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New insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N = 273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models. Higher age-and sex- adjusted z-scored BMI was significantly correlated with household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r = 0.31, P .0001), PhenoAge (r = 0.24, P .0001), and DunedinPoAm (r = 0.38, P .0001). In fully adjusted models, GrimAge (β = 0.07; P = .0009) and DunedinPoAm (β = 0.0017; P .0001) remained significantly associated with higher age- and sex-adjusted z-scored BMI. Maltreatment-status was not associated with accelerated epigenetic aging. In a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk.

Joint bleeding, or haemarthrosis, is the most common type of bleeding episode experienced by individuals with haemophilia A and B. This leads to changes within the joints, including synovial proliferation, which results in further bleeding and chronic synovitis. Blood in the joint can also directly damage the cartilage, and with repeated bleeding, there is progressive destruction of both cartilage and bone. The end result is known as haemophilic arthropathy. The joints most commonly affected are the knees, elbows and ankles, although any synovial joint may be involved. In the ankle, both the tibiotalar and subtalar joints may be affected and joint bleeding and arthropathy can lead to a number of deformities. Haemophilic arthropathy can be prevented through regular factor replacement prophylaxis and implementing physiotherapy. However, when necessary, there are multiple surgical and non-surgical options available. In early ankle arthropathy with absent or minimal joint changes, both radioisotopic and chemical synoviorthesis can be used to reduce the hypertrophied synovium. These procedures can decrease the frequency of bleeding episodes, minimizing the risk of articular cartilage damage. Achilles tendon lengthening can be performed, in isolation or in combination with other surgical measures, to correct Achilles tendon contractures. Both arthroscopic and open synovectomies are available as a means to remove the friable villous layer of the synovium and are often indicated when bleeding episodes cannot be properly controlled by factor replacement therapy or synoviorthesis. In the later stages of ankle arthropathy, other surgical options may be considered. Debridement may be indicated when there are loose pieces of cartilage or anterior osteophytes, and can help to improve the joint function, even in the presence of articular cartilage damage. Supramalleolar tibial osteotomy may be indicated in patients with a valgus deformity of the hindfoot without degenerative radiographic findings. Joint fusion, or arthrodesis, is the treatment of choice in the advanced stages of ankle arthropathy although total ankle replacement is currently available. Early ankle replacement components were associated with a poor outcome, but as implant designs have improved, there have been successful outcomes achieved. As the ankle is a commonly affected joint in many individuals with haemophilia, it is important to add to the knowledge base to validate indications and timing of surgical and non-surgical interventions in ankle arthropathy.

For antidepressants, the translation of evidence of comparative effectiveness into practice is suboptimal. This deficit directly affects outcomes and quality of care for patients with depression. To overcome this problem, we developed the Depression Medication Choice (DMC) encounter decision aid, designed to help patients and clinicians consider the available antidepressants and the extent to which they improved depression and other issues important to patients.Estimate the effect of DMC on quality of the decision-making process and depression outcomes.We conducted a cluster randomized trial of adults with moderate to severe depression considering treatment with an antidepressant. Primary care practices in 10 rural, suburban, and urban primary care practices across Minnesota and Wisconsin were randomly allocated to treatment of depression with or without use of the DMC decision aid.Depression Medication Choice, a series of cards, each highlighting the effect of the available options on an issue of importance to patients for use during face-to-face consultations.Decision-making quality as judged by patient knowledge and involvement in decision making, patient and clinician decisional comfort (Decisional Conflict Scale) and satisfaction, encounter duration, medication adherence, depression symptoms, and the Patient Health Questionnaire for depression (PHQ-9).We enrolled 117 clinicians and 301 patients (67% women; mean [SD] age, 44 [15] years; mean [SD] PHQ-9 score, 15 [4]) into the trial. Compared with usual care (UC), use of DMC significantly improved patients' decisional comfort (DMC, 80% vs UC, 75%; P = .02), knowledge (DMC, 65% vs UC, 56%; P = .03), satisfaction (risk ratio [RR], from 1.25 [P = .81] to RR, 2.4 [P = .002] depending on satisfaction domain), and involvement (DMC, 47% vs UC, 33%; P.001). It also improved clinicians' decisional comfort (DMC, 80% vs UC, 68%; P .001) and satisfaction (RR, 1.64; P = .02). There were no differences in encounter duration, medication adherence, or improvement of depression control between arms.The DMC decision aid helped primary care clinicians and patients with moderate to severe depression select antidepressants together, improving the decision-making process without extending the visit. On the other hand, DMC had no discernible effect on medication adherence or depression outcomes. By translating comparative effectiveness into patient-centered care, use of DMC improved the quality of primary care for patients with depression.clinicaltrials.gov Identifier: NCT01502891.

Joint and muscle injury associated with direct damage to the tissues and muscle atrophy may ensue following immobility. Rehabilitation of the injury is linked with the return to normal functional values such as range of motion, muscle strength, and muscle tone. It is, however, likely that subtle changes or differences still exist in the site of injury or haemarthrosis. In particular proprioception may be distorted due to the direct injury of sensory receptors and to feedback systems. The implications of such damage are important, where proprioception plays an important part in the control, timing and organisation of coordinated bodily actions.

Objectives: To assess the usage of carbon fibre orthoses in assisting post- polio syndrome patients who reported advancing weakness and difficulty in maintaining their independent ambulatory status.Design and interventions: Carbon fibre orthoses that are 30% lighter than metal braces were constructed.Subjects: Thirty patients who complained of difficulty in maintaining their ambulation using long-leg braces were provided with lightweight orthoses.Results: Seventy per cent of the patients reported satisfaction with their braces. There were, however, problems in construction and use.Conclusions: Ambulation can be preserved in some patients who report advancing weakness because of post-polio syndrome.

We thank Dr. Wiebe for her thoughtful commentary (1) on our study examining the association between hormonal contraceptive use and depressive symptoms and suicide attempts (2). It is true that women using hormonal contraceptives are different in myriad ways from women who are not, complicating inferences made from an observational study in which treatment is not assigned. Dr. Wiebe notes that the inferential problems faced in our analysis are analogous to findings in the observational literature on postmenopausal hormone treatment and other observational studies on the effects of particular treatment protocols. The larger question, then, is whether we can learn something about treatment effects from observational data. We submit that the field has made significant strides in developing innovative methods with which to infer treatment effects from observational data (e.g., see Hernan et al. (3)). These advances have been motivated in part by the conflicting results from observational and clinical trials. The challenge of using observational evidence lies in employing creative strategies for mitigating potential confounding (4) and in appropriately interpreting results while remaining vigilant to threats to validity. Mood-related discontinuation of hormonal contraception among former users would affect our results to the extent that women who discontinue use because of mood-related side effects are also more likely to have depressive symptoms and/or to attempt suicide at a later date (5). Unfortunately, there are few population-based data on the extent to which women who discontinue hormonal contraception because of nondiagnostic factors related to “mood” or “irritability” are more likely to experience depressive symptoms or attempt suicide. Further, while the population-based German study indeed found that former users were more likely to report irritability than current users (6), the totality of population-based research in the area of oral contraceptives and mood/affect side effects is decidedly mixed; a 2002 review of the literature, while largely based on small, nonepidemiologic samples, indicated that there was little consistent evidence for an effect of oral contraceptives on negative mood and affect but consistent evidence for less variability in affect across the menstrual cycle among hormonal contraceptive users (5). To address concerns about discontinuation effects, we controlled for prior use of hormonal contraceptives and prior level of depressive symptoms in our analyses. The results were robust, at least partially mitigating discontinuation effects. We appreciate the suggestion to examine within-individual differences in hormonal contraceptive use and depressive symptoms. We reanalyzed the data with a fixed-effects within-person regression approach. Use of hormonal birth control was inversely associated with past-week depressive symptoms (β =−2.22, 95% confidence interval (CI): −2.40, −2.04), high levels of depressive symptoms (odds ratio = 0.61, 95% CI: 0.55, 0.67), and suicide attempts (odds ratio = 0.59, 95% CI: 0.50, 0.71). Thus, a within-person approach yields the same associations as a between-person analysis. We note that there are limitations to this approach (e.g., only stable characteristics are controlled). We submit that the role of sex hormones in mental health, including but not limited to exogenous hormone use in the form of contraception, remains understudied in population-based epidemiologic samples. There are no questions on family planning or reproductive health in the major nationally representative psychiatric epidemiologic surveys, aside from questions on number of livebirths and current pregnancy status. Conversely, nationally representative surveys that routinely collect information on family planning often have limited, nondiagnostic measures of psychiatric disorders. Decisions regarding contraception and family planning are among the most central in women's lives; we cannot fully understand women's mental health without considering aspects of family planning, including the pharmacological actions of particular treatments, as well as the psychological processes involved in reproductive health decisions. Examination of the intersection of hormone use and mental health, including potential factors that select women into certain contraceptive options and the potential effects of those contraceptives on mental health, is critical yet overlooked in the field of women's health.

Aim of this study was to find out how many patients after a total laryngectomy (TLE) return to work successfully and what factors support vocational rehabilitation.Laryngectomees (n=231) aged up to 60 years completed questionnaires and structured interviews before TLE (t1), before rehabilitation (t2), at the end of rehabilitation (t3), 1 year after TLE (t4), 2 years after TLE (t5), and 3 years after TLE (t6).Prior to TLE, 38% of all respondents were employed, 34% were unemployed, 23% received disability-related and 3% age-related pension retirement. One year after TLE, 13% were employed, 15% 2 years and 14% 3 years after TLE. Unemployed were 10% (t4), 5% (t5), and 7% (t6) of the patients. For 59% of all respondents it was very important to have a job. Predictors of successful vocational rehabilitation were employment prior to TLE, age50 years, being self-employed or clerical employee, good physical functioning, good speech intelligibility, high motivation to go back to work, and support from colleagues.Only few laryngectomees return to work. However, even before TLE only a third of the patients was employed, another third was unemployed. Most of the patients receive pension retirement after TLE. As return to work is important for many patients, patient consultations should consider possibilities to support vocational rehabilitation before offering to apply for retirement.

We report the case of a 44 year old female gardener who presented to our emergency ward with lumbago, myalgia and fever of 39 degrees Celsius. She also reported acholic stools, darker looking urine and ikteric skin complexion. The patient was suffering from acute hepatitis A virus induced liver failure and was rapidly announced to a liver transplant centre. In the course of the illness the condition of the patient improved spontaneously and the serious hepatitis resolved and was self limiting. As a source of infection to possibilities were identified. Eating shellfish at the East Sea 4 weeks prior to admission or handling natural animal dung during her work as a gardener. One year after the event the patient once again is healthy and well.

UNLABELLED In haemophilic arthropathy there is a progressive limitation of the range of motion (ROM) which may lead to disabilities in the activities of daily living (ADL). In the literature the pathology of haemophilic arthropathy is described extensively, but only one paper describing functional limitations caused by limited range of motion (LOM) in haemophilia was found. The aim of the pilot study was to estimate on theoretical grounds, how many patients with haemophilia might suffer from functional disabilities. MATERIAL ROM of elbows, knees and ankles of 155 Haemophilia A and B patients. METHODS Flexion and extension were measured with an ordinary goniometer. The ROM of joints of patients with haemophilia was compared with normal values. RESULTS 39 of 155 patients had a normal ROM in both elbows; 22 in one elbow; 34 patients had disabilities in ADL with both arms; 14 with one arm; 18 were able to compensate; 89 had no problems; 79 of 155 patients had a near normal ROM of both knees; 38 patients could not ride an ordinary bicycle. CONCLUSION Only limited data are available concerning the normal ROM needed for individual ADL. Until additional data are available, it is not possible to predict which patients will be disabled in their activities of daily living and individual counselling should be done during the yearly outpatient comprehensive care clinics. Conservative and surgical measures should be taken to ensure elbow flexion of at least 120 degrees and knee flexion of 100 degrees for Western societies. In Asian countries patients with haemophilia need maximum knee flexion and ankle dorsi flexion.

Thirty-seven patients with volume-retaining disorders (liver cirrhosis with ascites, n = 8; heart failure NYHA III-IV, n = 12; endstage renal failure, n = 17) and twelve healthy age-matched controls were given a small dose (33 micrograms) of hANF (human atrial natriuretic factor). We tested the resulting hemodynamic and renal effects as well as the effect on plasma cyclic GMP levels and compared them with the properties of platelet ANF receptors. The ANF injection evoked an increase in cyclic GMP plasma levels of 19.3 +/- 2.2 nM in healthy controls. This increase tended to be smaller in the cirrhosis group (15.5 +/- 3.3 nM) and in the heart failure group (16.8 +/- 2.3 nM) than in the dialysis group (20.5 +/- 2.5 nM). The invasion rates of cyclic GMP were comparable in all groups, but the evasion rates increased more in the heart failure and endstage renal failure groups (27.9 +/- 7.7 min and 26.1 +/- 3.4 min, respectively) than in the cirrhosis and control groups (14.9 +/- 1.9 min and 14.2 +/- 1.9 min, respectively). Patients with endstage renal failure and congestive heart failure showed a smaller decrease in diastolic blood pressure than controls and patients with liver cirrhosis. Renal actions of ANF were diminished in cirrhosis and heart failure patients. Binding capacities of platelet ANF receptors were higher in the control group (12.2 +/- 1.5 receptors/cell) than in the patient groups (cirrhosis, 7.8 +/- 1.2; endstage renal failure, 8.0 +/- 0.9; heart insufficiency, 8.0 +/- 1.0 receptors/cell), with no differences among the patient groups. Binding affinities were not significantly different. Correlation analysis showed that the relationship between the actions of ANF and the increases in plasma cyclic GMP levels is loose and cannot predict the hemodynamic or renal effects of exogenous ANF in a given patient. Although the behavior of plasma cyclic GMP levels fails to predict the responsiveness of the body to ANF in a given patient, it does reflect the differences between the patient groups and the control group. In contrast, we found no correlation between the properties of platelet ANF receptors and ANF action.

A 24-year old patient with severe haemophilia A and chronic hepatitis C developed two weeks after transjugular liver biopsy (TJLB) haemobilia with colicky upper abdominal pain, coffee ground emesis, melaena and anaemia. Abdominal ultrasound and endoscopic retrograde cholangiogram confirmed the diagnosis. After adequate factor VIII substitution and revision with a balloon catheter the patient became asymptomatic. Haemobilia is a uncommon complication after liver biopsy. This complication should be kept in mind even if the occurrence is delayed after intervention. TJLB is an established and safe method to obtain liver specimen in patients with coagulation disorders.

Previously instituted policies regarding prosthetic limb provision had been deemed dependable. A follow-up home visit study showed that 18 of 60 patients that had been provided with prostheses, did not make use of them. Analysis showed that three categories of patients made up the large majority of the non-users; double amputees, blind persons and those with psychiatric disorders. In order to attempt to eliminate the wastage of prosthetic provision to non-ambulators a new policy decision was made. Doubtful ambulators and those from the three aforementioned categories will be initially provided with temporary prostheses. Only after a period of months of temporary prosthetic usage at home will a decision be made as to whether a permanent prosthesis will be issued.

Aims : To describe the pathological and radiological features of four cases of liposclerosing myxofibrous tumour (LSMFT). LSMFT is a benign fibro-osseous lesion of bone with a marked predilection for the intertrochanteric region of the proximal femur. It is characterized by a complex mixture of histological elements including fibrous dysplasia-like bony trabeculae, myxofibrous tissue, lipomatous areas, xanthoma cells and pseudo-Paget's bone. This lesion is not a universally accepted pathological entity and often appears in the literature under variants of fibrous dysplasia or other benign lytic bone lesions. Methods and results : All lesions exhibited histological and/or radiological overlap with fibrous dysplasia. A relationship to trauma was noted in three of the cases. The hypothesis that these lesions represent a traumatized variant of fibrous dysplasia was explored. After reviewing the biomechanics of the proximal femur, a possible relationship between predilection of LSFMT for this anatomical region and increased susceptibility to fracture was noted. Conclusions : We hypothesize that when fibrous dysplasia involves the proximal femur, it makes the bone more susceptible to fatigue fracture, thereby altering its histological appearance. The wide variety of histological patterns in LSMFT could represent the end result of repeated reaction to fatigue stresses.

The present investigation was designed to evaluate the acute effect of aerobic exercise on oxidative stress and the flow properties of the blood. Fourteen clinically healthy subjects (7 men and 7 women aged 56+/-19 yr) underwent maximal treadmill exercise with blood samples drawn prior to and immediately after exercise. Post-exercise significant increases were observed in plasma lipid hydroperoxides from 6.5+/-2.0 microM to 7.9+/-1.9 microM (p0.0001) and the relative concentration of plasma fluorescent products associated with red cell peroxidation from 138+/-28 RF to 220+/-92 RF (p0.005). After exercise there was a rise in the hematocrit from 41.4+/-3.7% to 44.4+/-4.1% (p0.0001), increases in whole blood viscosity at shear rates of 22.5/sec to 450/sec (p0.0005), an increase in plasma viscosity from 1.27+/-0.12 cP to 1.36+/-0.11 cP (p0.01), an increase in red cell rigidity from 2.44+/-0.48 cP to 2.62+/-0.42 cP (p0.001) and a decrease in erythrocyte sedimentation rate from 26.9+/-18.6 mm/h to 22.5+/-15.9 mm/h (p0.01). The findings suggest that acute aerobic exercise induces oxidative damage to red blood cells and adversely affects rheological properties of the peripheral blood.

A 44-year-old female presented with tenderness of her abdomen, vomiting, intestinal obstruction, hypoalbuminemia and blood eosinophilia. Gastroscopy was normal and colonoscopic biopsies showed only non-specific inflammation of the colonic mucosa and submucosa. CT revealed large amounts of ascites and bilateral pleural effusions but eosinophil counts in the ascites were normal. At CT the jejunum was dilated and showed marked prominence of the valvulae whereas the ileum and the colon presented with a diffuse and hypoattenuating bowel wall thickening. The bowel wall thickening was most pronounced in the colon which especially showed also an impressive thickening and hyperenhancement mainly of its outer bowel wall layers. Parasitic infection could be excluded as well as a specific allergic response. In context with the known blood eosinophilia the diagnosis of an eosinophilic enterocolitis was suspected already by CT but finally only surgical full thickness biopsies could confirm the rare diagnosis of an eosinophilic enterocolitis with predominantly serosal and muscular bowel wall infiltration.

The benefits and feasibility of progressive resistance training on muscle strength and bleeding profile were studied prospectively in two patients with severe haemophilia. Additionally, retrospective data were collected from three patients who had been training for 11-21 years (one patient for 21 years and two patients for 11 years). Muscle strength increased, especially in muscle groups surrounding the target joints (elbow and knee). Bleeding frequency decreased from 2-3 times per week to 1-2 times per week. Patients who had been training for11 years reported bleeding episodes of 2-4 times per month prior to training, but after11 years of progressive training a marked decrease in bleeding occurred, as well as a decrease in severity. These data support the importance of resistance training for haemophilia patients, not only for increasing muscle strength, but also for decreasing the frequency and severity of bleeding episodes and the associated pain. A controlled study, with a greater number of patients, is needed to confirm the suggested benefits of resistance training in haemophilia patients.

Complications of the pneumatic tourniquet used during limb surgery result from excessive direct pressure. Traditional recommendations suggests parameters for maximum pressure and time limits rather than the minimal effective pressure to achieve a bloodless field. A clinical study was undertaken to evaluate the pneumatic tourniquet setting required for adequate haemostasis in the upper limb. The correlations between several possible influencing parameters (age, sex, arm fat thickness, extremity length, systolic, diastolic, and mean blood pressures) and the minimal pneumatic tourniquet pressure at which the peripheral pulse reappeared were studied in 50 patients undergoing surgery, using a Doppler stethoscope. The average Doppler Opening Pressure was 168.5 ± 42.7 mmHg and the only significant clinical variable was the mean blood pressure. From these results an equation was derived to predict the minimal effective tourniquet pressure. The mean calculated tourniquet pressure was 202.3 ± 34.2 mmHg, well below the 250 to 300 mmHg previously recommended. The technique consisted of inflating the tourniquet to a pressure of 300 mmHg, then reducing it to the calculated value. A bloodless field was maintained in all patients.

We examined 50 patients with endogenous depressions and 50 patients with schizophrenic psychosis. We found disturbed colour vision in 54 % of the endogenous depressions and in 72 % of the schizophrenic psychosis. We discuss the aetiopathogenic from disturbed colour vision in the endogenous psychosis.

When encountering complaints of pain in the area of the Achilles tendon, the clinician seldom reaches a correct and precise diagnosis based solely on the grounds of physical examination and standard X-rays.To assess the usefulness of ultrasound in diagnosing pathologies of the Achilles tendon.We conducted a retrospective review of patients presenting at our orthopedic clinics.Sonography was used to evaluate 41 patients with achillodynia. This modality enabled the diagnoses of 19 abnormal tendons (46%), peritendinous and other lesions; a complete rupture in two patients (5%); a partial rupture of the Achilles tendon in 3 (7%); various degrees of calcification of the tendon in 7 (17%); and peritendinous lesions discerned by the tendon's hypoechoic regions with disorganized arrangement of collagen fibrils in 4 patients (10%). Other lesions included tendonitis (3 patients, 7%), retrocalcaneal bursitis (3 patients, 7%), lipoma (1 patient, 2%), and foreign bodies (2 patients, 5%). The mean diameter of the pathological tendons was 10.4 +/- 2.7 mm, while normal tendons measured 5.2 +/- 0.8 mm (P0.001).As in many other soft tissue lesions, ultrasonography is a useful tool in the evaluation of the underlying pathology in patients presenting with achillodynia.

Foreign bodies are sometimes overlooked in the initial evaluation of soft tissue wounds in the emergency room setting. The physical examination identifies foreign bodies that are superficial enough to be seen or palpated, while radiographs reveal those that are radio-opaque. If these two criteria are not met, however, the foreign body may remain undetected. These patients present later with long-standing pain in the area of penetration sometimes associated with localized tenderness.To assess the role of ultrasonography in the diagnosis and management of patients with a suspected retained foreign body.Ultrasound was used in 21 patients with suspected retained foreign bodies and the diagnosis was positive in 19. Fifteen underwent a surgical exploration in which the ultrasound was used as an adjunctive modality either pre- or intraoperatively to assist in the localization of the foreign body.All procedures were successful. No postoperative complications were recorded at an average follow-up of 2 years. Three patients gradually became asymptomatic and were left untreated. One patient was lost to follow-up.Sonography is an extremely effective tool for the late diagnosis of retained foreign bodies in the soft tissues. We suggest that its availability in the emergency room may decrease the rate of misdiagnosis and avoid these unfortunate cases, although this remains to be proven.

A consecutive series of 16 patients with classical Haemophilia underwent 21 total knee replacements between 1989 and 1997 for haemophilic arthropathy. The patients received Factor VIII replacement therapy via continuous infusion, and fibrin glue was used to facilitate haemostasis. Three different types of prostheses were used. A follow-up evaluation was undertaken between 2 and 10 years after the operation (mean 5.6 years) and two patients with infection were excluded. Knee scores averaged 77.5 (pre-operative 24. 1) and functional scores averaged 84.4 (preoperative 23.2). There were no cases with aseptic loosening of the prosthesis. Complications included one early deep infection controlled by conversion of the TKR into an arthrodesis, one case of late septic loosening that had to be re-operated upon, one case of patellar dislocation, two cases of stiff knee (fibro-arthrosis) that required manipulation under anaesthesia, one postoperative hepatitis, one superficial infection treated by incision and drainage and four febrile patients with no clear source of infection, who responded to antibiotics alone. In conclusion, TKR offers haemophilic patients a long-lasting improvement of their quality of life and we therefore advocate its use with the appropriate indications.

Recurrent haemarthroses stimulate the hypertrophy of synovial tissues that if left in situ will eventually cause joint destruction. Synovectomies have been the cornerstone of joint preservation and a number of different methods exist. We report two patients who suffered complications after an arthroscopic procedure. No previous complications of this nature have been reported in the literature.

The clinical picture of a fixed flexed hip associated with pain in a person with haemophilia is suggestive of a haemorrhage in that area. Sonography facilitates differentiation between a haemarthrosis, intraperitoneal haemorrhage, subperiosteal bleed, a bleed into the soft tissue around the hip joint or a psoas haematoma. All these aforementioned causes may result in the same clinical presentation. Two cases are described in which coxhaemarthrosis resulted in a flexion contracture of the joint associated with severe intractable pain. Narcotic drugs failed to alleviate the severe pain. Joint aspiration produced dramatic pain relief and early joint rehabilitation.

Summary. In view of reports of FVIII assay discrepancies in post-infusion plasma samples depending on methods used, we compared FVIII results run by each of four different methods following infusion of rFVIII (Kogenate®). Nine persons with haemophilia A were infused with each of two lots of product. Plasma samples were obtained at baseline, and at 10 min, 30 min, 1, 2, 4, 8, 12, 14, 30 and 48 h post-infusion for measurement of FVIII. FVIII assay methods were chromogenic, and one-stage APTT using three different types of activators: micronized, silica, ellagic acid, and kaolin. The same reference plasma standard was used throughout. Results demonstrated a consistent difference in FVIII values, with chromogenic assays being considerably higher than those run by one-stage assays. The discrepancy was greatest when kaolin was the activator. These results point out the problems in attempting to determine the “correct” FVIII level in patient plasma samples following infusion of high purity FVIII preparations. Potential “pitfalls” include the standard used for defining product potency, the methods, reagents, instrumentation and standards used in assaying plasma samples and, in some instances, the characteristics of the product itself. This situation has considerable cost implications, potential impact on patient care, and makes it difficult to compare results between laboratories.

Summary. Musculoskeletal dysfunction is a common manifestation of haemophilia. This dysfunction may be associated with imbalances between muscle groups. Evidence emerging from the literature suggests that the rehabilitation of this dysfunction is very relevant for the patient with musculoskeletal problems. Treatment of muscle imbalance may be linked with a reduction in recurrence of symptoms. Further research is needed to establish the relevance of this area in patients with haemophilia but the clinical evidence supports the developing work in this field.

Summary. The monthly challenge of menstruation as well as the haemostatic challenge of childbirth post partum renders more females than males symptomatic with von Willebrand disease. Among vWD patients, the obstetrical and gynaecological morbidity is certainly more pronounced in Type 2,3 patients compared to Type 1 patients, but even in the latter group there is a high proportion of menorrhagia with associated anaemia, loss of time from work/school and the use of hysterectomy for ultimate control of bleeding. Despite the well known adage of the “gestational palliation” of vWD, there is a high proportion of postpartum haemorrhage in Type 1 patients also especially after the first 24 h after delivery. This may occur despite normalization of the factor VIIIc level in the third trimester, particularly in Type 2,3 patients. With the increasing availability of intranasal/subcutaneous DDAVP that could be readily administered at home for menorrhagia, there recently has been ongoing efforts internationally to determine the prevalence of vWD in females presenting with menorrhagia with a prevalence of 17% combined from two studies of 180 patients total. Issues remain regarding the optimal dose/schedule of intranasal/subcutaneous DDAVP for menorrhagia and the relative efficacy of antifibrinolytic agents. The proper role of oral contraceptives and danazol also deserves further study in vWd patients with menorrhagia. In sum, a comprehensive care approach in females with vWD is warranted analogous to the successful model of care of male haemophiliacs with the intent to (a) reduce unnecessary surgical interventions for menorrhagia, (b) improve the quality of life during menses and (c) optimize peri-partum management.

A random sample of patients (n = 43) had been investigated to detect any difference in response of bright light therapy in lithium-treated inpatients (n = 18) suffering from depression. Only 27% of the lithium-based inpatients respond to bright light therapy, but 73% of patients respond who were not treated with lithium. We conclude that lithium therapy reduces the chance of achieving t remission of depression by bright light therapy.

Increases in plasma cyclic GMP levels have been shown to correlate with increased plasma levels of atrial natriuretic peptide (ANP) in patients with fluid overload due to increased secretion of ANP. There is evidence that plasma cyclic GMP levels are also elevated in some patients with acute leukemia, but increased ANP secretion has not been demonstrated. To elucidate the possibility that a newly expressed guanylyl cyclase may be responsible for the increase of plasma cyclic GMP levels patients with acute and chronic leukemia as well as patients with lymphoma and healthy volunteers were studied. Plasma levels of cyclic GMP were measured and isolated peripheral blood mononuclear or bone marrow cells were incubated with increasing concentrations of ANP. The stimulation of cells was measured as cGMP accumulation in the supernatant. Furthermore guanylyl cyclase activity was measured in membrane preparations of peripheral blood mononuclear cells. While leukocytes of healthy subjects were devoid of detectable ANP-stimulated particulate guanylyl cyclase activity, ANP-sensitivity was observed in seven patients with acute lymphoblastic and in three patients with acute myelogenous leukemia. Cyclic GMP in the supernatant of cells was elevated between 2- and 132-fold of basal when cells were incubated with 1 microM ANP for 60 minutes. Like in healthy volunteers, no effect of ANP on freshly isolated mononuclear cells was observed in cases with chronic leukemia or in patients with lymphoma. Expression of ANP-sensitive particulate gunaylyl cyclase may be connected with malignant transformation of lymphocytes in patients with acute leukemia and might be useful for their diagnosis and classification.

8% of the men and approximately 0.5% of the women in a normal population suffer from congenital colour anomaly. We examined 75 women suffering from endogenous depressions. We found disturbed colour vision in 63% of them. We discuss the aetiopathogenic relationship between endogenous depression and disturbed colour vision.

Objectives: To assess the yield of emergency computed tomography of the brain in patients with a first generalised epileptic seizure and to evaluate a four item screening questionnaire on alcohol misuse (CAGE questionnaire) as a triage tool to avoid unnecessary scans in cases of seizures related to withdrawal from alcohol. Design: Prospective, observational. Setting: Medical casualty unit in a university hospital. Patients: 119 adult patients presenting to casualty within one hour of a generalised seizure. Measurements: A clinical examination focusing on focal neurological symptoms, the CAGE questionnaire, and computed tomography of the brain with contrast enhancement. Results: Computed tomography showed a focal, structural lesion of the brain in 40 patients (34% (95% confidence interval 25% to 42%)). In 20 patients (17% (10% to 24%)) an important therapeutic intervention resulted. The presence of a focal neurological deficit had a sensitivity of 50% and a specificity of 89% in predicting focal lesions on computed comography. Answering “yes” to fewer than two CAGE questions had a sensitivity of 90% and specificity of 44% in identifying patients with focal computed tomography lesions. Focal lesions were not detected on computed tomography in any of the 35 patients (0% (0% to 10%)) who showed no focal neurological symptoms and answered “yes” to two or more CAGE questions. Conclusions: The diagnostic yield of computed tomography of the brain in adults after a first generalised seizure is high. Combined with the clinical examination, the CAGE questionnaire can reliably identify patients with uncomplicated seizures related to withdrawal from alcohol, in whom computed tomography may not be absolutely necessary.

The quantification and distinction of particulate guanylyl cyclases in the human intestine were considered by an enzymatic approach, which comprised the signal transduction from receptor binding to cGMP formation, and, in addition, by showing the expression of an intracellular portion of these transmembrane proteins. Basal guanylyl cyclase (GC) activities were 50 to 80 pmol cGMP formation/min/mg protein and were stimulated up to twofold by heat stable enterotoxin, but were not significantly influenced by atrial natriuretic factor. Enzymatic analysis of colonoscopic specimens pointed to the prevalence of guanylyl cyclase C in the terminal ileum and in the large bowel including colon ascendens, colon descendens, sigmoid, and rectum. The availability of sequence information on human guanylyl cyclases permitted the development of a polymerase chain reaction approach for distinguishing the expression of GC-A and GC-C in human tissue samples. The expression levels of particulate guanylyl cyclases found by polymerase chain reaction in surgical biopsy specimens confirmed the enzymatic data, in that substantial expression of GC-C was found not only in the small intestine but also in the large bowel. According to the restriction mapping of amplificates, GC-C prevailed over GC-A throughout the human intestine, particularly in the mucosal layers.

The following case is presented to illustrate the roentgenographic and clinical findings of a condition of interest to the orthopaedic surgeon. Initial history, physical findings, and roentgenographic examinations are found on the first page. The final clinical and roentgenographic differential diagnoses are presented on the following pages.

The medical literature has, on the whole, passed seething criticism toward the Chopart foot amputation. The equinous, short, unbalanced stump is prone to pressure injury and the orthopaedic footwear has proved problematic. Many therapeutic modalities have been proposed, such as arthrodeses, tendon transfers, and tenotomies to improve functional ability. Many propose that the results of the Syme amputation are functionally superior and aesthetically more acceptable. The pros and cons of the Syme and Chopart amputations are discussed and a new orthotic device is suggested that improves the function of the Chopart amputation and minimizes the previously described complications.

We investigated, whether plasma cyclic guanosine 3':5'-monophosphate (cGMP) may be suited as a marker of hyperhydration in hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). In 81 HD patients the levels of atrial natriuretic peptide (ANP) and cGMP were markedly elevated before HD (ANP: 165 +/- 11.1 pg/ml; cGMP 43.5 +/- 2.2 pmol/ml). Significantly lower values (P0.01) were found after HD (ANP: 97 +/- 8.4 pmol/ml; cGMP 19.5 +/- 1.5 pmol/ml). Twenty-three patients had cGMP levels above 20 pmol/ml after HD. Therefore "dry body weight" was reduced in these patients. This resulted in a "normalization" of cGMP values to a postdialytic range below 20 pmol/ml in the majority of patients. All seven patients with persistently high cGMP levels despite weight reduction had left sided heart failure. In 33 CAPD patients ANP was slightly lower than after HD (68 +/- 10.4 pg/ml), and the cGMP level (22.4 +/- 2.3 pmol/ml) was between pre- and postdialytic values in HD. In eight CAPD patients with clinical signs of hypervolemia plasma cGMP, but not ANP, was significantly elevated. We conclude that the plasma cGMP level appears to be a reliable marker for fluid overload in patients on renal replacement therapy with normal heart function.

Twelve patients with reflex sympathetic dystrophy were referred to a comprehensive orthopaedic rehabilitation center after failure of conservative management. Ten underwent amputation of the affected limb and, although functional improvement occurred in the patients undergoing lower limb amputation, psychosocial dysfunction persisted. All the patients required psychological support. In cases of post-Sudeck amputation, early orthopaedic diagnosis and referral to a comprehensive treatment center are recommended. In the 12 cases described here, apart from the obvious limb pathology, severe psychological inadequacies were found to be present.

The parents of asthmatic children treated in the pediatric respiratory service of Wolfson Hospital were randomly divided into two groups. One group compromised 26 parents who voluntarily attended a teaching session. After completion of the course, a questionnaire was completed by parents who had attended the course and parents who had not. The first group showed greater knowledge of all aspects of the disease and, after a year's follow up, it was noted that there was a statistically significant lower hospitalization rate of their asthmatic child.

During a transverse survey, 3 groups of men with the same weight and age were compared. Group I included 42 patients with coronary disease documented by coronarography, group 2 included 19 subjects with normal coronary angiograms, and group 3 included 27 healthy controls who had not undergone coronarography. Subjects presenting diabetes or any factor associated with secondary dyslipidemia or able to modify lipid levels were excluded from study. The following parameters were measured: total cholesterol (Chol), triglycerides (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), apoprotein A1 (apoA1), apoprotein B (apoB), lipoprotein (a) or Lp(a), fibrinogen, insulinemia and plasminogen activator inhibitor activity (PAI). The levels of chol, LDL-C and ApoB were the same in the 3 groups. The levels of TG, HDL-C, apoA1 and the ApoA-1/APoB ratio were significantly different between groups 1 and 2, on the one hand, and groups 1 and 3, on the other hand. The levels of Lp(a) and insulin were similar in the 3 groups. Fibrinogen levels were slightly higher in group 1 than in group 3. There was no significant difference between groups 1 and 2 with regard to any of the parameters. Subjects with angiographically normal coronary arteries and subjects with documented coronary disease exhibited similar lipid abnormalities. In this study, TG, HDL-chol, apoA1 and the apoB ratio were better predictors of cardiovascular risk than Chol, LDL-C or apoB.

A new method for directly measuring LpAI lipoparticles containing apolipoprotein AI, but not apolipoprotein AII, is now disponible for laboratories. Concentrations of LpAI were measured in serum from 158 presumably healthy normolipidemic subjects (72 male, 86 female), for the age group 30-60 years. Concentrations of LpAI were also measured in subjects with angiographically defined coronary artery disease (coro+) and without angiographically defined coronary artery disease (coro-). After comparison of the groups, lipoprotein particle LpAI did not appear to be a better discriminative marker than HDL cholesterol or apolipoprotein AI for atherogen risk.

The purpose of the present work was to investigate the ex vivo platelet-inhibiting properties of the nitric oxide-containing vasodilator, molsidomine, and the organic nitrate, isosorbide-5-mononitrate, in comparison with placebo. Ex vivo platelet aggregation in 11 healthy volunteers was measured before, as well as 30 and 60 min after, the intake of either 4 mg molsidomine, 20 mg isosorbide-5-mononitrate (ISMN) or placebo in a randomized double-blind fashion. The release of thromboxane was also determined. Threshold doses of platelet-activating factor (PAF) to induce irreversible aggregation were significantly increased by 100 and 120% 30 and 60 min after molsidomine. Slopes of aggregation curves (aggregation induced with 50 and 200 nM PAF) were significantly reduced after molsidomine (P less than 0.01). Small platelet-inhibiting effects were also observed after ISMN and after placebo intake. The release of thromboxane was not influenced when platelets were maximally stimulated either during clotting of whole blood or during aggregation of platelet-rich plasma with a high dose of PAF. Thromboxane release with a low dose of PAF was reduced 30 and 60 min after drug intake, independent of whether molsidomine, ISMN or placebo was applied. The data indicate that the usual clinical doses of molsidomine, but not of ISMN inhibit platelet aggregation in healthy man.

Three patients with hematologic relapse after bone marrow transplantation for chronic myelogenous leukemia were treated with interferon alpha and transfusion of viable donor buffy coat. All had complete hematologic and cytogenetic remission, which persisted 32 to 91 weeks after treatment. In two patients graft-versus-host disease developed and was treated by immunosuppression. These results are an example of adoptive immunotherapy without cytoreductive chemotherapy or radiotherapy in human chimeras.

To find out whether 3-morpholino-sydnonimine (SIN 1), the active metabolite of molsidomine, exerts its antiaggregatory effects not only in vitro but also in vivo, we tested ex vivo aggregation before and after intravenous application of molsidomine in healthy volunteers. We also measured plasma levels of guanosine 3′∶5′-cyclic monophosphate (cyclic GMP) as SIN 1, the bioactive metabolite of molsidomine, becomes effective via activation of soluble guanylate cyclase. In eight out of ten subjects molsidomine had an inhibitory effect on platelet aggregation and a higher threshold concentration of platelet-activating factor was required after molsidomine application to induce irreversible aggregation. Despite the effect on platelets, plasma cyclic GMP levels did not increase. These results suggest that the nitric oxide-containing SIN 1 inhibits platelet aggregation not only in vitro but also in vivo and that this property can be a beneficial effect in antianginal therapy.

Three members of a family, the father and two children, present a primary empty sella. The only clinical symptom is headache. The ophthalmologic examen, and the pituitary function are quite normal. No other anomaly is associated. This type of cases has never been published.

A total of 144 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin/etoposide (PE) or ifosfamide/etoposide (IE) combination chemotherapy. PE consisted of cisplatin, 80 mg/m2, intravenously (IV) on day 1, and etoposide, 150 mg/m2, IV on days 3 through 5. IE consisted of ifosfamide, 1,500 mg/m2, IV on days 1 through 5, and etoposide, 120 mg/m2, IV on days 3 through 5. Six cycles were administered in 3-week intervals. Nonresponders were switched immediately to CAV, consisting of cyclophosphamide, 600 mg/m2, IV on days 1 and 2, Adriamycin (Adria Laboratories, Columbus, OH), 50 mg/m2, IV on day 1, and vincristine, 2 mg, IV on day 1. Patients obtaining complete remission (CR) received prophylactic cranial irradiation with 30 Gy. After completion of chemotherapy, patients with limited disease received chest irradiation with 45 Gy. No maintenance therapy was given to patients in CR. Minimum follow-up was 2 years. Of the 141 patients evaluable, the overall response rate was 65% in PE therapy and 68% in IE therapy. The CR rate was 32% v 20% for all patients, 50% v 24% for limited disease, and 22% v 18% for extensive disease, all in favor of PE therapy. Median survival for all patients was 11.6 months v 9.4 months, for limited disease 14.8 months v 11.0 months, and for extensive disease 8.9 months v 7.5 months, all preferring PE therapy. The 2-year survival rate was higher in PE therapy than in IE therapy for all patients (12% v 9%) and for limited disease (23% v 10%), but not for extensive disease (5% v 9%). Median progression-free survival was 7.5 months v 6.0 months for all patients, 12.2 months v 8.8 months for limited disease, and 5.9 months v 4.4 months for extensive disease, all in favor of PE. Relapse in the area of the primary tumor was found less often after PE than after IE therapy (25% v 38%). Response to second-line CAV was seen in 30% of patients with prior PE and 43% with prior IE therapy, but was usually short lasting, and only one patient achieved CR. Toxicity included three lethal complications. Nausea, vomiting, diarrhea, and skin lesions occurred more often after PE than after IE therapy. These results suggest that PE is superior to IE chemotherapy in limited-stage, but not in extensive-stage SCLC, and that CAV is cross-resistant to PE, as well as to IE in the majority of patients.

Sonography was performed on 23 hemophilic patients presenting with positive iliopsoas sign. In 21 of these patients sonography confirmed the presence of hematomas. Comparison of the presumed clinical location and the sonographic location, however, revealed a significant discrepancy. Only seven of 15 hematomas that were clinically suspected to be in the iliopsoas muscle were confirmed by sonography at that location. Of the remaining cases, three were localized in the hip joint, one in the proximal thigh, one in the abdominal wall, and one in the iliac fossa. Hemorrhage was not found in two cases. This study indicates that sonography provides valuable information about the site of hematoma in these patients.