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Background: The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti-Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient., Results: Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI., Conclusions: Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA., (© 2023. The Author(s).)

During aging, mitochondrial DNA (mtDNA) can accumulate mutations leading to increasing levels of reactive oxygen species (ROS). Increased ROS were described to activate formerly quiescent hematopoietic stem cells (HSC). Mutations in mtDNA were shown to enhance the risk for myelodysplastic syndrome and leukemia. However, the complex relationship between mtDNA variations, ROS and aging of the hematopoietic system is not fully understood.Herein, three mouse strains with mtDNA polymorphisms in genes of respiratory chain complexes I (ND4), III (CYTB) and IV (COX3) were compared to a reference strain during aging. Analysis focused on ROS and ATP levels, bone marrow composition and blood counts. Additionally, hematopoietic restoration capacity following cytotoxic stress was tested.Mice with polymorphisms in ND4 and CYTB gene had significantly decreasing ROS levels in bone marrow cells during aging, without effecting ATP levels. In addition, the frequency of stem and progenitor cells increased during aging but the amount of lymphocytes in the peripheral blood decreased during aging.In summary, the presence of mtDNA polymorphisms affecting the respiratory chain complexes I, III and IV was associated with altered ROS levels as well as changes in BM and peripheral blood composition during aging.

Background: Mitochondrial DNA (mtDNA) encodes for the respiratory chain proteins. Genetic alterations in mtDNA have been described during aging and linked to impaired hematopoiesis., Materials and Methods: We investigated two novel conplastic mouse strains harboring a mitochondrial nt7778 G/T polymorphism leading to an amino acid exchange in respiratory chain complex V. Effects on reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, as well as bone marrow composition and peripheral blood counts, were investigated during aging (up to 24 month)., Results: The polymorphism correlated with significantly decreased ROS levels in aged mice. Effects on hematopoiesis were marginal and not statistically significant: numbers of erythroid cells in bone marrow, as well as mean corpuscular hemoglobin, tended to decrease over time., Conclusion: The investigated polymorphism is associated with decreased ROS levels in aged hematopoietic cells but does not significantly influence hematopoiesis itself., (Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Progress of age-related hematopoietic diseases such as myelodysplastic syndrome has previously been linked to enhanced levels of reactive oxygen species (ROS). Uncoupling protein 2 (UCP2) was found to reduce mitochondrial ROS production through uncoupling of the respiratory chain. The impact of UCP2 loss and elevated ROS on hematopoiesis during aging has not yet been investigated. In this study, UCP2 knockout mice were analyzed at aging stages of 3, 12, and 24 months with respect to oxidative and energy status of bone marrow cells. Further, the cellular bone marrow subpopulation composition was characterized, as were the differential blood counts at all time points. UCP2 knockout mice revealed enhanced levels of mitochondrial superoxide in elderly animals. Following oxidative stress, adenosine triphosphate (ATP) levels decreased more in the knockout mice than in the wild type. Investigation of bone marrow and blood counts of the knockout mice revealed an enhanced amount of monocytes and neutrophils, as well as a decreased amount of B cells and impaired erythropoiesis throughout aging. In summary, UCP2 induces protective effects on ROS and ATP levels during aging. Additionally, the results suggest an imbalance in hematopoiesis because of the lack of UCP2., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Background: The nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom., Methods: We performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA., Results: Ocular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo-/dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups., Conclusions: Systematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment.

A 21-year-old male patient from Borna, Saxony, in Eastern Germany, suffered from acute kidney injury (AKI) and symptoms typical for a hantavirus infection. These symptoms included nausea, vomiting, abdominal pain, diarrhea, and acute renal failure. Serological investigations by indirect IgM and IgG in-house ELISAs, commercial immunofluorescence and line assays, as well as chemiluminescence focus reduction neutralization assay confirmed an acute Dobrava-Belgrade virus (DOBV) infection of the patient. Serological and RT-PCR analyses of striped field mouse (Apodemus agrarius) trapped in a neighboring region of the residence of the patient identified an infection by DOBV, genotype Kurkino. This is the first report of an autochthonous DOBV infection in a German patient living far from the known endemic region in the north of the country. This finding has implications for the awareness of physicians in areas which are not recognized as hantavirus endemic regions but where the reservoir host of the virus is present.

Background: Prognosis of adult patients suffering from acute lymphoblastic leukemia (ALL) is still unsatisfactory. Targeted therapy via inhibition of deregulated signaling pathways appears to be a promising therapeutic option for the treatment of ALL. Herein, we evaluated the influence of a novel arylindolylmaleimide (PDA-66), a potential GSK3β inhibitor, on several ALL cell lines., Methods: ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were exposed to different concentrations of PDA-66. Subsequently, proliferation, metabolic activity, apoptosis and necrosis, cell cycle distribution and protein expression of Wnt and PI3K/Akt signaling pathways were analyzed at different time points., Results: PDA-66 inhibited the proliferation of ALL cells significantly by reduction of metabolic activity. The 72 h IC50 values ranged between 0.41 to 1.28 μM PDA-66. Additionally, caspase activated induction of apoptosis could be detected in the analyzed cell lines. PDA-66 influenced the cell cycle distribution of ALL cell lines differently. While RS4;11 and MOLT4 cells were found to be arrested in G2 phase, SEM cells showed an increased cell cycle in G0/1 phase., Conclusion: PDA-66 displays significant antileukemic activity in ALL cells and classifies as candidate for further evaluation as a potential drug in targeted therapy of ALL.

It is unknown whether birds are able to retain the memory of purely sensory auditory information such as white noise over an extended period of time. In a Pavlovian heart rate conditioning paradigm, four pigeons were trained to associate a mild electric shock with periodic random waveforms, and no shock with aperiodic noise. Periodic waveform detection requires echoic memory, i.e., the online retention of a waveform pattern over a limited time. Starting with 40ms, the waveform period was increased after successful learning until no significant stimulus discrimination could be found. Significant discrimination was achieved at periods of up to 2560ms. This is the first demonstration that echoic memory performance in birds is clearly superior to cats and gerbils, and comparable to naive human performance.

The aims of this study were to assess the frequency of traumatic injuries in patients with syncope and apparently normal hearts and their influence on the diagnostic evaluation and recurrence of syncope. Patients presenting with syncope before head-up tilt testing frequently had a history of syncope-related injuries. Syncope-related injuries seemed to be random: they was not related to patients' histories, including the number of previous syncopal attacks, and they had no predictive value for the outcome of head-up tilt testing or for the recurrence of syncope during 1-year follow-up.

External electrocardiographic loop recording permits extended cardiac rhythm monitoring and ECG storage before and after device activation. The purpose of the study was to assess the diagnostic yield of external loop recorders in patients with more than two syncopal events within the last 6 months and a negative tilt table test. Twenty-four consecutive patients (51 +/- 14 years, male n = 9) were enrolled with 3 +/- 4 recurrent syncopal events within the last 6 months and no overt structural heart disease. The loop recorder CardioCall continuously records a two-channel ECG via skin electrodes. When activated, up to 4.5 minutes of the ECG preceding activation is stored. The time between tilt table testing and monitoring was 5 +/- 4 weeks. The average monitoring period covered 50 +/- 22 days. Recording was either unsuccessful or terminated prematurely in 5 patients. The reasons were skin irritation secondary to the electrodes in two patients, cable damage in one patient, and two patients inadvertently erased the stored data when replacing the batteries. Fourteen patients activated the loop recorder at least once. Symptoms leading to device activation were syncope (n = 1), dizziness (n = 11), feeling unwell (n = 7), palpitations (n = 5), headaches (n = 1), and chest pain (n = 1). The loop recorder documented sinus tachycardia during the syncopal event. Sinus tachycardia was also observed in 7 other patients, and atrial flutter in two patients. Eight patients had recurrent syncope with two patients experiencing syncope prior to the monitoring period, one syncope occurred in a patient who inadvertently erased the stored data, one event coincided with sinus tachycardia, and 4 (17%) patients had syncope during 15 +/- 10 months after termination of loop monitoring. The external loop recorder was not very useful for arrhythmia detection in patients with syncopal events, no overt heart disease, and a negative tilt table test because the cardiac rhythm was stored in only 1 of 8 (13%) patients with recurrent syncope. Reasons for the low diagnostic yield of external loop recorders were infrequent syncopal events after the baseline evaluation, with rare events during the limited monitoring period in particular, and premature termination or unsuccessful recording in 21% of patients.

Tumor necrosis factor (TNF) activity in the circulation of several animal species was determined by a bioassay, using the murine cell line L929. In healthy adult cattle, horses, pigs and dogs, species specific differences of systemic TNF activity were visible. In cattle, TNF activity in the circulation increased during growing up from calf to adult animal. In cattle suffering from various diseases, unchanged, elevated, but also reduced systemic TNF activity have proved to possess clinical relevance. Low systemic TNF activity frequently occurs during lethal inflammatory diseases and may be an indicator of generalized monozyte paralysis.

Tumor-necrosis factor alpha (TNF) has been shown to have a pivotal role in mediating biological effects of endotoxins. Therefore, TNF measurement in the circulation is thought to be a useful diagnostic and prognostic instrument in patients exposed to endotoxin. However, the character of the TNF response depends on the mode of endotoxin exposure and is influenced by a variety of factors. Furthermore, to interpret the TNF state, the regulative effects of the two soluble TNF receptors have to be considered. Finally, the current techniques of TNF determination have to be improved and standardized to obtain reliable and comparable results and to establish TNF measurement as a valuable laboratory parameter.

The eventful beginnings of the concept of schizophrenia are not widely known in France. Most of the relevant texts are German in origin and French readers have access to very few of them. Yet the concept of schizophrenia has largely been adopted; everything that can contribute to the understanding of its elaboration is of importance. This elaboration did not take the form of a series of brilliant ideas from Kahlbaum, Kraepelin and Bleuler but rather the synthesis by these authors of the theories of their time - theories generally unknown to the French public. One such is the theory of intrapsychical incoordination, propounded by the prolific and interesting Viennese, Erwin Stransky, well known in German-speaking countries but not in France. He was, in 1903, the first to emphasize the importance of inaffectivity in dementia praecox. He devised an explanatory model of this disease, indicating its origin as the variable alteration of the relationship between what he termed thymo and noopsyche. Stransky was the first to speak of intrapsychical ataxy, his model offers an explanation for spectacular remissions from dementia praecox and for pseudo-lucidity. Intrapsychical ataxy, according to the model, is of diagnostic value, allowing a distinction to be made between the paralogies and "wordsalads" of hysterics (only thymopsychic) and those of dementia praecox (only noopsychic).(ABSTRACT TRUNCATED AT 250 WORDS)

Because of the intensive efforts required and the dissatisfactory sensitivity achieved with the traditional serological diagnostic techniques for Avian Encephalomyelitis, an ELISA was developed and tested to show the presence of antibodies in chicken serum. Using a multi-phase antigen preparation and optimizing the reagents and serum dilutions, a method was developed which shows considerable advantages in sensitivity, specificity, practicability and costs compared with the Embryo Serum Neutralization Test.

In experiments adapted to natural conditions it was established that--a conjunctival infection with about 100 RHD-virus particles was successful--in a milieu without flies transmission over a distance of only 50 cm did not take place--iridescent flies (Phormia spp.) seven hours after contamination with RHD-virus material from died rabbits transmitted RHD to susceptible rabbits in an isolated cage. It ist supposed that transmission in this way will be an epizootiological important one for spreading in narrow distances.

Further observations concerning the previously described RiV-particles are reported. They were isolated from a diploid cell line of bovine origin, embryonal duck fibroblasts and BHK-21 cells. A protective effect against foot-and-mouth-disease virus in guinea pigs could be observed following inoculation with the RiV-preparation of bovine origin. All 3 preparations isolated from the 3 cell lines showed immunologic cross reactions.

In a retrospective analysis, we evaluated our results with endoscopic dilation of enterostomy stenoses that complicated gastric procedures performed for the treatment of morbid obesity. Of 541 patients who underwent a gastric procedure for treatment of morbid obesity, we found 19 patients in whom endoscopic dilations of stenoses had been attempted. We also include three patients who had surgery elsewhere but who underwent dilations at our institution. Fourteen had stenoses complicating gastric bypass with Roux-en-Y anastomoses, and eight had stenoses complicating a gastroplasty (gastrogastrostomy). Two different types of dilation were attempted during the interval reviewed--Fogarty balloon dilations and Grüntzig balloon dilations. None of the eight patients with gastroplasties benefited from the attempted dilation, but 10 of the 14 patients with stenoses complicating gastric bypasses have done well. We found no significant difference between Fogarty and Grüntzig balloon dilations. We conclude that balloon dilation is an effective means of treating stenosis that complicates gastric bypass performed with Roux-en-Y anastomoses in cases of morbid obesity.