BRCAsearch: written pre-test information and <Emphasis Type="Italic">BRCA1/2</Emphasis> germline mutation testing in unselected patients with newly diagnosed breast cancer

Purpose

Chemotherapy-induced alopecia is a distressing side effect of cancer treatment. The aim of this registry study was to assess efficacy and tolerability of scalp hypothermia using Penguin Cold Caps (Penguin) in breast cancer patients.

Methods

Hair loss was assessed by patients using a 100-point Visual Analog Scale (VAS) and by physicians using the 5-point Dean Scale at baseline, every 3–4 weeks during chemotherapy, and at least 1 month after completion of chemotherapy. The primary efficacy endpoint for success was defined as ≤50% hair loss by patient report (VAS) at follow-up (FUP). Tolerability and satisfaction were assessed by patient report.

Results

103 patients enrolled between 7/2010 and 6/2015; 97 are evaluable for the primary endpoint. Chemotherapy included docetaxel/cyclophosphamide (TC; n = 50) for 4–6 cycles every 3 weeks, weekly paclitaxel for 12 weeks then doxorubicin/cyclophosphamide (P/AC; n = 23) for 4 cycles every 2–3 weeks, AC then paclitaxel (AC/P; n = 10), docetaxel/carboplatin ± trastuzumab (TCH; n = 4) for 4–6 cycles every 3 weeks. Overall, 61% of patients successfully prevented CIA; impact was regimen specific: TCH 100%, TC × 4 84%, TC × 5–6 50%, P/AC 43%, AC/P 20%. The most common toxicity was headache, reported by 78.5% of patients with mean pain level 37/100. Satisfaction among those who completed scalp cooling (SC) and FUP ranged from 74 to 100%. All patients who completed SC/FUP recommended Penguin.

Conclusions

Scalp hypothermia with Penguin is effective in reducing alopecia, particularly for non-anthracycline-based shorter regimens. Penguin was well tolerated and viewed favorably by most patients.

     

Differences between (+)- and (−)-amphetamine in effects on locomotor activity and l-dopa potentiating action in mice

Summary The l-Dopa-potentiating effects of the two optical isomers of amphetamine, as well as the effects of their own, were investigated in mice, using locomotor activity as test parameter. The study was performed in three steps. First, the time-course were studied for the effects of (+)- and (–)-amphetamine and l-Dopa. Second, dose-response relationships were established for the amphetamine enantiomers. Third, the l-Dopa-potentiating effects, of a few, selected doses of the amphetamine isomers were investigated by establishing dose-response curves for l-Dopa with and without the amphetamines. All animals given l-Dopa were pretreated with an inhibitor of extracerebral aromatic amino acid decarboyxlase. (+)-Amphetamine, 0.5–8 mg/kg, caused a dose-dependent stimulation of locomotoractivity, whereas (–)-amphetamine, 1–4 mg/kg, caused a dose-dependent depression. Doses higher than 8 mg/kg of the laevo-isomer caused stimulation of the activity. (+)-Amphetamine, 0.25 mg/kg, and (–)-amphetamine, 0.5 mg/kg, i.e. doses without any effect on locomotor activity of their own, caused virtually the same shift to the left of the dose-response curve for l-Dopa. (–)-Amphetamine, 4 mg/kg which per se caused depression of locomotor activity, caused a marked potentiation of the l-Dopa-induced stimulation of motor activity. Thus, there does not exist a close correlation between the l-Dopa-potentiating action of the amphetamines and their stimulating properties per se.     

Indomethacin inhibits bone resorptionin vitro without affecting bone collagen synthesis

The effect of indomethacin on the synthesis of collagen, non-collagen proteins and on bone resorption was studied in a bone organ culture system, using calvarial bones from 6-day-old mice. It was found that indomethacin reduced the release of calcium, inorganic phosphate and hydroxyproline without affecting the total amount of hydroxyproline in the cultures. Indomethacin had no effect on the synthesis of non-collagen proteins as estimated by the uptake of³H-tryptophan. The inhibition of the release of hydroxyproline and minerals could be seen in concentrations of indomethacin from 10^–5 to 10^–8 M. Prostaglandin E₂ (10^–7 M) could prevent the blocking capacity of indomethacin (10^–6 M), suggesting that the inhibitory action of the drug was due to the inhibition of endogenous prostaglandin synthesis. The results presented are compatible with the concept that indomethacin causes the reported detrimental skeletal effects by means of reduced osteoclastic rather than by reduced osteoblastic activity.Supported by the Swedish Medical Research Council (14X-05426), the Royal 80 Year Fund of Gustav V, and the Swedish Association Against Rheumatic Diseases.     

Pseudohypoparathyroidism type I and Albright''s hereditary osteodystrophy with a proximal 15q chromosomal deletion in mother and daughter

A 33-year-old woman and her 71-year-old mother were both found to have pseudohypoparathyroidism type I with Albright's hereditary osteodystrophy associated with a cytogenetic deletion of the proximal part of one chromosome 15, resembling that found in Prader-Willi syndrome. As there are overlapping clinical features between these two syndromes a causal relationship cannot be excluded. However, molecular analyses with 10 probes from this region did not detect any uniparental disomy or deletion, features frequently found in Prader-Willi syndrome.     

Inhibitory circuits and the nature of their interactions in the human motor cortex – a pharmacological TMS study

Inhibitory circuits are crucial in modulating corticospinal output in the primary motor cortex (M1). Relatively little is known about how these inhibitory circuits interact. Here we measured three forms of inhibition in M1 by paired-pulse transcranial magnetic stimulation: short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and short-interval interhemispheric inhibition (SIHI). We specifically tested their interactions under pharmacological challenge with a single oral dose of diazepam, a positive allosteric modulator of the γ-aminobutyric acid type A receptor (GABA_AR), or baclofen, a specific agonist at the GABA type B receptor (GABA_BR). Motor evoked potentials were recorded bilaterally from the first dorsal interosseous muscle in eight right-handed healthy volunteers. Diazepam enhanced SICI, and baclofen produced a trend towards enhanced LICI, corroborating the view that SICI reflects inhibition mediated by the GABA_AR, and LICI very likely reflects inhibition mediated by the GABA_BR. The pharmacology of SIHI was inconclusive and warrants further investigation. Findings strongly suggest that SICI, LICI and SIHI recruit three distinct inhibitory circuits in the human M1. The interactions between SIHI and SICI, LICI and SIHI, and LICI and SICI were all negative, that is SIHI suppressed SICI, and LICI suppressed both SIHI and SICI. Diazepam partially restored SICI in the presence of LICI, while all other interactions remained unaffected by diazepam or baclofen. It will be argued that the negative interactions between SIHI and SICI, LICI and SIHI, and LICI and SICI are most likely due to presynaptic GABA_BR-mediated autoinhibition.     

Effects of neonatal thyroid hormone stimulation and differential preweaning rearing on open-field behavior in adult rats

In 2 experiments, rats were given a mixture containing high doses of 1-tri-iodothyronine and 1-thyroxine-sodium on Day 4 after birth (Group T)Controls (C) received equivalent amounts of saline. During the preweaning period, half of the litters in the T and C groups were raised in an impoverished (I) condition, and half in an enriched (E) condition. Open-field ambulation, rearing, defecation, and, in Experiment 2, grooming behavior were recorded during a 4-day period at 210 days (Experiment 1) and at 90 days of age (Experiment 2). A consistent augmenting action of neonatal hormone stimulation on ambulation and rearing was found for both males and females. Hormone-treated animals did not habituate their rate of general motor activity with repeated testings in the open-field. An over-all pattern of a larger effect of hormone-treatment in the I condition than in the E condition was noted, particularly among the females. Thus, the experience of preweaning enrichment partly “normalized” the open-field behavior of the T groups. The results are discussed in relation to an hypothesis concerning the interaction of rate of development of the central nervous system and environmental stimulation in determining later behavior.     

A method for the preparation of imprints from the nasal mucosa

Important immunological reactions take place on the surface of mucosal membranes. Improved methods for the sampling and quantitative study of the cells taking part in these reactions are therefore desirable. We here describe a new technique for the preparation of imprints from the nasal mucosa. The method utilizes a plastic film coated with a thin layer of an albumin-glycerol mixture to improve cell adherence to the surface. The membrane is gently pressed onto a defined portion of the mucous membrane. Fixation and staining procedures are performed on the plastic film, which is then mounted on a slide and covered by a coverslip. The preparations have excellent optical properties and specific cell types can be easily studied, quantified and related to the specific area of the mucosa from which the imprint was taken.     

Inhibitory circuits and the nature of their interactions in the human motor cortex a pharmacological TMS study.

Inhibitory circuits are crucial in modulating corticospinal output in the primary motor cortex (M1). Relatively little is known about how these inhibitory circuits interact. Here we measured three forms of inhibition in M1 by paired-pulse transcranial magnetic stimulation: short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and short-interval interhemispheric inhibition (SIHI). We specifically tested their interactions under pharmacological challenge with a single oral dose of diazepam, a positive allosteric modulator of the gamma-aminobutyric acid type A receptor (GABA A R), or baclofen, a specific agonist at the GABA type B receptor (GABA B R). Motor evoked potentials were recorded bilaterally from the first dorsal interosseous muscle in eight right-handed healthy volunteers. Diazepam enhanced SICI, and baclofen produced a trend towards enhanced LICI, corroborating the view that SICI reflects inhibition mediated by the GABA A R, and LICI very likely reflects inhibition mediated by the GABA B R. The pharmacology of SIHI was inconclusive and warrants further investigation. Findings strongly suggest that SICI, LICI and SIHI recruit three distinct inhibitory circuits in the human M1. The interactions between SIHI and SICI, LICI and SIHI, and LICI and SICI were all negative, that is SIHI suppressed SICI, and LICI suppressed both SIHI and SICI. Diazepam partially restored SICI in the presence of LICI, while all other interactions remained unaffected by diazepam or baclofen. It will be argued that the negative interactions between SIHI and SICI, LICI and SIHI, and LICI and SICI are most likely due to presynaptic GABA B R-mediated autoinhibition.     

Clonally expanded CD4+CD28null T cells in rheumatoid arthritis use distinct combinations of T cell receptor BV and BJ elements

Clonally expanded, autoreactive CD4(+)CD28(null) cells can be found in the peripheral blood of patients with rheumatoid arthritis and have been shown to be associated with severeextra-articular disease manifestations. We investigated the size of the CD4(+)CD28(null) compartment and the TCR beta chain repertoire of expanded CD4(+) clonotypes in 94 rheumatoid arthritis patients by complementarity-determining region 3 (CDR3) length analysis (spectratyping) in the BV6 and BV14 TCR families, with primers specific for three arbitrarily chosen beta chain joining elements (BJ1S2, BJ2S3 and BJ2S7). The spectratyping results showed a strong correlation of the size of the CD4(+)CD28(null) compartment with the detected number of BV14 clonotypes, whereas no association with BV6 oligoclonality was found. Only clones using the BV14-BJ1S2 and BV14-BJ2S3 combinations contributed to this correlation, however, whereas BV14-BJ2S7 clones did not. This preferential correlation implies a role for the TCR beta chain in stimulating clonal outgrowth and argues against the previously suggested superantigenic stimulation of in-vivo-expanded clones. Instead, since no evidence for shared antigen specificity could be detected, clonal expansion of T cells in rheumatoid arthritis might be influenced by the BJ elements because of changes in the flexibility of the protein backbone of the beta-chain.