Miltefosine (Impavido): the first oral treatment against leishmaniasis

Miltefosine is a novel antileishmanial drug that has significant selectivity in both in vitro and in vivo models. Clinical efficacy was demonstrated for the treatment of visceral leishmaniasis with the advantage of oral administration over the currently recommended antileishmanial drugs that require parenteral administration. Miltefosine produces high cure rates also in patients resistant to the standard antimonial therapy.     

Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies

Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen.     

Histomorphometry of bone marrow biopsies in primary osteomyelofibrosis/-sclerosis (agnogenic myeloid metaplasia) - correlations between clinical and morphological features

Summary Histomorphometry was performed on representative trephine biopsies of the bone marrow on admission of 50 patients (21 male, 29 female-age 67 years) with so-called primary osteomyelofibrosis/-sclerosis (OMF) not preceded by any other subtype of chronic myeloproliferative disorders. This study was firstly aimed at testing correlations between histological features (amount of haematopoiesis, cytological aspects of mega-karyocytes, density of reticulin and collagen fibres and degree of osteosclerosis) and laboratory data, as well as spleen size and duration of relevant prediagnostic symptoms. Secondly, we concentrated on a discrimination of OMF patients into two sub-groups according to bone marrow morphology and clinical variables. Statistical evaluation of histomorphometric variables and haematological findings disclosed that there was a progressive fibro-osteosclerotic process in the evolution of disease features. Increase in medullary fibrosis was significantly paralleled by an abnormal or pleomorphic megakaryopoiesis in the bone marrow: there was an increase in irregularity of perimeters for megakaryocytes and naked nuclei combined with smaller sizes of these elements including the nuclei. Additionally, there was a greater number of pycnotic bare nuclei. A number of morphometric features (density of fibres, degree of osteosclerosis, amount of haematopoiesis) were associated with corresponding clinical data (spleen size, length of preclinical history). By consideration of a set of basic histomorphometric variables our co-hort of 50 patients could be divided into an early hyperplastic subtype with no or minimal medullary reticulin and another group with conspicuous fibrotic and osteosclerotic alterations of the bone marrow. It was noticeable that we found no significant correlation between amount of haematopoiesis or marrow cellularity with splenomegaly. This result suggests that splenic haematopoiesis (myeloid metaplasia) may represent an autonomous or neoplastic process and not only compensation for a failing fibro-osteosclerotic bone marrow.Supported by a grant from the Deutsche Forschungsgemeinschaft (DFG-Th 390/1-1)     

Attachment representations in 6-year-olds: related longitudinally to the quality of attachment in infancy and mothers' attachment representations

A new method to assess attachment representations in children by applying a story completion procedure in doll play (SCPDP) is presented. Transmission and continuity of attachment were tested in 28 German families by using the Strange Situation procedure (SS) with the mother and her infant, the Adult Attachment Interview (AAI) with the mother when the child is 5 years old, and the attachment representations (SCPDP) of the 6-year-olds. Relying on the twofold distinction (secure/insecure), results revealed a significant continuity of attachment from 1 to 6 years of age, and a correspondence between maternal AAI and child's attachment quality in SS, as well as a correspondence between maternal AAI and the 6-year-olds' attachment representations. Using configural frequency analysis, we found continuity in patterns of security and insecurity when looking across the measures of infant and pre-school attachment and maternal adult attachment. Processes underlying the high match of mothers' and children's attachment representations are discussed.     

Infrared spectroscopy: A new diagnostic tool in Alzheimer disease

Biological markers play an evolving role in the diagnosis of Alzheimer disease (AD). We compare conventional measurements of cerebrospinal fluid (CSF) tau and β-amyloid_1–42 proteins to a novel approach – Fourier transformed infrared (FT-IR) spectroscopy – a simple technique derived from chemical and physical sciences that characterizes intramolecular bonds. For automatic diagnostic analysis, we developed an artificial neural network (ANN). We examined 71 patients with a clinical diagnosis of AD and 66 controls. β-Amyloid_1–42 was decreased (sensitivity 80% and specificity 78%); tau was elevated (sensitivity 76% and specificity 88%) in CSF of AD patients. The combined tau/β-amyloid_1–42 quotient was able to distinguish healthy from diseased subjects with 99% sensitivity and 86% specificity. The ANN could separate FT-IR spectroscopy data with 88.5% sensitivity and 80% specificity. FT-IR spectroscopy proved to be cost-effective and simple to perform. Diagnostic sensitivity and specificity is in the range of CSF tau and β-amyloid_1–42 protein analysis. Larger sample numbers for ANN training and validation could increase diagnostic accuracy and thus prove to be a useful screening tool.     

Clinical outcomes in pediatric tibial lengthening and deformity correction: a comparison of the Taylor Spatial Frame with the Orthex Hexapod System

PurposeComparison of two hexapod frame systems in paediatric tibial deformity correction; the Taylor Spatial Frame (TSF) and Orthex Hexapod System.MethodsPaediatric patients with congenital and acquired tibial deformities treated with either TSF (between 2014 and 2016) or Orthex (between 2017 and 2019) frames were included in a retrospective comparative study. Outcome measures were healing index, pin infection rate, regenerate quality and density, software residual rate, deformity correction accuracy, strut exchanges and quality of life (QoL).ResultsThe TSF group had 17 patients (18 frames) and the Orthex group had 21 patients (25 frames). The most common indications for tibial deformity correction were fibular hemimelia (14) and septic or traumatic growth arrest (8). The median time in frame was 230 days (TSF) versus 203 days (Orthex) (p= 0.06). The mean lengthening achieved was 54 mm (TSF) and 51 mm (Orthex) (p = 0.41). The healing index was 41 days/cm (TSF) versus 43 days/cm (Orthex) (p = 0.70). Pin site infections occurred more in the TSF cohort (40%) than in the Orthex cohort (18%) (p < 0.001). The regenerate in the Orthex group showed higher density at three months (p = 0.029) and was more homogenous (p = 0.023) at six months after frame application. Strut exchanges were less frequent with the Orthex system (p < 0.0001). QoL measures were similar in both cohorts (p = 0.92).ConclusionsThis is the first study to compare two hexapod designs in paediatric orthopaedics. The Orthex system showed superiority in regenerate quality and a significant reduction in pin site infection rates. Both systems delivered predictable and accurate limb deformity correction.Level of evidenceIII     

Familial Papillary Thyroid Carcinoma: Genetics, Criteria for Diagnosis, Clinical Features, and Surgical Treatment

Hereditable predisposition to papillary thyroid carcinoma (PTC) and multinodular goiter (MNG) without evidence of an association with other malignancies as a distinct entity was recognized only recently. A meta-review of the literature on familial PTC (FPTC) was undertaken, and characteristics of families with frequent occurrence of PTC or MNG (or both) were summarized. A database on thyroid cancer patients maintained in our institution was searched for potential FPTC families. Clinical examinations were performed in 6 of 12 Hannover kindreds identified, and blood samples of all family members were collected for genetic analyses. Clinical presentations and histopathologic features of the FPTC cases were compiled. Based on the FPTC meta-review and own experience, predictive criteria to identify families at risk were developed: Exclusion criteria were previous radiation exposure and coincidence with neoplasia syndromes. Primary criteria for susceptibility to FPTC are (1) PTC in two or more first-degree relatives and (2) MNG in at least three first- or second-degree relatives of a PTC patient. Secondary criteria are diagnosis in a patient younger than 33 years, multifocal or bilateral PTC, organ-exceeding tumor growth (T4), metastasis (N1, M1), and familial accumulation of adolescent-onset thyroid disease. A hereditary predisposition to PTC is considered if both primary criteria or one primary criterion plus three secondary criteria are present. Family history-taking is recommended for all PTC patients to identify FPTC kindreds at risk. Blood relatives of FPTC index patients who harbor MNG should undergo thorough and regular clinical screening. Suspicious lesions should prompt early surgical intervention.     

Clinicopathological Impact of the Interaction Between Megakaryocytes and Myeloid Stroma in Chronic Myeloproliferative Disorders: A Concise Update

In this report an attempt has been made to discuss some of the issues pertinent to myelofibrosis complicating chronic myeloproliferative disorders (CMPDs) that are significantly associated with megakaryocyte function. In this context, biochemical, clinical and particularly morphological features were reviewed. Morphological findings based on elaborate techniques were in keeping with the assumption that in chronic myeloid leukemia (1) the number of CD61-positive megakaryocytes, and in particular their precursors were the parameters most closely associated with myelofibrosis (2) an increased content of reticulin fibers in follow-up biopsies significantly correlated with laboratory data indicative of a high tumor burden (anemia, peripheral blasts, hepatosplenomegaly) and thus a more advanced stage of the disease process (3) even a slight increase in reticulin, i.e. doubling of the normal fiber density was associated with a worse prognosis independent of therapeutic regimens given (4) Dynamics of myelofibrosis was significantly influenced by treatment. In this context, calculation of the myelofibrosis progression index (MPI) revealed a higher score following interferon therapy compared with busulfan. In addition, in idiopathic myelofibrosis (5) the evolution of myelofibrosis was unpredictable and according to the MPI, progression occurred at a relatively low rate (6) proliferation and dilatation of sinusoids accompanying intravascular hematopoiesis and collagen type IV deposits were predominant features in later (fibro-osteosclerotic) stages in the course of disease (7) transmural migration of megakaryocytes demonstrated by three dimensional reconstruction revealed a mole-like tunneling through the thickened sinusoidal wall. A very careful assessment of the numerous correlations between bone marrow features and laboratory data will allow clinicians and pathologists to gain a better insight into the mutual relationships between hematological and morphological findings in CMPDs.     

Spatio-Temporal Monitoring of Benthic Anatoxin-a-Producing Tychonema sp. in the River Lech,Germany

Incidents with toxic benthic cyanobacteria blooms have been increasing recently. In 2019, several dogs were poisoned in the river Lech (Germany) by the benthic anatoxin-a-producing genus Tychonema. To characterize spatial and temporal distribution of potentially toxic Tychonema in this river, a systematic monitoring was carried out in 2020, focusing on the occurrence of the genus, its toxin production and habitat requirements. Tychonema and cyanobacterial community composition in benthic mats and pelagic samples were identified using a combined approach of microscopy and DNA sequencing of the 16S rRNA gene. In addition, anatoxin-a concentrations of selected samples were measured using the ELISA method. The habitat was characterized to assess the ecological requirements and growth conditions of Tychonema. Tychonema mats and anatoxin-a were detected at several sampling sites throughout the entire study period. Toxin concentrations increased with the progression of the vegetation period and with flow direction, reaching values between 0 and 220.5 µg/L. Community composition differed among pelagic and benthic samples, with life zone and substrate condition being the most important factors. The results of this study highlight the importance of monitoring and understanding the factors determining occurrence and toxin production of both pelagic and benthic cyanobacteria due to their relevance for the health of humans and aquatic ecosystems.