Clinical Spectrum and Geographic Distribution of Keratitis Fugax Hereditaria Caused by the Pathogenic Variant c.61G>C in NLRP3.

PURPOSE: To chart clinical findings in individuals with keratitis fugax hereditaria (KFH) and the geographic distribution of their ancestors. DESIGN: A prospective cross-sectional study. METHODS: This study took place in a tertiary referral center with a cohort of 84 Finnish patients (55% female) from 25 families with the pathogenic nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) variant c.61G>C. Observation procedures and main outcome measures were Sanger sequencing, clinical examination, corneal imaging, and a questionnaire regarding symptoms, quality of life, treatment, and comorbidities. RESULTS: The oldest members in each family were born in Ostrobothnia in Western Finland or in Southwestern Finland with historical ties to Sweden. One carrier was asymptomatic. Most (77%, 46/60) experienced their first attack between age 6 and 20 years. Three-quarters had unilateral attacks 3 to 5 times annually, primarily triggered by cold wind or air, or stress. Eighty percent (48/60) reported ocular pain (median, 7 on scale 1-10), conjunctival injection, photophobia, foreign body sensation, and tearing during attacks. Visual blur occurred in 75% (45/60) and 91% (55/60) during and after the attack, respectively, for a median of 10 days (range, 1 day-2 months). Forty-seven percent (39/60) had corneal oval opacities with irregular tomography patterns and mild to moderate decrease (20/60 or better) in best-corrected visual acuity that improved with scleral contact lenses. Except for headache in 40%, systemic symptoms were absent during the attacks. CONCLUSIONS: Symptoms and signs of KFH are restricted to the anterior segment of the eye and vary widely between individuals. We recommend scleral contact lenses as the first-line treatment for reduced vision. Allele frequencies suggest that KFH goes unrecognized in Sweden and populations with Scandinavian heritage.

A randomized phase II study of stem cell mobilization with cyclophosphamide+G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma.

The most common means of mobilizing autologous stem cells is G-CSF alone or combined with cyclophosphamide (CY) to obtain sufficient CD34+ cells for one to two transplants. There are few prospective, randomized studies investigating mobilization regimens in multiple myeloma (MM), especially after lenalidomide-based induction. We designed this prospective, randomized study to compare low-dose CY 2 g/m2 +G-CSF (arm A) and G-CSF alone (arm B) after lenalidomide-based up-front induction in MM. Of the 80 initially randomized patients, 69 patients were evaluable, 34 and 35 patients in arms A and B, respectively. The primary end point was the proportion of patients achieving a yield of ⩾3 × 10(6)/kg CD34+ cells with 1-2 aphereses, which was achieved in 94% and 77% in arms A and B, respectively (P=0.084). The median number of aphereses needed to reach the yield of ⩾3 × 10(6)/kg was lower in arm A than in arm B (1 vs. 2, P=0.035). Two patients needed plerixafor in arm A and five patients in arm B (P=0.428). Although CY-based mobilization was more effective, G-CSF alone was successful in a great majority of patients to reach the defined collection target after three cycles of lenalidomide-based induction.

The effect of diketopyrrolopyrrole (DPP) group inclusion in p-cyanophenyl end-capped oligothiophene used as a dopant in P3HT:PCBM BHJ solar cells.

In this work, two p-cyanophenyl end-capped oligothiophenes, and , were compared as dopants in the P3HT:PC60BM bulk heterojunction (BHJ) layer of inverted organic solar cells. Inclusion of significantly increased the average efficiency of the solar cells, while the increase using doping in the cell efficiency was minor. In the BHJ photoactive layer, the dopant molecules are close to and interact with P3HT and PC60BM molecules. Intra- and intermolecular interactions of the dopant molecules with P3HT and PC60BM were studied in chloroform solutions. Energy or electron transfer from the dopant molecules to PC60BM takes place as the fluorescence emission intensity and lifetime of the dopant molecules decreased in the presence of PC60BM. In the case of doping with , doped cells had higher absorbance than the non-doped reference cell and doping broadens the cell absorption to the near IR-region. Thus, the dopant molecules act as additional light absorbers in the photoactive layer and transfer energy or electrons to PC60BM, which increases the short circuit current and power conversion efficiency of the cell. Also, the emission of the cells doped with decreased when compared to that of the reference cell. In this case, P3HT can give electrons or energy to dopant molecules and the cell current and efficiency are further increased.

Long-term follow-up of a randomized clinical trial of open versus laparoscopic appendicectomy.

BACKGROUND: The aim of this study was to assess long-term outcome following open versus laparoscopic appendicectomy. METHODS: A total of 105 patients with suspected acute appendicitis were randomized to LA (51) or OA (54) between 1997 and 1999 at one hospital. Perioperative factors and follow-up data from the outpatient clinic were recorded. Information about symptoms and overall satisfaction was obtained by telephone interview. In addition, appendicectomy data for 2008 were analysed retrospectively for comparison in a contemporary setting. RESULTS: Data from 52 patients who had OA and 47 who had LA were analysed. OA was performed mostly by trainees, but LA was more likely to be undertaken by a consultant. The open procedure was quicker than the laparoscopic operation in the trial period (median 38 versus 65 min respectively; P < 0.001), but the difference was only 10 min in 2008. The OA group returned to work later than the LA group (median 13 versus 8 days; P = 0.013) and had more complications (22 versus 6; P = 0.014). Only one patient (OA) had a reoperation, owing to abdominal adhesions. Among 76 patients available for telephone interview, satisfaction scores were marginally higher for LA than OA. CONCLUSION: LA has some advantages compared with an open approach. REGISTRATION NUMBER: NCT00908804 (http://www.clinicaltrials.gov).

Blood stem cell mobilization and collection in patients with chronic lymphocytic leukaemia: a nationwide analysis.

Some reports suggest that blood stem cell mobilization is difficult in a proportion of patients with CLL. We evaluated this issue in a large cohort of CLL patients. One hundred and twenty-eight patients with CLL underwent blood stem cell mobilization during 1995-2005 in Finland. Ninety-five percent of the patients had received fludarabine. The most common mobilization regimen was intermediate-dose CY plus G-CSF (90 patients, 70%). At least 2 x 10(6)/kg CD34+ cells were collected after the first mobilization attempt in 83 patients (65%), whereas 45 patients (35%) failed to reach this collection target. No differences were observed between these patient groups with regard to age, time from the diagnosis to mobilization, number of previous treatment lines, number of fludarabine courses, time from the last fludarabine-containing chemotherapy to mobilization, disease status or degree of marrow infiltration. Patients who failed collection had platelets <100 x 10(9)/l more commonly at the time of mobilization (30 vs 4%, P<0.001). A significant proportion of patients with CLL were difficult to mobilize. Adequate marrow function including platelet counts >100 x 10(9)/l seem to be important factors in terms of successful blood stem cell collection.

Intensifying treatment of rheumatoid arthritis with combinations of traditional disease-modifying anti-rheumatic drugs among patients with persistent disease did not reduce the need for large joint surgery.

OBJECTIVE: To analyse how treatment of patients with rheumatoid arthritis (RA) influenced the duration of the disease before the first large joint surgery, arthrodesis or arthroplasty, in two patient cohorts 10 years apart. METHODS: Data on patients with RA having an arthrodesis or arthroplasty of a large joint from 1990 to 1992 and from 2000 to 2002 and the type of medication used among all patients with RA in 1988-2002 were extracted from the data set of Kuopio University Hospital. RESULTS: The median duration of the disease before the decision of arthrodesis was 6.0 (range 1-25) years in 1990-92 and 9.0 (1-31) years (p = 0.307) in 2000-02, and of arthroplasty 10.5 (0-27) and 12.5 (0-59) years (p = 0.820), respectively. A significant shift from only symptomatic treatment or one disease-modifying anti-rheumatic drug (DMARD) to the more common use of immunosuppressants and/or combinations of at least two DMARDs occurred between 1992 and 2002. CONCLUSIONS: Treatment of RA at diagnosis and during the first years after diagnosis was traditional. Intensifying treatment later in the disease course did not reduce the need for large joint surgery as it occurred in the same time range in both cohorts.

Insertion-deletion polymorphism in the gene for angiotensin-converting enzyme is associated with obstetric cholestasis but not with preeclampsia.

OBJECTIVE: Our purpose was to investigate the contribution of angiotensin-converting enzyme insertion-deletion polymorphism in the development of obstetric complications. STUDY DESIGN: In a retrospective case-control study, angiotensin-converting enzyme insertion-deletion polymorphism was investigated in a control group of healthy women (n = 115) and in a group of women diagnosed with preeclampsia (n = 133) and obstetric cholestasis (n = 57). Polymerase chain reaction detection of insertion-deletion polymorphism was used to determine the presence of the two angiotensin-converting enzyme alleles in the groups; the frequencies in the general population in our area are presented for comparison. RESULTS: The frequency of the D allele was 43.9% among women with obstetric cholestasis and 27% among healthy fertile women, which is close to the rate in the general population in our area (28%). The odds ratio for obstetric cholestasis associated with the DD genotype was 2.12 (95% CI, 1.08-4.12) compared with the pooled II and ID genotypes (P = .03). Neither the ID genotype distributions nor the allele frequencies differed significantly between preeclamptic and normotensive pregnancies (P = .36). CONCLUSION: The present data indicate that the DD genotype is a genetic marker associated with an elevated risk of obstetric cholestasis, but this polymorphism of the angiotensin-converting enzyme gene is unlikely to play any significant role in preeclampsia.

Maternal susceptibility locus for obstetric cholestasis maps to chromosome region 2p13 in Finnish patients.

BACKGROUND: Obstetric cholestasis, attributed to maternal hypersensitivity to estrogens, is a pregnancy-specific disorder characterized by pruritus and biochemical cholestasis in the second or third trimester of pregnancy. The pathophysiology of the disorder is incompletely understood, but the familial nature of the disease has long been recognized. Carriership of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency has been reported to be associated with an increased risk of obstetric cholestasis and the gene is located in the p23 region of chromosome 2. METHODS: On the basis of this information, we conducted population-based linkage disequilibrium (LD) screening to find potential cholestasis-associated loci on chromosome 2. The study was carried out in 47 unrelated control women and in 45 cholestatic women, eight of whom had a positive family history. RESULTS: During initial screening with chromosome 2-specific microsatellite markers, the tetranucleotide marker D2S1394 was found to be in LD in the 2p13 region. Screening this region with additional microsatellite markers revealed that the adjacent marker D2S1374 was also significantly associated with obstetric cholestasis, whereas no association was found with the markers located in the vicinity of the hydroxyacyl-CoA dehyrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit (HADHA) gene. CONCLUSIONS: Collectively, these data suggest that there may be a novel obstetric cholestasis-associated gene located in the vicinity of the 2p13 LD region.

Bone mineral metabolism after total gastrectomy.

Gastric surgery is mostly needed for treatment of gastric malignancy. To investigate the effect of total gastrectomy on bone mineral density (BMD) and bone mineral metabolism we evaluated 18 patients after total gastrectomy. Mean interval since operation was 71 +/- 20 months. BMD results were compared with age- and gender-matched controls (n = 46) and also expressed as T and Z scores. Bone mineral density measured by dual-energy X-ray absorptiometry (DXA) was found to be significantly lower in patients after total gastrectomy compared with healthy controls in the lumbar spine (p = 0.017 for women, p = 0.002 for men), femoral neck (p = 0.004 for women, p = 0.001 for men), Ward's triangle (p = 0.031 for women, p = 0.003 for men), and greater trochanter (p = 0.001 for women, p = 0.001 for men). Z scores for lumbar spine, femoral neck, Ward's triangle, and greater trochanter were -0.83, -1.54, -1.02, and -1.19, respectively. Biochemical measurements correlated poorly with BMD and were found to be of lesser value in diagnosing reduced bone mass as well as in differential diagnosis of etiology of osteopenia. The results of our study show the deleterious effect of total gastrectomy on bone mineral status and suggest an increased fracture risk in these patients.

Apolipoprotein E alleles in women with intrahepatic cholestasis of pregnancy.

OBJECTIVE: To investigate the frequency of apolipoprotein E (apoE) alleles among women with intrahepatic cholestasis of pregnancy. METHODS: The presence of the three most common apoE alleles (epsilon2, epsilon3, epsilon4) was determined by polymerase chain reaction-restriction fragment length polymorphism in two groups of women: healthy pregnant women (n = 47) and pregnant women with a diagnosis of intrahepatic cholestasis of pregnancy (n = 44). In addition, the frequencies of the alleles in the general population in our area are presented for comparison. RESULTS: The frequency of the apo epsilon4 allele was 21.6% among women with intrahepatic cholestasis and it was 16.0% among healthy pregnant women (Fisher exact test; P= 0.216), which is close to the rate in the general population in our area (19%). None of the apoE genotypes was significantly over-represented, and homozygous genotype epsilon4 was not associated with more severe clinical disease than other genotypes. CONCLUSION: The observed profiles of allele and genotype frequencies confirm the equilibrium state between apoE polymorphism and obstetric cholestasis and suggest that apoE does not play a major role in the development of intrahepatic cholestasis of pregnancy.

Taxane sensitivity of ovarian carcinoma in vitro.

Paclitaxel, the first clinically available taxane, has proven to be effective in the treatment of ovarian carcinoma. Docetaxel is the second taxoid derivative which has also shown activity in ovarian carcinoma. These two compounds have clear differences in pharmacokinetics and side-effects. In the present study we have tested the cytotoxic effect of docetaxel in seven ovarian carcinoma cell lines using the 96-well plate clonogenic assay. These results have been compared with data obtained from our recent study on cisplatin and paclitaxel sensitivities of the same cell lines. Chemosensitivity has been expressed as IC50 value, the drug concentration causing 50% inhibition of clonogenic survival. The IC50 values for docetaxel were 0.23-2.30 nM showing a 10-fold difference between individual cell lines. On a molar basis, docetaxel was 1.2 to 2.6 times more active than paclitaxel in six out of seven cell lines. This may be explained by differences in the mechanism of action or by differences in other pharmacological properties.

Linking patient medication data with laboratory information system.

Dozens of new drugs are taken into clinical use each year. Even if the clinicians were able to learn the most important therapeutic effects of the drugs they prescribe, they would still be unable to remember all of their minor effects. After storing patient related medication data on computerized patient records it is possible to build decision support modules which automatically remind of possible drug influences on laboratory tests and cause alarms or alerts of drug interactions. Medication profiles coded using the Anatomical Therapeutic Chemical-code (ATC-code) constitutes a valuable part of an Electronic Patient Record (EPR). In this paper, we describe the benefits of our system. By building links to commercially available drug and laboratory databases we can automatically inform clinicians on clinically relevant drug influences on laboratory test results.

Using computerized individual medication data to detect drug effects on clinical laboratory tests.

In clinical practice, thousands of drugs are used daily. Clinicians know the therapeutic effects of drugs but other minor drug effects are often ignored either because of inadequate knowledge of these effects or simply because of the limited memory capacity of a human being. This problem can be solved by using a computerized information system, which includes medication data of individual patients as well as information about non-therapeutic drug-effects. One of these non-therapeutic confusing drug effects is the influence of drugs on laboratory tests; a problem that should be taken into account in clinical practice and diagnostics. Other complicating drug effects include drug interactions and patient related adverse drug reactions. In a computerized information system, it is possible to build decision support modules that automatically give alarms or alerts of important drug effects other than therapeutic effects. If these warnings concern laboratory tests they are checked by a laboratory physician and only those with clinical significance are sent to clinicians. Warnings of drug interactions and adverse drug reactions are immediately evaluated by the physician responsible for the treatment. By means of the computerized information system, it is also possible to get better information of current medication practice which in turn gives better chances to agree on common guidelines and enables better quality assurance.