Dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease (CD), which causes an itching and blistering rash, typically on the elbows, knees and buttocks. DH and CD share a similar genetic background, small bowel mucosal alterations, and an autoimmune response against tissue transglutaminase in the serum and small bowel. DH is typically diagnosed during adulthood, and it is slightly more common among males than females. The incidence of DH seems to be decreasing, in contrast to the detected four-fold increase in the incidence of CD. In addition to typical clinical picture, diagnosis of DH relies on the demonstration by direct immunofluorescence of pathognomonic granular IgA deposits in the papillary dermis. Circulating tissue transglutaminase antibodies support the diagnosis, but their absence does not exclude DH. Obtainment of small bowel mucosal biopsies is not necessary when DH is diagnosed, but if performed, the majority of patients are found to have villous atrophy, and even those with normal villous architecture evince CD-type inflammation. The treatment of choice in DH is a strict, life-long adherence to a gluten-free diet (GFD). In addition to alleviating the symptoms of DH and healing the small bowel mucosal damage, a GFD increases the quality of life for patients, and decreases the risk for lymphoma in DH. Further, the mortality rate of patients with DH treated with a GFD seems to be lower than that of the general population. However, as changing to a GFD has a rather slow effect on the DH rash, patients with severe skin symptoms should additionally be treated with dapsone medication. This review article is based on a presentation given at the British Society for Medical Dermatology blistering skin diseases meeting 2019.

Reduced mortality in dermatitis herpetiformis: a population-based study of 476 patients.

BACKGROUND: Dermatitis herpetiformis (DH) is an extra-intestinal manifestation of coeliac disease and most patients adhere to a life-long gluten free diet (GFD). Increased mortality rates have been reported in coeliac disease but knowledge in DH is scanty. OBJECTIVES: To survey the mortality rate and causes of death in a large cohort of patients with DH. MATERIAL AND METHODS: Patients with DH (n = 476 consecutive patients) diagnosed from 1970 onwards at the Tampere University Hospital were analysed for causes of death during 1971-2010. A questionnaire survey on key aspects of health behaviour was performed in patients with DH and comparisons were made with the Finnish population. RESULTS: The total number of deaths during 9079 person years followed up was 77 whereas 110 were expected. The standardized mortality rate (SMR) for all causes of death was significantly reduced, being 0·70 (95% CI 0·55-0·87), and similar in both sexes. The SMR was equal in the patients with DH with (0·73) and without (0·77) small bowel villous atrophy. The SMR was significantly reduced (0·38) for deaths due to cerebrovascular diseases. The SMR due to lymphoproliferative malignancies was significantly increased (6·86) in the first 5 years of follow-up but not thereafter. The questionnaire survey documented that 97·7% of the patients with DH adhered to a GFD. The patients reported significantly less hypercholesterolaemia and there were fewer current and past smokers compared with the age- and sex-matched control population. CONCLUSIONS: The present long-term follow-up study of DH documented significantly reduced all-cause and cerebrovascular disease mortality. Strict adherence to a GFD, less smoking and hypercholesterolaemia may play a role in the observed health benefit.

Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from Finland.

BACKGROUND: Dermatitis herpetiformis (DH) is an external manifestation of coeliac disease presenting with blistering rash and pathognomonic cutaneous IgA deposits. Better knowledge of subclinical forms and serological testing has resulted in a sharp increase in the incidence and prevalence of coeliac disease. OBJECTIVES: To investigate the prevalence of DH and analyse whether the incidence of DH changed when the occurrence of coeliac disease increased. METHODS: All 477 patients with DH diagnosed from 1970 onwards at the Tampere University Hospital were analysed for prevalence in 2009. The incidence of DH was calculated in three 10-year periods from the year 1980. RESULTS: The prevalence of DH was 75·3 per 100,000 which is eight times lower than the prevalence of coeliac disease in our area. The annual incidence of DH in the whole period was 3·5 per 100,000, and in the three 10-year periods 5·2, 2·9 and 2·7 per 100,000, respectively. The decrease in incidence between the first and second 10-year period was significant (P<0·001). The male to female ratio of DH was 1·1:1. The mean age at diagnosis increased significantly during the study, in men from 35·3 to 51·1 years and in women from 36·3 to 45·8 years. CONCLUSIONS: The present study shows the highest prevalence of DH reported to date. Although the overall incidence of DH was also high, a significant decrease occurred in the 1990s, which is in contrast to the incidence of coeliac disease.

The N-myc proto-oncogene and IGF-II growth factor mRNAs are expressed by distinct cells in human fetal kidney and brain.

We studied the expression of the N-myc proto-oncogene and the insulin-like growth factor-II (IGF-II) gene in human fetuses of 16-19 gestational wk. Both genes have specific roles in the growth and differentiation of embryonic tissues, such as the kidney and neural tissue. Since continued expression of N-myc and IGF-II mRNAs is also a characteristic feature of Wilms' tumor, a childhood neoplasm of probable fetal kidney origin, we were particularly interested in the possibility that their expression might be linked or coordinately regulated in the developing kidney. Expression of N-myc mRNA was observed in the brain and in the kidney by Northern hybridization analysis. In in situ hybridization of the kidney, N-myc autoradiographic grains were primarily located over epithelially differentiating mesenchyme while most of the mesenchymal stromal cells showed only a background signal with the N-myc probe. N-myc mRNA was detectable throughout the developing brain with a slight accentuation in the intermediate zone cells in between the subependymal and cortical layers. Thus, even postmitotic neuroepithelial cells of the fetal cerebrum expressed N-myc mRNA. In Northern hybridization, IGF-II mRNA signal was abundant in the kidney but much weaker, though definite, in the brain. The regional distribution of IGF-II mRNA in the kidney was largely complementary to that of N-myc. IGF-II autoradiographic grains were located predominantly over the stromal and blastemal cells with a relative lack of hybridization over the epithelial structures. In the brain, IGF-II mRNA was about two- to threefold more abundant in the subependymal and intermediate layers than in the cortical plate and ependymal zone, respectively. The fetal expression patterns of the N-myc and IGF-II mRNAs are reflected by the types of tumors known to express the corresponding genes during postnatal life such as Wilms' tumor. However, the apparent coexpression of the IGF-II and N-myc genes in immature kidneys occurs largely in distinct cell types.

Immunoglobulin A autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease.

BACKGROUND: Reliable markers of early developing coeliac diseases are needed. Coeliac autoantibodies in the serum or Marsh I inflammation may be indicators of subsequent coeliac disease. AIM: To investigate whether determination of intestinal transglutaminase 2-targeted autoantibody deposits would detect early developing coeliac disease better than previous methods. METHODS: The study investigated patients previously excluded for coeliac disease: 25 had positive serum coeliac autoantibodies (endomysial), 25 antibody-negative had Marsh I, and 25 antibody-negative had Marsh 0 finding. Seven (median) years after baseline investigation, new coeliac cases were recorded, and small bowel biopsy was offered to the rest of the patients. Serum and intestinal coeliac autoantibodies and intraepithelial lymphocytes were assessed as indicators of developing coeliac disease. RESULTS: Seventeen patients had developed coeliac disease: 13 in the autoantibody-positive group, three in the Marsh I group and one in the Marsh 0 group. At baseline, intestinal coeliac autoantibody deposits had a sensitivity and specificity of 93% and 93% in detecting subsequent coeliac disease, CD3+ 59% and 57%, gammadelta+ 76% and 60%, and villous tip intraepithelial lymphocytes 88% and 71%, respectively. CONCLUSIONS: Endomysial antibodies with normal histology indicates early developing coeliac disease. Transglutaminase 2-targeted intestinal autoantibody deposits proved the best predictor of subsequent coeliac disease.

Amifostine protects against early but not late toxic effects of doxorubicin in infant rats.

The improved prognosis and increased expected lifetime among long-term survivors of childhood malignancies have made these patients especially sensitiveto the late toxicity of cancer therapy and prone to secondary malignancies. Recently, new strategies aiming to protect against cancer treatment toxicity have been developed, including the drug amifostine (Ethyol), which is suggested to protect normal tissues from the toxic effects of radiation and cytotoxic agents. In the present study, the possible protective effect of amifostine against toxicity induced by a single injection of doxorubicin (3 mg/kg) in immature rats was evaluated. Specifically, we evaluated the protection against long-term toxicity and the effects of amifostine on growing immature tissues. Amifostine (50-200 mg/kg) given 15 min before doxorubicin had a significant protective effect against doxorubicin-induced early alopecia in young rats. Significant protection against cataract formation was obtained by the use of low-dose amifostine (50 mg/kg). However, amifostine did not protect young rats against the late toxic effect of doxoubicin on linear growth, body weight, plasma leptin levels, and heart or testicular tissue. Worrisome, and in contrast to earlier studies in adult rats, an increased doxorubicin toxicity actually was observed and mortality was increased when the higher doses of amifostine (100-200 mg/kg) were used. The present results suggest that more data from growing immature animal models are needed to analyze the safety of amifostine treatment and its mechanisms of action before wider clinical use of this drug in pediatric cancer patients is recommended.

No GIST-type c-kit gain of function mutations in neuroblastic tumours.

AIMS: Neuroblastic tumours (NTs) have been shown to respond to imatinib treatment in vivo and in vitro, possibly via inactivating the c-kit receptor. The purpose of this study was to identify gastrointestinal stromal tumour (GIST)-type c-kit gene associated mutations in exons 9, 11, 13, and 17 in NTs to recognise a subset of tumours that would probably respond to imatinib treatment. METHODS: Expression of the c-kit protein was detected immunohistochemically in a total of 37 archival paraffin wax embedded NTs using polyclonal rabbit antihuman c-kit antibody. After immunohistochemistry, c-kit gene associated chromosomal mutations in all cases of NT were detected with denaturing high performance liquid chromatography (HPLC). RESULTS: Denaturing HLPC analysis did not reveal GIST-type mutations in four immunohistochemically detected c-kit positive or in 33 c-kit negative NTs. CONCLUSIONS: c-kit receptor expression and GIST-type c-kit gene mutations are rare events in NTs. Oncogenic activation of c-kit in NTs presumably differs from that of GISTs, which may influence their responsiveness to imatinib treatment. Whether c-kit has an essential role in the pathogenesis of NTs remains to be investigated.

Reactions of Leydig cells and blood vessels to lymphoblastic leukemia in the rat testis.

The testis is the third common site of relapse in childhood acute lymphoblastic leukemia (ALL). Despite the apparent clinical importance of testicular relapse, its pathogenesis is still unknown. The studies with an animal model of ALL have shown that many testicular factors are able to control the intratesticular infiltration and proliferation of leukemic lymphoblasts during the untreated course of ALL. In the present study, the ultrastructure of rat testicular interstitium infiltrated by leukemic lymphoblasts was studied in two groups of rats transplanted with rat T cell leukemia in early and late puberty. In both groups most of the leukemic cells infiltrating testicular interstitium were totally or partly enveloped by one or more Leydig cells, and the endothelial cells of capillaries, arterioles and venules were hypertrophic. The Leydig cells of the younger experimental group were by nuclear and cytoplasmic ultrastructure similar to the undifferentiated Leydig cells normally seen on the third postnatal week. The results suggest that Leydig cells bind leukemic lymphoblasts on their surface in vivo as also previously observed in vitro, and that ALL may disturb the pubertal maturation of Leydig cells. The occlusion of arterial and capillary lumina by folds of hypertrophic endothelial cells together with adhered leukemic lymphoblasts may impair the circulation of leukemic testes.

Regulation of testicular infiltration in acute lymphoblastic leukaemia of the rat.

The testis is a common site of relapse in childhood acute lymphoblastic leukaemia (ALL). In adults, testicular relapses of ALL are very rare. A similar age-difference in the frequency of the testicular infiltration exists also in the rat T-cell leukaemia. In the present investigation, the effect of various hormonal treatments and unilateral cryptorchidism on the form of testicular infiltrates by the rat T-cell leukaemia was studied. Inhibition of testicular activity by estradiol treatment (E2) of early pubertal rats injected i.p. with rat T-leukaemic lymphoblasts significantly decreased the proportion of the testis occupied by leukaemic infiltrates. The proportion of the testis occupied by leukaemic infiltrates was significantly higher in the abdominal testes of both early and late pubertal unilaterally cryptorchid rats, than in the scrotal testes of leukaemic control rats. Daily treatment of early pubertal rats with human chorionic gonadotrophin (hCG), or human menopausal gonadotrophin (hMG), did not have an effect on testicular leukaemic infiltration. These studies demonstrate that the leukaemic infiltration of the testis is influenced by the changes in the physiological activity of the testes.

Childhood cancer patients at school.

The aim of this study was to assess the school-related problems of childhood cancer patients. A cross-sectional questionnaire study for school-aged children with extracranial malignancies, in the area of Turku University Hospital serving around 1000000 people. Siblings, healthy pupils and teachers were studied as controls. 43 patients responded. None of the patients or controls was placed in special educational programmes. However, 30.8% of the patients, 15.7% of the controls and 3.7% of the siblings had required extra tutoring. The patients' results differed statistically from both the siblings' (P=0.022) and the controls' (P=0.041) results. The school marks in mathematics (P=0.05) and in foreign languages (P=0.06) tended to be worse for the patients than for the healthy controls. Bullying was reported by 31.7% of the patients, 10.9% of controls (P=0.0012) and 8.3% of the siblings (P=0.056). The biggest problem faced by the cancer patients was bullying-the patients reported approximately 3 times as much bullying as the healthy children did. It seems that there are still several aspects which need to be reconsidered when these children return to school or start their school-life as survivors of childhood cancer. Some proposals are presented.

Low serum inhibin B concentrations in male survivors of childhood malignancy.

The aim of this study was to assess the value of serum inhibin B in detecting male gonadal dysfunction in childhood cancer survivors. 27 male postpubertal (Tanner's pubertal stage G5 or P6) and 12 pubertal (> or = G2) patients were drawn from the endocrine follow-up protocol of childhood cancer patients at the Paediatric Clinic of Turku University Hospital, Turku, Finland. The average time (mean +/- S.D.) between the diagnosis and this study was 11.7 +/- 4.5 years in the postpubertal and 7.0 +/- 3.9 years in the pubertal group. Serum samples for the determination of follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, testosterone, and inhibin A and B dimers were collected. The demographic factors, pubertal stage and testicular size of the patient were measured at the same routine outpatient visit. Serum inhibin concentrations were correlated to testicular volume and gonadotrophin concentrations. Strong correlations were observed between testicular size (r = 0.80, P < 0.001) or FSH (r = -0.58, P = 0.002) and inhibin B concentration in the postpubertal group. Inhibin A was not detectable (< 2 pg/ml). Testicular volume measurement was accurately documented in 21 postpubertal subjects. Patients with small testicles (< 10 ml) had inhibin B concentrations under 42 pg/ml and those whose testicular size was over 13 ml had inhibin B concentrations exceeding 100 pg/ml. In all 12 pubertal survivors, serum inhibin B levels were > or = 94 pg/ml, except in one case of testicular cancer where inhibin B was 8.1 pg/ml and the FSH concentration was elevated. Inhibin B seems to be an indicator of male gonadal function in postpubertal childhood cancer survivors and could be used in the estimation of gonadal function of male survivors earlier than testicular volume or semen analyses would be routinely possible. However, the correct cut-off level of serum inhibin B, as well as the details of inhibin B physiology during puberty, remain to be determined before semen analysis can be replaced by the measurement of inhibin B.

Cerebral blood flow and glucose metabolism in long-term survivors of childhood acute lymphoblastic leukaemia.

Central nervous system treatment for childhood acute lymphoblastic leukaemia (ALL) has been reported to cause changes in cerebral blood flow and glucose metabolism. Little is known about the association of these functional changes with neuropsychological defects and structural changes. The aim of the present study was to assess the relationship between changes in regional cerebral blood flow and glucose utilisation in long-term survivors of ALL, and the association of these functional abnormalities with neurocognitive and structural defects. 8 survivors of childhood ALL were studied with single photon emission tomography (SPECT) using Tc99m-ethyl cysteinate dimer (ECD) as tracer and with positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) as tracer. 8 healthy controls also underwent FDG-PET. All subjects also underwent magnetic resonance imaging and neuropsychological assessment 5 years after cessation of the therapy. Focal cerebral blood flow abnormalities were found in ECD-SPECT in 5 of the 8 survivors. Glucose utilisation appeared normal in the corresponding regions. However, glucose utilisation was decreased in thalamus and cerebellum in the survivors of ALL as compared with healthy controls. 3 patients had severe and 5 patients mild neurocognitive difficulties. The changes in cerebral blood flow and FDG uptake did not correspond neuroanatomically with the neurocognitive defects. Focal defects in cerebral blood flow in long-term survivors of ALL are not associated with changes in local cerebral glucose utilisation. Neurocognitive difficulties are not consistently associated with either changes in cerebral blood flow or with decreased glucose utilisation. Therefore, based on the present set of studies FDG-PET and ECD-SPECT cannot yet be recommended for the evaluation of long-term neurocognitive defects associated with treatment of ALL.

Respiratory virus infections during anticancer treatment in children.

To evaluate the occurrence and clinical significance of respiratory virus infections in children during anticancer treatment, we studied 75 consecutive episodes of febrile infection in 32 children during 17 months. Viral antigen detection for 7 respiratory viruses, viral culture for rhinoviruses and enzyme immunoassay serology were used. Evidence for respiratory virus infection was found in 28 (37%) cases. Rhinovirus was the most common virus detected in 13 (17%) episodes. The other etiologic agents were respiratory syncytial virus (6 episodes), parainfluenza virus type 3 (5 episodes), adenovirus (4 episodes), influenza A virus (3 episodes), and influenza B virus (1 episode). Respiratory virus infections were diagnosed as often in leukopenic as in non-leukopenic patients (37% vs. 38%). In 4 cases bacteremic infection was diagnosed. We found no difference in serum C-reactive protein values when episodes positive for respiratory viruses were compared with virus-negative episodes. Our observations show that respiratory virus infections are common in febrile children receiving anticancer treatment. Diagnostic tests for respiratory viruses should be used more often in evaluation of fever in these patients.

Inhibin gene expression in a large cell calcifying Sertoli cell tumour and serum inhibin and activin levels.

Inhibin is a potential tumour suppressor gene product in the gonads. While inhibin gene products may have a role in tumourigenesis, serum inhibin levels can be used as a marker for ovarian tumours derived from granulosa cells. Tumours derived from Sertoli cells, testicular counterparts of granulosa cells, are rare. To assess whether inhibin could be used as a human Sertoli cell tumour marker, serum inhibin and activin levels and inhibin subunit mRNA expression in the testis were studied. Northern blot and in situ hybridization revealed abundant expression of inhibin alpha, beta A, and beta B subunit mRNAs in large cell calcifying Sertoli cell tumours found in a 12-year old boy with Carney complex. The tumours were multifocal and bilateral. Serum inhibin levels were clearly elevated at the time of the diagnosis, decreased by 50% after one of the testes was removed, and were low or undetectable after the second orchidectomy six weeks later. Activin was undetectable before the orchidectomies, while a low concentration of activin-A was measured after them. Follicle stimulating hormone (FSH) concentration increased from normal pubertal value to castration level as expected. Normal seminiferous tubules also showed inhibin subunit alpha and beta B mRNA expression, whereas inhibin beta A mRNA was expressed in normal Leydig cells. These data suggest that serum inhibin reflects Sertoli cell activity and can be used as a human tumour marker.

Effects of testicular cytokines on proliferation of rat T-leukaemic lymphoblasts in vitro.

A rat acute lymphoblastic leukaemia (ALL) model was used to study the mechanisms involved in the tendency to testicular relapse of ALL in boys. Previous studies have indicated that the infiltration and growth of leukaemic lymphoblasts in the testis are influenced by the same endocrine and paracrine control systems that regulate normal testicular function. In the present study the effects of aqueous extracts of scrotal, abdominal and estrogen-treated postpubertal rat testes on rat-leukaemic lymphoblast proliferation were evaluated. The effects of recombinant cytokines analogous to those observed in the testis on leukaemic cell DNA-synthesis were also evaluated since changes in the levels of these factors have been observed in association with cryptorchidism and low levels of gonadotropins. Transforming growth factor-beta 1 (TGF-beta1), significantly inhibited the proliferation of leukaemic rat lymphoblasts after 24 h of culture, whereas TGF-beta 2, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6 or combinations of them were inactive. Extracts of estrogen-treated testes and abdominal testes of unilaterally cryptorchid animals inhibited leukaemic T-cell proliferation significantly more than extracts of normal testes. The inhibitory activity in abdominal testes could be neutralized by anti-TGF-beta 1 antibodies. These results suggest that testicular TGF-beta 1 may influence growth of leukaemic lymphoblasts in the testis but also that other as yet unknown, testicular factors are involved in the regulation of leukaemic cell function in the testis.

L-myc and N-myc in hematopoietic malignancies.

The myc proto-oncogenes encode nuclear DNA-binding phosphoproteins which regulate cell proliferation and differentiation. The c-myc gene is implicated in hematopoietic malignancies on the basis of its frequent deregulation in naturally occurring leukemias and lymphomas. Recent evidence suggests that also the N-myc and L-myc genes may have a role in normal and malignant hematopoiesis. N-myc and to a certain degree L-myc can substitute for c-myc in transformation assays in vitro, and their overexpression can block the differentiation of leukemia cell lines. Immunoglobulin heavy chain enhancer (IgH) -driven overexpression of N-myc or L-myc genes cause lymphatic and myeloid tumors, respectively, in transgenic mice. Furthermore, the L-myc and N-myc genes are expressed in several human leukemias and leukemia cell lines, L-myc predominantly in myeloid and N-myc both in myeloid and in some lymphoid leukemias. All N/L-myc positive leukemias and leukemia cell lines coexpress the c-myc gene, thus exemplifying a lack of negative cross-regulation between the different myc genes in leukemia cells. Taken together, these data suggest that L-myc and N-myc may participate in the growth regulation of hematopoietic cells.

Event-related alpha synchronization/desynchronization in a memory-search task in adolescent survivors of childhood cancer.

OBJECTIVES: Event-related desynchronization (ERD) and synchronization (ERS) of the 8-10 and 10-12 Hz frequency bands of the background EEG were studied in 19 adolescent survivors of childhood cancer (11 leukemias, 8 solid tumors) and in 10 healthy control subjects performing an auditory memory task. METHODS: The stimuli were auditory Finnish words presented as a Sternberg-type memory-scanning paradigm. Each trial started with the presentation of a 4 word set for memorization whereafter a probe word was presented to be identified by the subject as belonging or not belonging to the memorized set. RESULTS: Encoding of the memory set elicited ERS and retrieval ERD at both frequency bands. However, in the survivors of leukemia, ERS was turned to ERD during encoding at the lower alpha frequency band. ERD was lasting longer at the lower frequency band than at the higher frequency band, in each study group. At both frequency bands, the maximum of ERD was achieved later in the cancer survivors than in the control group. CONCLUSION: The previously reported type of ERD/ERS during an auditory memory task was reproducible also in the survivors of childhood cancer, at different alpha frequency bands. However, the temporal deviance in ERD/ERS magnitudes, in the cancer survivors, was interpreted to indicate that both survivor groups had prolonged information processing time and/or they used ineffective cognitive strategies. This finding was more pronounced in the group of leukemia survivors, at the lower alpha frequency band, suggesting that the main problem of this patient group might be in the field of attention.

Nurses' knowledge about pharmacological and nonpharmacological pain management in children.

The purpose of this study was to investigate the knowledge base and practices of Finnish nurses in the area of children in pain. The convenience sample consisted of 265 nurses working on children's wards in university hospitals. Data were collected using an instrument designed for the study. The results showed that there remain gaps in the knowledge base of nurses with regard to both pharmacological and nonpharmacological pain management in children. The education and the area of expertise were significant influences on knowledge scores. Nurses used a fairly wide range of nonpharmacological pain alleviation methods but most of these were such that the nurse was in an active role and the child was passive. There is a clear need for further education. Nurses should take a more active role in seeking new information and also should be encouraged to use nonpharmacological methods that let the children be active participants in their own care.