Ichthyosis with laminated membrane structures

Clinical, light-microscopic, and electron-microscopic features of a new type of ichthyosis are presented. The ichthyotic disease of a 75-year-old woman appeared in early childhood as dry and scaly skin. It slowly progressed to thickened and folded hyperkeratosis on her neck and axillae. The skin on the other parts of her body was shiny, red and hard. Her physical development was normal. Light microscopy showed acanthosis and papillomatosis with hyperkeratosis. The granular cells were vacuolated. Electron microscopy revealed diagnostic changes, i.e., concentric or parallel lamellar membrane structures and amorphous material in upper epidermal cells. Corresponding lamellar material was also seen in the cornified cells. The keratinosomes were abnormal and a hypothesis is presented indicating that a defect in keratinosome formation results in vacuolization and abnormal desquamation in this disease. According to the current classification, the present type of ichthyosis is one subgroup of lamellar ichthyosis. We have called it ichthyosis with laminated membrane structures, because they are electron-microscopically diagnostic. The mode of inheritance is unknown.     

Epidemiology of laboratory-confirmed influenza among kidney transplant recipients compared to the general population—A nationwide cohort study

Seasonal influenza causes morbidity and mortality after organ transplantation. We quantified the detection of laboratory-confirmed influenza among kidney transplant recipients compared to the general population in a nationwide cohort. All laboratory-confirmed cases of influenza and hospitalizations due to influenza among all kidney transplant recipients in our country between 1995 and 2017 were captured with database linkage from statutory national registries. Data from the general population of Finland, population 5.5 million, were used for comparisons. Annual incidences of influenza and hospitalizations due to influenza, and standardized incidence ratios (SIR) were calculated. Altogether 3904 kidney transplant recipients with a total follow-up of 37 175 patient-years were included. Incidence of laboratory-confirmed influenza was 9.0 per 1000 patient years in 2003–2019, and 18.0 per 1000 patient years during 2015–2019. The risk of laboratory-confirmed influenza was significantly higher among kidney transplant recipients compared to the general population (SIR 5.1, 95% CI 4.5–5.7). SIR for hospitalization due to influenza was 4.4 (95% CI 3.4–4.7). Mortality of the hospitalized patients was 9%, and 5% of the patients with laboratory-confirmed influenza. Detection of laboratory-confirmed influenza is increased fivefold and risk of hospitalization due to influenza more than fourfold among kidney transplant recipients compared to the general population.     

Occupational protein contact dermatitis and paronychia from natural rubber latex

Protein contact dermatitis (PCD) is a chronic recurrent dermatitis caused by contact with a proteinaceous material. PCD may also present as paronychia. Here a case of PCD and paronychia from natural rubber latex (NRL) is presented. The correct diagnosis would not have been established if prick testing with NRL had not been performed. This case shows that contact allergy presenting as dermatitis may occur despite negative patch test results. PCD from NRL may be relatively common, although very few cases have been published. This is probably due to the fact that the term contact urticaria is so closely connected to NRL that automatically all cases of type I allergy to NRL are considered contact urticaria, although the clinical picture is a dermatitis, i.e. PCD.     

Changing the adenovirus fiber for retaining gene delivery efficacy in the presence of neutralizing antibodies

Prior infection has primed most adult humans for a rapid neutralizing antibody (NAb) response when re-exposed to adenovirus. NAb induction can severely limit the efficacy of systemic re-administration of adenoviral gene therapy. We hypothesized that changing the fiber knob could overcome NAb. Immune-competent mice were exposed to serotype 5 adenovirus (Ad5)(GL), Ad5/3luc1, Ad5lucRGD or Ad5pK7(GL). Mice immunized with Ad5(GL) featured reduced intravenous Ad5(GL) gene transfer to most organs, including the liver, lung and spleen. Ad5(GL) gene transfer was affected much less by exposure to capsid-modified viruses. Anti-Ad5(GL) NAb blocked intravenous Ad5(GL) gene transfer to orthotopic lung cancer xenografts, whereas capsid-modified viruses were not affected. When gene transfer to fresh cancer and normal lung explants was analyzed, we found that capsid-modified viruses allowed effective gene delivery to tumors in the presence of anti-Ad5(GL) NAb, whereas Ad5(GL) was blocked. In contrast, crossblocking by NAbs induced by different viruses affected gene delivery to normal human lung explants, suggesting the importance of non-fiber-knob-mediated infection mechanisms. We conclude that changing the adenovirus fiber knob is sufficient to allow a relative degree of escape from preexisting NAb. If confirmed in trials, this approach might improve the efficacy of re-administration of adenoviral gene therapy to humans.     

Community-Associated Methicillin-Resistant Staphylococcus aureus Isolated in Finland in 2004 to 2006

A nationwide population-based study on community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in Finland during 2004 to 2006 showed that both incidence (1.9/100,000 population) and strain variation increased in comparison to years 1997 to 1999. There were 7 community-associated epidemic and 25 sporadic MRSA strain types. Half of these had Panton-Valentine leukocidin genes.Few population-based estimates of the burden of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) have previously been published (1-3, 12, 14). In Finland, the incidence of MRSA has been low. During 1997 to 1999, one-fifth of the 526 Finnish MRSA isolations were from persons without any connection to a hospital, and three strain types were associated with community acquisition (14). However, the total number of MRSA findings reported to the National Infectious Disease Register in Finland in 2004 to 2006 increased eightfold since 1997 to 1999. This increase has mostly been due to outbreaks and active screening in hospitals and hospital-associated strains (6, 15).In this study, we estimated the proportion of CA-MRSA strains among the MRSA isolates obtained either by screening or from a clinical specimen and determined the incidence and type of clinical CA-MRSA infections during 2004 to 2006. The MRSA strain types obtained from persons with and without hospitalization were compared.In Finland (population, 5.3 million), all clinical microbiology laboratories notify MRSA findings, including only the first isolate from a person, to the National Infectious Disease Register and send the corresponding isolates to the reference laboratory. During 2004 to 2006, a total of 4,054 (97%) isolates from 4,166 newly detected MRSA-positive persons were received.For each MRSA isolate, pulsed-field gel electrophoresis (PFGE) and antimicrobial drug susceptibility testing were performed (6, 10, 15). Multilocus sequence type (MLST), spa type, and SCCmec determinations were performed for isolates with a PFGE type shared by five or more persons (15). Panton-Valentine leukocidin (PVL) genes (lukS-PV, lukF-PV) were tested for by PCR in all CA-MRSA isolates. Identical or closely related PFGE types, MLSTs, and spa types (4) defined a strain type designated by a FIN number. A sporadic strain was shared by five or fewer persons.For all 4,030 persons with an MRSA isolate from 2004 to 2006, excluding 24 persons with an erroneous national identity code, data on previous hospitalizations were retrieved from the National Hospital Discharge Register. Background information was obtained for each person with MRSA isolated outside a hospital setting or within 2 days of hospital admission and who had not been hospitalized within 2 years of a positive MRSA culture by sending a questionnaire to infection control nurses at the relevant health care facilities. These data included risk factors for MRSA acquisition, the reason for obtaining the culture (screening or infection), and the type and treatment of a possible infection as recorded in medical charts by the patient''s primary health care provider. The Ministry of Social Affairs and Health, the Finnish data protection authority, and the National Research and Development Center for Welfare and Health approved the use of data from the National Hospital Discharge Register.Community association was calculated for each MRSA strain type carried by at least 10 persons. The chi-square test with Yates correction or Fisher''s exact test, as appropriate, was used for categorical variables. The means and medians of the continuous variables were compared by Student''s t test or the Mann-Whitney U test, depending on the sample distribution.A total of 570 persons without previous hospitalization in the last 2 years were identified. Based on the survey, 94 health care workers, 158 long-term care facility residents, and 20 newborns less than 28 days old were excluded. Thus, 298 (7.4%) of the 4,030 MRSA-positive persons and isolates were community associated (range by year, 5.8 to 8.9%); 185 (62%) and 113 (38%) were obtained as clinical specimens and by screening, respectively. Ultimately, 191 (64%) had a clinical infection. The mean annualized incidences of all CA-MRSA findings and CA-MRSA infections, respectively, were 1.9 and 1.2/100,000 population (ranges of annual incidences, 1.6 to 2.1 and 1.0 to 1.4). Persons with a CA-MRSA isolate were younger (median, 37 versus 75 years, P < 0.001) and more often males (56 versus 49%, P < 0.05) than those with previous hospitalization.Among the 4,030 MRSA isolates, our typing scheme showed a total of 148 strain types, of which 109 (74%) were sporadic and 39 (26%) were shared by at least five persons. Twenty-five strain types, each of which was isolated from ≥10 persons, represented 3,971 (99%) of the 4,030 isolates. Seven of these strain types, including two of the three old CA-MRSA strain types and 25 sporadic strain types, were associated with community acquisition (Table ​(Table11).

TABLE 1.

MRSA strain types significantly more often isolated in persons without previous hospitalization, i.e., CA-MRSA strain types, in Finland in 2004 to 2006

Bell’s palsy – the effect of prednisolone and/or valaciclovir versus placebo in relation to baseline severity in a randomised controlled trial

Clin. Otolaryngol. 2012, 37 , 283–290 Objectives: To evaluate the treatment effect of prednisolone and/or valaciclovir in Bell’s palsy patients with different baseline severity of palsy. Design: Patient data were collected from the Scandinavian Bell’s Palsy Study, a prospective, randomised, double‐blind, placebo‐controlled, multi‐centre trial. Setting: Sixteen otorhinolaryngological centres in Sweden and one in Finland. Participants: Altogether, 829 patients aged 18–75 years were treated within 72 h of palsy onset. Patients were randomly assigned to treatment with prednisolone plus placebo (n = 210), valaciclovir plus placebo (n = 207), prednisolone plus valaciclovir (n = 206), placebo plus placebo (n = 206). Follow‐up was 12 months. Main outcome measures: Facial function was assessed using the Sunnybrook grading scale at baseline and at 12 months. Complete recovery was defined as Sunnybrook score = 100. Results: All patients, regardless of baseline severity, showed significantly higher complete recovery rates if treated with prednisolone compared with no prednisolone. In patients with severe palsy, recovery at 12 months was 51% with prednisolone treatment versus 31% without prednisolone (P = 0.02). Corresponding results were 68%versus 51% (P = 0.004) for moderate, and 83%versus 73% (P = 0.02) for mild palsy. In patient groups with moderate and mild palsy at baseline, significantly fewer prednisolone‐treated patients had synkinesis at 12 months (P = 0.04 and P < 0.0001, respectively). For patients with severe palsy at baseline, prednisolone versus no prednisolone made no significant difference regarding synkinesis at 12 months. Valaciclovir did not add any significant effect to prednisolone regarding recovery rate or synkinesis at 12 months. Conclusion: Prednisolone treatment resulted in higher complete recovery rates, regardless of severity at baseline. Prednisolone treatment should be considered in all patients irrespective of degree of palsy.     

Prednisolone and valaciclovir in Bell's palsy: a randomised, double-blind, placebo-controlled, multicentre trial

BACKGROUND: Previous trials of corticosteroid or antiviral treatments for Bell's palsy have been underpowered or have had insufficient follow-up. The aim of this study was to compare the short-term and long-term effects of prednisolone and valaciclovir in the recovery of the affected facial nerve in a large number of patients. METHODS: In this randomised, double-blind, placebo-controlled, multicentre trial, patients aged 18 to 75 years who sought care directly or were referred from emergency departments or general practitioners within 72 h of onset of acute, unilateral, peripheral facial palsy, between May, 2001, and September, 2006, were assessed. Patients were randomly assigned in permuted blocks of eight to receive placebo plus placebo; 60 mg prednisolone per day for 5 days then reduced by 10 mg per day (for a total treatment time of 10 days) plus placebo; 1000 mg valaciclovir three times per day for 7 days plus placebo; or prednisolone (10 days) plus valaciclovir (7 days). Follow-up was for 12 months. The primary outcome event was time to complete recovery of facial function, as assessed with a regional Sunnybrook scale score of 100 points. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00510263. FINDINGS: Of 839 patients who were randomly assigned, 829 were included in the modified intention-to-treat analysis: 206 received placebo plus placebo, 210 prednisolone plus placebo, 207 valaciclovir plus placebo, and 206 prednisolone plus valaciclovir. Time to recovery was significantly shorter in the 416 patients who received prednisolone compared with the 413 patients who did not (hazard ratio 1.40, 95% CI 1.18 to 1.64; p<0.0001). There was no difference in time to recovery between the 413 patients treated with valaciclovir and the 416 patients who did not receive valaciclovir (1.01, 0.85 to 1.19; p=0.90). The number of patients with adverse events was similar in all treatment arms. INTERPRETATION: Prednisolone shortened the time to complete recovery in patients with Bell's palsy, whereas valaciclovir did not affect facial recovery.     

Etoposide pharmacokinetics in children treated for acute myeloid leukemia

We studied the pharmacokinetics of etoposide in 45 children treated for newly diagnosed acute myeloid leukemia. Etoposide, 100 mg/m body surface area/24 h, was administered by 96-h continuous intravenous infusion. Concomitantly, the children received cytarabine 200 mg/m/24 h by intravenous infusion and 6-thioguanine 100 mg/m twice daily orally. Median total body clearance in children 0.5-1.8 (n=4) and 2.3-17.7 years old (n=36) without Down's syndrome was 17.1 and 17.6 ml/min/m, respectively (P=0.96). Five children with Down's syndrome had a median clearance of 13.6 ml/min/m (P=0.067 compared with non-Down's syndrome children). Eighteen of the children received a second identical treatment course 3-4 weeks later; there was a significant correlation between individual clearance values (rho=0.56; P=0.017). We found no significant correlation between etoposide pharmacokinetics and the remission rate or the relapse rate. In conclusion, our findings indicate that special dose-calculation guidelines for infants above 3 months old are not substantiated by age-dependent pharmacokinetics of etoposide. Down's syndrome children might be candidates for dose reduction if our data are confirmed in larger numbers of patients. Low course-to-course variability indicates that pharmacokinetically guided dosing of etoposide might be clinically relevant, if larger studies can demonstrate that this approach decreases toxicity or increases response rates.     

Doxorubicin pharmacokinetics is correlated to the effect of induction therapy in children with acute myeloid leukemia

We studied the pharmacokinetics of doxorubicin in 41 children treated for newly diagnosed acute myeloid leukemia. Doxorubicin, 75 mg/m2 body surface area, was administered by constant i.v. infusion over 8 h. Four children with Down's syndrome (DS), 1.2-2.3 years old, had a median total body clearance of 523 ml/min/m2. The median clearance in non-DS children, 0.6-1.8 years old (n = 4) and 2.5-17.7 years old (n = 33), was 446 and 538 ml/min/m2, respectively. Patients who went into complete remission (CR) after induction therapy had a significantly higher median plasma concentration of doxorubicin than those who did not, 249 compared with 180 ng/ml, respectively (P = 0.036; analysis restricted to non-DS patients). Doxorubicin plasma concentration was an independent factor for CR, both in univariate (P = 0.031) and multivariate analysis including sex, age and white blood cell count at diagnosis (P = 0.021). Patients who reached CR had a significantly lower doxorubicin clearance than those who did not, 513 and 657 ml/min/m2, respectively (P = 0.017). In conclusion, doxorubicin plasma concentration and total body clearance during up-front treatment were correlated to the effect of induction therapy. Prospective studies should be performed to confirm the concentration-effect relationship and explore the possibility of therapeutic monitoring.