A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies.

Microtubule severing enzymes implement a diverse range of tissue-specific molecular functions throughout development and into adulthood. Although microtubule severing is fundamental to many dynamic neural processes, little is known regarding the role of the family member Katanin p60 subunit A-like 1, KATNAL1, in central nervous system (CNS) function. Recent studies reporting that microdeletions incorporating the KATNAL1 locus in humans result in intellectual disability and microcephaly suggest that KATNAL1 may play a prominent role in the CNS; however, such associations lack the functional data required to highlight potential mechanisms which link the gene to disease symptoms. Here we identify and characterise a mouse line carrying a loss of function allele in Katnal1. We show that mutants express behavioural deficits including in circadian rhythms, sleep, anxiety and learning/memory. Furthermore, in the brains of Katnal1 mutant mice we reveal numerous morphological abnormalities and defects in neuronal migration and morphology. Furthermore we demonstrate defects in the motile cilia of the ventricular ependymal cells of mutants, suggesting a role for Katnal1 in the development of ciliary function. We believe the data we present here are the first to associate KATNAL1 with such phenotypes, demonstrating that the protein plays keys roles in a number of processes integral to the development of neuronal function and behaviour.

Computerized working memory training after stroke--a pilot study.

AIM: To examine the effects of working memory (WM) training in adult patients with stroke. METHODS: A randomized pilot study with a treatment group and a passive control group; 18 participants (12 males) in a vocational age group (mean age 54 years) were randomized to either the treatment or the control condition. The intervention consisted of computerized training on various WM tasks for five weeks. A neuropsychological test battery and self-rating on cognitive functioning in daily life (the CFQ) were administered both before and after the treatment. RESULTS: Statistically significant training effects were found on the non-trained tests for WM and attention, i.e., tests that measure related cognitive functions but are not identical to tasks in the training programme (Span board p < 0.05; PASAT p < 0.001; Ruff 2&7 p < 0.005). There was a significant decrease in symptoms of cognitive problems as measured by the CFQ (p < 0.005). CONCLUSION: More than one year after a stroke, systematic WM training can significantly improve WM and attention.

[Poor leadership behind poor pain relief. Medical audit of cancer-related pain treatment]. / Dåligt ledarskap bakom dålig smärtvård. Medicinsk revision av cancersmärtvård.

A clinical audit of the treatment of cancer-related pain, ordered by Stockholm County Council and the Karolinska Institute, was performed at two Stockholm hospitals. Of 153 consecutive cancer patients interviewed while attending the preoperative out-patient clinic of the Dept. of Anaesthesiology at Karolinska Hospital, 93 (61%) reported pain varying in intensity from 2.4 to 6.6 on a 10-point visual analogue scale. The pain was cancer-related in 20 patients, treatment-related in 28 patients, and associated with disease in 40 patients (e.g., post-herpetic neuralgia, urethritis, decubital ulcer or constipation). Nine patients had undetected neuropathic pain components, and 18 patients reported both significant pain intensity and dissatisfaction with the treatment. The auditors found these patients to have persistent pain problems despite the availability of time and opportunity to resolve them. The audit included interviews with staff at three hospital departments, who filled in questionnaires, and scrutiny of the medical records of about 120 cancer patients, 5-10 records from each department being selected to illustrate the management of pain problems. Findings from the staff questionnaires and interviews were compared with the picture of pain management elicited from the patients' records. The hospital departments were all found to be characterised by similar problems: lack of pain analysis or diagnosis, failure to detect neuropathic pain components, and underdosing of opioid analgesics irrespective of pain intensity. The auditors' conclusions included a need of pain education, particularly for doctors as fewer doctors than nurses had attended pain courses.

Occurrence of magnetic material in teleosts.

Fishes representing the main groups of teleosts have been investigated for magnetic material by susceptibility measurements. All the investigated species contain magnetic material. Bone samples from the skull and the vertebral column contain magnetic particles which yield a saturation magnetization in the range 10(-4) emu g-1 to 10(-3) emu g-1 in a sample. The localization of the magnetization is diffuse within the tissues connected to the bone. There are no significant differences between the amounts of magnetic material that are found in migrating or more stationary species.

Estrogen receptor level and other factors in early recurrence of breast cancer.

At the time of treatment in 1977 for primary breast cancer of all stages, the tumors of 270 women were examined for estrogen-receptor (ER) content by isoelectric focusing on polyacrylamide gel. The procedures for the initial and follow-up examinations were standardized. Postoperative adjuvant radiotherapy or chemotherapy was given to pre- and postmenopausal women aged up to 70 years with nodal involvement. Adjuvant tamoxifen treatment (20 mg twice daily for 2 years) was given to one-half of the postmenopausal patients aged 70 years or less, selected at random, and irrespective of any other adjuvant therapy. These forms of treatment appeared not to introduce bias into the results of the study. There was no correlation between the ER content and tumor spread. Symptom-free survival during the follow-up period was best for the patients with tumors with a high ER content, poorer for the patients with tumors of intermediate ER content and least favorable for patients with tumors having low ER content. (Ranges for high, intermediate and low levels: 2.18-9.08, 0.13-2.17 and 0-0.12 fmoles/microgram DNA). The differences between the survival curves were significant. For the 120 operable patients with nodal involvement there were also significant differences in recurrence-free survival. The premenopausal patients in this group likewise showed a significant difference in survival with respect to ER content. For the operable patients with nodal involvement and poorly differentiated tumors there was also a difference in the survival rate depending on the ER content. In this study the ER content of breast cancer was shown to be a quantitative rather than a qualitative entity. The study confirms the independent prognostic importance of the ER content and points to its potential value as a stratification criterion in adjuvant therapy trials.

Tamoxifen and fluoxymesterone in advanced breast cancer: a controlled clinical trial.

Seventy-nine postmenopausal women with stage IV breast cancer and no previous endocrine therapy or chemotherapy received tamoxifen or fluoxymesterone in an open, randomized, cross-over trial. The overall remission rate was 30% with tamoxifen as the first course of treatment and 19% with fluoxymesterone as the first course of treatment. Bone metastases were seen in 21 patients receiving tamoxifen and in 20 patients receiving fluoxymesterone. There were six and five remissions in these two groups respectively. The time to the first change in therapy was significantly longer for the tamoxifen group (P = 0.003). The survival of the patients who received tamoxifen as the first course of endocrine treatment was better (P = 0.05).

Anti-oestrogen therapy of advanced mammary carcinoma.

Forty mg daily of tamoxifen (Nolvadex) was administered orally to 89 patients with advanced soft tissue mammary carcinoma. At two months 43 per cent of the patients responded. At 6, 12 and 18 months, 42, 35 and 32 per cent, respectively, were still responding to therapy. The side effects were limited, fatique being the most frequent complaint. Oestrogen dependent side effects were not encountered. The therapeutic effect of tamoxifen is similar to that of oestrogen, but the side effects are less.

3H-thymidine incorporation into mammary carcinoma cells obtained by needle aspiration before and during endocrine therapy.

3H-thymidine autoradiography was used to evaluate DNA-synthesis in carcinoma cells obtained by fine-needle aspiration biopsy from mammary carcinomas. Needle aspirates were analyzed before and after oophorectomy, and before and during treatment with oestrogen or anti-oestrogen (tamoxifen). Tumor regression occurred in 18 patients-in one of four following oophorectomy, in 15 of 38 treated with tamoxifen and in two of three given oestrogen. Seven tumors remained stationary for long periods-up to a year. In 20 cases there was tumor progression. Regression of tumors was preceded by a decrease in the fraction of 3H-thymidine-labeled cells (s-phase cells). The tumors that remained stationary or progressed retained significant levels of 3H-thymidine incorporation. This study thus showed that 3H-thymidine autoradiography can give an early estimate of tumour response to endocrine therapy. Considerable differences were found between the carcinomas in regard to proportions of S-phase cells. Further insight into this parameter may be useful for planning chemotherapy with S-phase specific agents.

PIP: Variations in DNA synthesis as measured by tritiated-thymidine autoradiography in mammary carcinoma before and during endocrine therapy were studied in patients treated for inoperable or locally recurrent mammary carcinoma. Tumor cells were collected by aspiration biopsy and immediately expelled into the incubating solution. Cell viability was assessed by staining unfixed cells with trypan blue and fixed cells with orecin. To assess viability tritiated-uridine incorporation was used in some experiments. The same cells were identified by each method. Bilateral oophorectomy was done in 4 patients. In the 1 case in which regression followed, a 5-fold decrease in DNA-synthesis was noted 1 week after oophorectomy but at 2 weeks no cells incoporated thymidine. In the 3 patients with tumor progression the fraction of labeled cells was unchanged. For antiestrogen therapy, Tamoxifen (Nolvadex) was used. Serial needle aspirates were collected from 38 patients who received 20 mg of Tamoxifen twice daily. Complete remission followed in 7, incomplete remission in 8, stationary disease in 7, and progression in 16. DNA synthesis fell to very low values after 1-3 weeks and remained low in the 7 cases with complete regression. Tumors showing partial regression showed diminished fractions of 5-phase cells (tritiated-thymidine-labeled cells) after 1-5 weeks. In 1 instance at 72 weeks the S-phase fraction of cells was higher than initial value. Tumor value remained stationary for 40 weeks and then increased. Antiestrogen therapy was stopped at 82 weeks. In those with progressive tumor growth there was high DNA synthesis. Between 20-30% of the cells were replicating DNA. None showed decrease in the fraction of S-phase cells, and 1 showed increase. For estrogen therapy, estradiol valepianate was given im every 2 weeks. Of the 3 patients who received estrogen therapy, 2 of the tumors responded and the DNA-synthesis rapidly decreased until none was measurable after 4 weeks. S-phase values prior to endocrine therapy showed no correlation with the therapeutic response. Tumors that responded showed a decrease in the proportion of S-phase cells during the first 3 weeks. In tumors responding to encocrine therapy the decrease in tritiated-thymidine incorporation was rapid and preceded reduction in tumor size. Data suggest that 2 aspirates should be studied before therapy and repeated after 2-4 weeks in order to include the minimal proportion of S-phase cells. The patients accepted the needle biopsies well. There were no growths of carcinoma at the puncture sites. About 5 weeks must elapse before tumor response can be assessed. Determining hormone receptors in surgically removed carcinoma specimens gives much more rapid indications as to possible response to endocrine therapy.