Real-world treatment patterns in patients with nontuberculous mycobacterial lung disease in the Netherlands based on medication dispensing data.

PURPOSE: Real-world data on antibiotic management of nontuberculous mycobacterial lung disease (NTM-LD) is limited for many countries. This study aimed to evaluate real-world treatment practices of NTM-LD in the Netherlands using medication dispensing data. METHODS: A retrospective longitudinal real-world study was conducted using IQVIA's Dutch pharmaceutical dispensing database. The data are collected monthly and include approximately 70% of all outpatient prescriptions in the Netherlands. Patients initiated on specific NTM-LD treatment regimens between October 2015 and September 2020 were included. The main areas of investigation were initial treatment regimens, persistence on treatment, treatment switching, treatment compliance in terms of medication possession rate (MPR) and restarts of treatment. RESULTS: The database included 465 unique patients initiated on triple- or dual-drug regimens for the treatment of NTM-LD. Treatment switches were common and occurred approximately 1.6 per quarter throughout the treatment period. The average MPR of patients initiated on triple-drug therapy was 90%. The median time on therapy for these patients was 119 days; after six months and one year, 47% and 20% of the patients, respectively, were still on antibiotic therapy. Of 187 patients initiated on triple-drug therapy, 33 (18%) patients restarted antibiotic therapy after the initial treatment had been stopped. CONCLUSION: When on therapy, patients were compliant with the NTM-LD treatment; however, many patients stopped their therapy prematurely, treatment switches often occurred, and part of patients had to restart their therapy after a longer treatment gap. NTM-LD management should be improved through greater guideline adherence and appropriate involvement of expert centers.

[Two patients with isolated vasculitis of the central nervous system]. / Twee patiënten met geïsoleerde vasculitis van het centrale zenuwstelsel.

Over the course of time, a 43-year-old woman and a 39-year-old man developed visual, sensory, motor, cerebellar and cognitive disturbances. Initially these occurred episodically, but later became continuous. Isolated vasculitis of the central nervous system was only diagnosed after brain biopsies were taken, upon which treatment with prednisone and cyclophosphamide was instituted. In both patients the symptoms persisted for 23 and 19 months, respectively, after treatment was initiated, but no new symptoms developed. The woman did, however, develop pancytopenia as a result of the cyclophosphamide treatment. Non-infectious vasculitis of the small veins and arterioles of the brain is lethal if left untreated. Leptomeningeal and cortical biopsy is essential in establishing the diagnosis in order to rule out other causative diseases. Combination therapy consisting of prednisone and cyclophosphamide for at least one year is recommended. The efficacy of this treatment is unknown due to the rarity of this disease.

DNA repair mechanisms and gametogenesis.

In mammals, there is a complex and intriguing relationship between DNA repair and gametogenesis. DNA repair mechanisms are involved not only in the repair of different types of DNA damage in developing germline cells, but also take part in the meiotic recombination process. Furthermore, the DNA repair mechanisms should tolerate mutations occurring during gametogenesis, to a limited extent. In the present review, several gametogenic aspects of DNA mismatch repair, homologous recombination repair and postreplication repair are discussed. In addition, the role of DNA damage-induced cell cycle checkpoint control is considered briefly. It appears that many genes encoding proteins that take part in DNA repair mechanisms show enhanced or specialized expression during mammalian gametogenesis, and several gene knockout mouse models show male or female infertility. On the basis of such knowledge and models, future experiments may provide more information about the precise relationship between DNA repair, chromatin dynamics, and genomic stability versus instability during gametogenesis.

Effective population size, reproductive success and sperm precedence in the butterfly, Bicyclus anynana, in captivity.

A pedigree approach is used to estimate the effective population size yn two population cages of the butterfly, Bicyclus anynana. Each cage was founded with 54 individually marked adults of each sex. Matings were recorded over a 3-day period. Eggs were then collected from each female over a similar period before the numbers of hatching larvae were counted to assess progeny number. The males showed a higher variance in reproductive success than the females. Since about one-quarter of all females mated more than once, we also examined the pattern of sperm precedence using molecular markers or, in separate crossing experiments, wing pattern mutants. Both instances of complete first and last male sperm precedence, as well as of sperm mixing, were found. In some crosses a 'leakiness' was found in which some of the early eggs laid by a female were fertilized by a male partner which was subsequently completely unsuccessful. However, the estimates of effective population size were largely unaffected by the pattern of sperm precedence. Estimates for Ne : N in each cage were close to 0.60. The possibility of obtaining comparable estimates in selected natural populations of butterflies is discussed.

Specific aspects of the ubiquitin system in spermatogenesis.

The ubiquitin system is involved in numerous cellular processes, regulating the amounts and/or activities of specific proteins through posttranslational coupling with ubiquitin or ubiquitin-like proteins. In spermatogenesis, there appears to be a special requirement for certain components of the ubiquitin system, as exemplified in human and mouse by mutation of USP9Y and HR6B, respectively. Both genes encode proteins which take part in the ubiquitin system and are ubiquitously expressed, but their mutation generates no apparent phenotype other than male infertility. Different phases of mammalian spermatogenesis probably require different specialized activities of the ubiquitin system. It is anticipated that ubiquitination activities similar to those required during mitotic cell cycle regulation will play some role in control of the meiotic divisions. In spermatocytes, there is an intricate link among DNA repair, the ubiquitin system, and regulation of meiotic chromatin structure, as indicated by the co-localization of proteins involved in these processes on meiotic recombination complexes. HR6B and its nearly identical homolog HR6A are multiple function proteins, with ubiquitin-conjugating activity and essential roles in post-replication DNA repair. HR6B, possibly together with the ubiquitin-ligating enzyme mRAD1 8Sc, is most likely involved in chromatin re-organization during the meiotic and post-meiotic phases of spermatogenesis. Biochemical data indicate that, in particular during spermiogenesis, the general activity of the ubiquitin system is high, which most likely is related to the high requirement for massive breakdown of cytoplasmatic and nuclear proteins during this last phase of spermatogenesis.

Characterization of mRAD18Sc, a mouse homolog of the yeast postreplication repair gene RAD18.

The RAD18 gene of the yeast Saccharomyces cerevisiae encodes a protein with ssDNA binding activity that interacts with the ubiquitin-conjugating enzyme RAD6 and plays an important role in postreplication repair. We identified and characterized the putative mouse homolog of RAD18, designated mRAD18Sc. The mRAD18Sc open reading frame encodes a 509-amino-acid polypeptide that is strongly conserved in size and sequence between yeast and mammals, with specific conservation of the RING-zinc-finger and the classic zinc-finger domain. The degree of sequence conservation between mRAD18Sc, RAD18, and homologous sequences identified in other species (NuvA from Aspergillus nidulans and Uvs-2 from Neurospora crassa) is entirely consistent with the evolutionary relationship of these organisms, strongly arguing that these genes are one another's homologs. Consistent with the presence of a nuclear translocation signal in the amino acid sequence, we observed the nuclear localization of GFP-tagged mRAD18Sc after stable transfection to HeLa cells. mRNA expression of mRAD18Sc in the mouse was observed in thymus, spleen, brain, and ovary, but was most pronounced in testis, with the highest level of expression in pachytene-stage primary spermatocytes, suggesting that mRAD18Sc plays a role in meiosis of spermatogenesis. Finally, we mapped the mRAD18Sc gene on mouse chromosome 6F.

Transcortical sensory aphasia in a right-handed patient following watershed infarcts in the right cerebral hemisphere: a 15-month evaluation of another case of crossed aphasia.

Well-documented cases of crossed (transcortical sensory) aphasia, especially those with longitudinal evaluation, are rare. We report a case of crossed transcortical sensory aphasia following watershed infarcts in the right hemisphere, from the moment of the accident until 15 months afterward. The aphasia type, and the course of recovery, is a "mirror" representation of that seen in cases of uncrossed aphasia. Unfortunately, the data do not permit strong conclusions regarding the lateralization of language in association with praxis and visuospatial abilities. This underlines the need for more well-documented (case) studies to come to a better understanding of the mechanisms through which lateralization occurs.

Intracranial chondrosarcoma: review of the literature and report of 15 cases.

The available data in the literature (177 cases), two current clinical patients, and cases which occurred in The Netherlands (13) were reviewed concerning the clinical presentation, pathological features, radiological data, and treatment options of chondrosarcoma of the cranial base. The mean age of patients was 37 years, the male/female ratio 1:1.1. The most frequent complaints were diplopia with oculomotor disorders (51%), headache (31%), and decreased hearing, dizziness, and tinnitus with statoacusticus dysfunction (21%). The mean duration of symptoms before diagnosis was 27 months. The chondrosarcomas were located in the petrosal bone in 37% (47 cases), in the occipital bone and clivus in 23% (30 cases), in the sphenoid bone in 20% (25 cases) and to a lesser extent in frontal, ethmoidal, and parietal bones (14%). In 6% (eight cases) the primary location was in dural tissue. Radiological examinations showed bone destruction and variable calcification (CT), involvement of neuronal and vascular structures (MRI), and mostly hypovascularity on angiography. On histological examination 51% of tumours were classified as grade I, 11% grade II, 30% mesenchymal, and 8% myxoid. The mesenchymal type was the most malignant as illustrated by a strong tendency to intradural and cerebral growth and possibly occurrence in younger age groups. The treatment of choice until recently was surgery because of the critical location and local aggressive nature. Regrowth of tumour after surgery occurred in 53% of the patients (average after 32 months). Charged particle irradiation gave a five year survival of 83-94% and a local control rate of 78%-91%. Both in surgery and radiotherapy there is treatment related morbidity and mortality that should be considered when offering these therapies. Recent promising results imply that charged particle radiotherapy, in combination with surgery, may be the therapeutical choice of the future.

Occult cerebrovascular malformations: 2 cases.

Since the introduction of high accuracy CT scanning and MR imaging, angiographically occult cerebrovascular malformations are a relatively common finding. The clinical presentation is usually related to hemorrhage. Asymptomatic intralesional bleeding frequently occurs. Currently, MR imaging is the most sensitive method for the detection of occult cerebrovascular malformations. The dynamic nature of these malformations seems to be a key factor in their therapeutic management. We present 2 cases of occult cerebrovascular malformations and discuss the clinical presentation, neuroradiologic appearance and current management of these lesions.

Computed tomography in the diagnosis and treatment of solitary splenic abscesses.

Solitary splenic abscess is a rare entity and difficult to diagnose. Late recognition results in a high mortality. Recently percutaneous drainage has proved to be beneficial. The CT and ultrasound findings of two patients with splenic abscesses are reported. In one patient the solitary splenic abscess was drained percutaneously. In the other patient, a HTLV-III-positive man, a splenectomy was performed.