician including discussion of evidence based obstetrics, guidance on implementation, and donation of Cochrane database and other materials. MAIN OUTCOME MEASURES: Rates of perineal suturing with polyglycolic acid, ventouse delivery, prophylactic antibiotics in caesarean section, and steroids in preterm delivery, before and 9 months after visits, and concordance of guidelines with review evidence for same marker practices before and after visits. RESULTS: Rates varied greatly, but the overall baseline mean of 43% (986/2312) increased to 54% (1189/2196) 9 months later. Rates of ventouse delivery increased significantly in intervention units but not in control units; there was no difference between the two types of units in uptake of other practices. Pooling rates from all 25 units, use of antibiotics in caesarean section and use of polyglycolic acid sutures increased significantly over the period, but use of steroids in preterm delivery was unchanged. Labour ward guidelines seldom agreed with evidence at baseline; this hardly improved after visits. Educational visits cost pound860 each (at 1995 prices). CONCLUSIONS: There was considerable uptake of evidence into practice in both control and intervention units between 1994 and 1995. Our educational visits added little to this, despite the informal setting, targeting of senior staff from two disciplines, and donation of educational materials. Further work is needed to define cost effective methods to enhance the uptake of evidence from systematic reviews and to clarify leadership and roles of senior obstetric staff in implementing the evidence.     

Non-isotopic in situ hybridization of HPV types in cervical intraepithelial lesions in patients with AIDS

Naturally produced methane shows different delta 13C-values with respect to its origin, e.g., geological or biological. Methane-production of ruminants is considered to be the dominant source from the animal kingdom. Isotopic values of rumen methane--given in literature--range between -80/1000 and -50/1000 and are related to feed composition and also sampling techniques. Keeping cows, camels and sheep under identical feed conditions and sampling rumen gases via implanted fistuale we compared delta PDB 13C-values of methane and CO2 between the species. Referring to mean values obtained from 4 or 5 samples at different times of 11 animals (n = 47) we calculated delta PDB 13C-medians resulting in small but not significant differences within and significant differences between the species for CO2 and methane. The delta PDB 13C-differences between methane and CO2 were statistically equal within and also between the species. Therefore a linear regression of methane values on CO2 is appropriate and leads to: delta PDB 13C(methane)/1000 = 1.57 * delta PDB 13C(CO2)/1000 - 47/1000 with a correlation coefficient of r = 0.87.     

P-selectin deficiency attenuates tumor growth and metastasis

Selectins are adhesion receptors that normally recognize certain vascular mucin-type glycoproteins bearing the carbohydrate structure sialyl-Lewisx. The clinical prognosis and metastatic progression of many epithelial carcinomas has been correlated independently with production of tumor mucins and with enhanced expression of sialyl-Lewisx. Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. We provide a link between these observations by showing that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells. Three potential pathophysiological mechanisms are demonstrated: first, intravenously injected tumor cells home to the lungs of P-selectin deficient mice at a lower rate; second, P-selectin-deficient mouse platelets fail to adhere to tumor cell-surface mucins; and third, tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin-deficient animals.