Transgenic mice over-expressing a serine protease in the skin: evidence of interferon gamma-independent MHC II expression by epidermal keratinocytes

Stratum corneum chymotryptic enzyme (SCCE; also known as kallikrein 7) is a serine protease that is preferentially expressed in cornifying epithelia and possibly involved in the desquamation process. We have recently described transgenic mice over-expressing human SCCE in the epidermis showing increased epidermal thickness, hyperkeratosis, and an apparent dermal inflammation with pruritus. This suggests that SCCE may be involved in the pathophysiology of inflammatory skin diseases. We therefore carried out a further characterization of the skin changes observed in scce-transgenic mice. An increase in number of dermal cells was verified by stereological measurements showing a more than twofold increase of the volume fraction of dermis occupied by cell nuclei. In some, but not all, animals the number of dermal mast cells was increased. The dermal cell infiltrate was shown to consist mainly of macrophages and granulocytes. The number of epidermal and dermal T-lymphocytes was not increased. Dermal changes were found in transgenic animals before the age they became pruritic. No increase in interferon-gamma expression could be detected in the skin of transgenic animals. In spite of this, keratinocytes of adult transgenic mice were found to express MHC II antigen. We suggest that increased expression and/or activity of epidermal SCCE may lead to skin changes that contribute to development and maintenance of inflammatory skin diseases.     

Dissecting karyotypic patterns in colorectal tumors: two distinct but overlapping pathways in the adenoma-carcinoma transition

More than 500 colorectal tumors with clonal chromosomal abnormalities have been reported. Although the pattern of aberrations is nonrandom, no specific primary or secondary karyotypic abnormality has been identified. Also, the chronological order in which the aberrations appear during disease progression is not well known. One reason why our understanding of the cytogenetic evolution is unclear is the high degree of karyotypic complexity seen in these tumors. To overcome some of these difficulties we have previously used several statistical methods that allow identification and interpretation of karyotypic pathways as well as establishment of a temporal order of appearance of the imbalances. These methods were applied on 531 colorectal tumor karyotypes. By using a resampling strategy, 1p-, +7, 7q-, and +12p were identified as early events. Two major and two minor cytogenetic pathways were identified by means of principal component analysis. The two major pathways were initiated with 1p- and +7, and the minor pathways were initiated with +12p and 7q-. The +7/+12p tumors were found to be hyperdiploid, whereas those with 1p-/7q- were pseudodiploid. We also show that the adenoma-carcinoma transition in the 1p- pathway is strongly linked to karyoytypic evolution, whereas the +7 pathway is not, and that the cytogenetic pathways are separated at both early and late stages.     

Risk factors for suicide in epilepsy: a case control study

PURPOSE: Suicide is considered to be one of the most important causes of death contributing to the increased mortality of persons with epilepsy. We investigated the association between the risk of suicide in persons with epilepsy and clinical factors that might increase or have been suggested to increase the risk of suicide. METHODS: A case-control study was nested within a cohort of 6,880 patients registered in the Stockholm County In-Patient Register with a diagnosis of epilepsy. The study population was followed up through the National Cause of Death Register. Twenty-six cases of suicide, 23 cases of suspected but not proven suicide, and 171 controls, living epilepsy patients, were selected from the cohort. Clinical data were collected through medical record review. RESULTS: There was a ninefold increase in risk of suicide with mental illness and a 10-fold increase in relative risk (RR) with the use of antipsychotic drugs. The estimated RR of suicide was 16.0 [95% confidence interval (CI), 4.4-58.3] for onset of epilepsy at younger than 18 years, compared with onset after 29 years. The risk of suicide seemed to increase with high seizure frequency and antiepileptic drug (AED) polytherapy, although the estimates were imprecise and the associations not statistically significant. Insufficient data on seizure frequency and changes in AED dosage due to incomplete case records were associated with high RRs. We found no association between risk of suicide and any particular AED, with type of epilepsy, or localization or lateralization of epileptogenic focus on EEG [RR = 0.3 (95% CI, 0.1-1.7)]. CONCLUSIONS: The profile of the epilepsy patient who commits suicide that emerges from our study is a patient with early onset (particularly onset during adolescence) but not necessarily severe epilepsy, psychiatric illness, and perhaps inadequate neurologic follow-up. Previous reports of an association with temporal lobe epilepsy could not be confirmed.     

Effect of switching from subcutaneous to intravenous administration of epoetin-alpha in haemodialysis patients: results from a Swedish multicentre survey

OBJECTIVE: In 2002, many haemodialysis patients were switched from subcutaneous (s.c.) to intravenous (i.v.) administration of epoetin-alpha following reports of antibody formation and development of pure red-cell aplasia in patients treated via the s.c. route. We evaluated the possible effect of this change in the route of administration on haemoglobin (Hb) levels and epoetin-alpha requirements. MATERIAL AND METHODS: This retrospective survey involved 223 haemodialysis patients from 25 Swedish centres. Variables were recorded before and after a mean period of 213 days (range 89-297 days) after the change in the route of administration. RESULTS: The mean epoetin-alpha do had to be increased from 159+/-104 to 185+/-122 U/kg/week (p<0.0001) to maintain a constant Hb level (121+/-12 vs 120+/-11 g/l). Plasma ferritin, albumin, C-reactive protein, iron, iron transferrin saturation and body mass index remained constant. The relative increase in epoetin-alpha dose was negatively correlated with the s.c. dose prior to the switch (R=-0.3; p<0.0001), with the most pronounced dose increases occurring in patients who received a low s.c. dose. CONCLUSIONS: A switch from s.c. to i.v. administration of epoetin-alpha in haemodialysis patients was accompanied by an increase in the mean dose requirement of 15%. This increase may be less pronounced in patients receiving high s.c. doses prior to the switch.     

Different levels of work-related stress and the effects on sleep, fatigue and cortisol

OBJECTIVES: The aim of the study was to relate different levels of work stress to measures of sleep and the diurnal pattern of salivary cortisol and subjective sleepiness. METHODS: Thirty-four white-collar workers participated under two different conditions. One workweek with a relatively high stress level (H) and one with a lower stress level (L) as measured through self-rated stress during workdays. The workers wore activity monitors, filled out a sleep diary, gave saliva samples (for cortisol), and rated their sleepiness and stress during one workday and one free day. RESULTS: During the week with stress the number of workhours increased and total sleep time decreased. Sleepiness showed a significant interaction between weeks and time of day, with particularly high levels towards the evenings of the stress week. Cortisol also showed a significant interaction, with a more flattened pattern, probably due to increased evening levels during the stress week. Stress (restlessness) at bedtime was significantly increased during the stress week. CONCLUSIONS: The results demonstrate that a workweek with a high workload and much stress increases sleepiness and workhours, impairs sleep, and affects the pattern of diurnal cortisol secretion.     

The future of work hours--the European view

In Europe the way work hours are handled varies between different countries. However, there are some issues that dominate the discussion in Europe and seem representative for what is happening. One such is the reduction of working hours--which was attempted in several countries but which now seems to be backfiring--probably related to the competition from countries outside Europe. Another area is compressed work hours--the drive towards maximizing the hours per work day in order to increase the number of days off. The health effects are debated--some find clear positive effects. A third area is company oriented flexible work hours, permitting the employer to make moderate changes in work hours when needed. The health impacts have not been evaluated but the loss of individual influence at work is obvious. In some parts of Europe self-determined work hours have been tried with very positive effects. The EU work hour directive is intended to provide uniformity but permits a counterproductive "opting out", creating problems of imbalance.     

External fixation versus locked intramedullary nailing in tibial shaft fractures: a prospective,randomised study of 78 patients

Introduction We performed a prospective, randomised study to compare the Ex-fi-re external fixator (EF) with locked intramedullary (IM) nailing in tibial fractures. Only fractures without soft-tissue problems of importance were included.Materials and methods Ex-fi-re is a unilateral, dynamic axial fixator with fracture reduction capabilities. The Grosse-Kempf nail was used for nailing. A total of 78 patients with 79 fractures were entered in the study (41 Ex-fi-re, 38 IM nails).Results Time to radiographic union and full weight-bearing did not differ significantly, but unprotected weight-bearing was achieved earlier in the IM group (12 vs 20 weeks; p<0.001). There were more reoperations due to secondary dislocation in the EF group. There were no differences in final angulation or shortening. After 6 months and 1 year there were no differences in knee motion, ankle motion, fracture site pain or ankle pain. Some 64% of the nailed patients complained of anterior knee pain after 1 year.Conclusion The results were comparable in most respects. Unprotected weight-bearing was achieved earlier after IM nailing. Anterior knee pain was frequent after nailing.     

Long-term follow-up after acute unilateral vestibular loss and comparison between subjects with and without remaining symptoms

CONCLUSIONS: About half of the subjects in this study reported remaining symptoms 3-6 years after acute unilateral vestibular loss. Differences could be seen between subjects with and without remaining symptoms regarding health-related quality of life, anxiety and depression. OBJECTIVE: To evaluate the presence of self-rated remaining symptoms 3-6 years after acute unilateral vestibular loss, and to compare subjects with and without such symptoms. MATERIAL AND METHODS: Firstly, 51 subjects answered a questionnaire which included the EuroQol EQ-5D, the Hospital Anxiety and Depression Scale, the University of California Los Angeles Dizziness Questionnaire, visual analogue scales and the Dizziness Handicap Inventory. Secondly, nine subjects with and nine without remaining symptoms participated in an extended testing procedure, including electronystagmography (ENG), determination of vestibular-evoked myogenic potentials (VEMPs) and clinical balance tests. RESULTS: In the first part of the study, 27 subjects reported remaining symptoms, 3 reported 1 additional period of symptoms and 21 had not experienced any symptoms at all in the 3-6 years since acute unilateral vestibular loss. In the second part, the group with remaining symptoms rated a lower health-related quality of life and a higher level of anxiety and depression. There were no differences between the two groups in terms of ENG tests, VEMPs or clinical balance tests.     

Closure after gastrostomy button

A gastrostomy device is removed from the gastrostoma when no longer needed. The aim of the study was to test the hypothesis of whether it is possible for the surgeon to decide which stoma has to be closed with a gastroraphy and which to leave for a spontaneous closure within a reasonable period of time. Out of a cohort of 321 patients, who had been operated with a video-assisted gastrostomy, we included all the 48 patients having had their gastrostomy button removed. These patients were carefully followed and the closure of the gastrostoma was registered. According to the institutional routine we waited at least 3 months after the removal of the gastrostomy device before suggesting to the child’s guardians an operative closure of the stoma. In 26 patients the stoma closed within 3 months, whereas in 22 patients a surgical gastroraphy was performed. We found no differences between the two groups regarding the patients’ diagnoses, the duration of the gastrostoma use or patient’s age at the time of removal of the gastrostomy device. This study rejected the hypothesis of predictability of the gastrostoma closure. Thus, we recommend a routine expectance after the removal of a gastrostomy device for at least 1 month. If no spontaneous closure occurs, then a gastroraphy should be performed.     

Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone

OBJECTIVE: To compare severity of negative mood and physical symptoms between women with different progesterone, allopregnanolone, and pregnanolone plasma concentrations during sequential Hormone Replacement Therapy (HRT) with vaginal progesterone suppositories. DESIGN: A randomized, placebo-controlled, double-blind, crossover study. METHOD: Postmenopausal women (n=36) with climacteric symptoms were treated with 2mg estradiol daily during three 28-day cycles. Vaginal progesterone suppositories with 400, 800 mg/day or placebo were added sequentially for 14 days per cycle. Daily symptom ratings using a validated rating scale were kept. Blood samples for progesterone, allopregnanolone, and pregnanolone radioimmunoassays were collected during each treatment cycle. RESULTS: Women were divided into three groups (low, medium, and high) based on plasma allopregnanolone concentration during progesterone treatment. The concentration of allopregnanolone in the medium group corresponds to the concentration seen during the mid luteal phase of the menstrual cycle. Within women with medium allopregnanolone concentration significantly more negative mood and physical symptoms were rated during progesterone treatment compared to treatment with unopposed estrogen or placebo. Between women significantly more negative mood symptoms were seen during progesterone treatment cycles with medium allopregnanolone concentration compared to cycles with low concentration. Plasma progesterone, allopregnanolone, and pregnanolone concentrations increased with increasing progesterone dose. Progesterone and allopregnanolone plasma concentrations increased 2h after vaginal administration of progesterone at 400 and 800 mg/day. CONCLUSION: Vaginal progesterone in sequential HRT causes negative mood, most likely mediated via allopregnanolone.