Childhood acute leukaemias are a heterogeneous group of malignant diseases. Based on cell origin, clinical manifestations, and molecular/chromosomal changes, we distinguish two main subtypes: acute myeloid leukaemia and acute lymphoblastic leukaemia. Acute lymphoblastic leukaemia (ALL) is the most frequent form of childhood leukaemia. Acute myeloid leukaemia (AML) is predominantly found in adults, being rarer in childhood. In the Czech Republic, the ALL is in childhood diagnosed approximately five times more often compared to AML. Despite the intensive research, aetiology of leukaemia has not been entirely clarified. So far, we only have knowledge of certain risk factors (ionising radiation, some chemicals and viruses) but in the vast majority of cases the aetiopathogenesis has not yet been made clear. Some of the answers may be provided by studies dealing with the presence of (pre)-leukaemic cells in a material archived prior to the clinical onset of the disease. Such are for example the so-called Guthrie cards, the dried blood samples collected immediately after birth and used in screening of the newborns for metabolic disorders. The better availability of material collected before the diagnosis of a secondary leukaemia (originally meant for the follow-up of the primary malignancy) might help us in better...

Cognitive impairments are a hallmark of many, if not all, psychiatric disorders. They include deficits in working memory, attention, and cognitive flexibility. The prefrontal cortex (PFC) is essential for these cognitive functions and has been implicated in psychiatric disorders, including schizophrenia. The PFC receives reciprocal inputs from the thalamus, and this thalamo-PFC circuitry supports cognition. In patients with schizophrenia, who have impaired cognitive functioning, thalamo-PFC connectivity is disrupted. This finding is also seen in adolescents at high risk for the disorder, even before diagnosis.While impaired cortical maturation has been postulated as a mechanism in the etiology of schizophrenia, the postnatal development of thalamo-PFC circuitry is still poorly understood. In sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. However, whether thalamic activity also shapes maturation of the PFC is unknown. Here, I will present evidence to support the hypothesis that adolescence represents a sensitive period, during which the PFC is susceptible to transient perturbations in thalamic input activity, resulting in persistent changes in circuitry. In Chapter 1, I present the existing literature on schizophrenia and our current understanding of its etiology. I then review the structure and connectivity of the PFC and its inputs, including the thalamus, in the context of schizophrenia and cognition. Next, I discuss the role of adolescence in the development of these structures and circuits. Finally, I introduce the concept of sensitive periods and outline the hypothesis that a similar process may occur in the context of the adolescent development of thalamo-PFC circuitry. To assess cognitive functioning in mouse models, I developed an operant-based working memory task. In Chapter 2, I describe this newly developed task and demonstrate that behavioral performance in the task is susceptible to PFC lesions. Thus, the task offers a new approach to studying PFC cognitive function. In Chapter 3, I discuss work done to address the hypothesis of adolescence as a sensitive period in the development of thalamo-PFC circuitry. I established an approach whereby I can transiently reduce activity in the thalamus during specific time windows. In this way, I compared the persistent effects of transient thalamic inhibition during adolescence and adulthood. I found that adolescent thalamic inhibition causes long-lasting deficits in cognitive behavioral performance, including the operant-based working memory task described in Chapter 2 and a cognitive flexibility task, decreased PFC cellular excitability, and reduced thalamo-PFC projection density. Meanwhile, adult thalamic inhibition has no persistent consequences on behavior or PFC excitability. Adolescent thalamic inhibition also results in disrupted PFC cellular cross-correlations and task outcome encoding during the cognitive flexibility task. Strikingly, exciting the thalamus in adulthood during the behavioral task rescues PFC cross-correlations, task outcome encoding, and the cognitive deficit. These data support the hypothesis that adolescence is a sensitive period in thalamo-PFC circuit maturation as adolescent thalamic inhibition has long-lasting consequences on PFC circuitry, while adult thalamic inhibition has no persistent effects. Moreover, these results highlight the role of the thalamus as a non-specific facilitator of PFC activity, expanding our understanding of this thalamic function to additional cognitive contexts. By supporting PFC network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders. Finally, in Chapter 4, I conclude with a general discussion. I highlight major take-aways from this work as well as next steps in our exploration of these crucial neural circuits. Together, the findings outlined here offer new promise for early diagnosis and treatment options for patients with cognitive impairments and psychiatric disorders.

The hippocampus is a brain structure known for its role in declarative memory- our ability to consciously recall facts and events. The hippocampus is a highly heterogeneous brain structure, and the small subregion CA2 has been shown to be necessary for the formation of social memories, the ability of an animal to recognize previously encountered conspecifics. Changes in excitatory/inhibitory balance have been observed in CA2 in humans with schizophrenia and in mouse models of schizophrenia, suggesting that these alterations may lead to some of the social dysfunction seen in schizophrenia. Although the hippocampal CA2 region has been implicated in social memory and neuropsychiatric disorders, little is known about how CA2 neural activity may encode social interactions and how this coding may be altered in disease. To see if and how CA2 codes for social interactions, I recorded extracellularly from CA2 pyramidal neurons as mice engage in a three-chamber social interaction task where the mice interact with the following task dimensions: space, novel objects, familiar social stimuli, novel social stimuli, and the passage of time. I found that whereas CA2 activity fails to provide a stable representation of space, unlike most other dorsal hippocampal subregions, it does code for contextual changes and for novel social stimuli. In Df(16)A+/- mice, which model the 22q11.2 microdeletion, a major schizophrenia risk factor, CA2 activity fails to encode context or social novelty, consistent with the deficit in social memory seen in these mice. In contrast, CA2 activity shows a surprising increase in spatial coding in Df(16)A+/- mice. These mice were previously shown to have a loss of inhibitory neurons within CA2, and a hyperpolarization of the CA2 pyramidal neuron resting potential. This hyperpolarization is likely due to upregulation of the outward rectifying TREK-1 K+ channel. I found that administration of a TREK-1 K+ channel antagonist rescued social memory and restored the normal CA2 coding properties in the mutants. These results demonstrate a crucial role for CA2 in the encoding of social stimuli and the expression of social memory, and suggest that dysfunction in CA2 may underlie deficits in social function seen in some forms of neuropsychiatric disease.

Tinnitus is defined as an auditory stimulus that is unrelated to external stimulation. There are many theories as to what causes tinnitus, therefore, there are many treatment options for tinnitus. This paper attempts to increase the audiologist's knowledge of the etiology, as well as, the most appropriate treatment for tinnitus. There are two types of tinnitus, objective and subjective. Subjective tinnitus is more common, although it is more difficult to treat than objective tinnitus. There are many theories as to what causes tinnitus. Several disorders that have tinnitus as a symptom, such as, Meniere's disease, acoustic neuroma, and dysfunction of serotonin levels, are discussed. Before treatment of tinnitus, the patient must undergo a medical and audiologic evaluation. Tests of tinnitus pitch, loudness, residual masking, and minimal masking are included. The implications of these tests on treatment are also discussed. There are many treatment options available for tinnitus, such as, electrical stimulation, medications, stress and psychological therapy, tinnitus maskers, and hearing aids. This paper focuses on mainly the treatments that are most feasible for an audiologist. In addition, included is an empirical study that was conducted to examine the effects of hearing aids and circuit type on tinnitus relief. To conclude, this paper will summarize the steps to follow in order to manage a patient that exhibits tinnitus. Although there are some treatments that seem to be more appropriate for an audiologist to utilize, (i.e., hearing aids, maskers, and Tinnitus Retraining Therapy, none have been proven to be effective in every patient. Research is still needed in this area.

No description available.

INTRODUCTION: Small intestinal bacterial overgrowth refers to the proliferation of abnormal numbers and types of microorganisms in the lumen of the proximal bowel. Bacterial overgrowth has been implicated as a possible factor in prolonging some episodes of infantile gastroenteritis. This thesis examines 2 different aspects of the duodenal flora of infants with gastroenteritis, and has therefore been divided into 2 separate studies. CARBOHYDRATE STUDY: Objective: To test the hypothesis that during a diarrhoeal episode the presence of malabsorbed carbohydrate in the duodenal lumen acts as a factor promoting bacterial proliferation. Patients and methods: Infants admitted to the rehydration ward with acute gastroenteritis were selected for study if they fulfilled various criteria in terms of age, nutritional status, previous diarrhoeal episodes and antibiotic administration. They were admitted to the research ward. Weights were measured and if they had severe diarrhoea (≥ 30g/kg) were included in the study. Twenty patients were entered into the study. On admission into the trial the first duodenal intubation was done to measure the duodenal flora quantitatively and qualitatively. Thereafter the patients were assigned on an alternate basis to one of 2 groups. One group (carbohydrate-containing group) received a soy-based infant formula containing carbohydrates (Isomil, Ross). The other group (carbohydrate-free group) received an identical milk but from which all carbohydrate had been omitted (Ross CHO-free). To these infants carbohydrate was given intravenously. Stool output was measured daily. After 3 days of the respective diets the duodenal flora was re-examined. Results: Longitudinal analysis of the duodenal flora of the carbohydrate-containing group showed a small decrease in the number of bacterial isolates and in their magnitude. The duodenal flora of the carbohydrate-free group was virtually unchanged. Comparing the duodenal bacteriology of the groups the only significant difference was that the number of isolates and the magnitude of Haemophilus was greater in the carbohydrate-free group- (p < 0.05). The diarrhoea resolved in 5 patients: 2 in the carbohydrate-containing and 3 in the carbohydrate-free group. Conclusions: The lack of difference in the response of the duodenal flora between the two groups studied suggests that the presence of carbohydrates in the lumen is not important in encouraging the growth of bacteria in that site. The possible causes for an increase in Haemophilus numbers in the carbohydrate-free group are discussed. BOWEL COCKTAIL STUDY: Objective: Small intestinal bacterial overgrowth has been proposed as a cause of progression of acute diarrhoeal episodes to persistence. The "bowel cocktail", a combination of oral gentamicin and cholestyramine, has been shown to be effective in terminating episodes of persistent diarrhoea. It has been postulated to work by eradicating small intestinal bacterial overgrowth, but its mode of action is not known. The objective of this study was to examine the changes in the duodenal flora associated with administration of the bowel cocktail in order to elucidate its possible mechanism or mechanisms of action. Patients and methods: The study group comprised 15 patients. Fourteen were infants from the carbohydrate study who had ongoing diarrhoea. The remaining infant (the "late entry") was selected from the rehydration ward. Severe diarrhoea, as defined by a stool output equal to or greater than 30g/kg/day, was a pre-requisite for entry into the study. The investigation involved 2 duodenal intubations for microbiological analysis of the duodenal fluid. After the first intubation (which was the second intubation for the 14 infants who had been in the carbohydrate study) the bowel cocktail was administered. This comprised a 3-day course of oral gentamicin and 5 days of oral cholestyramine. Forty-eight hours after the start of therapy the duodenal bacteriology was repeated. The patient management was the same as during the carbohydrate study and the feeding regimen of the infants was not altered. The study ended immediately after completion of the bowel cocktail course. Results: Administration of the bowel cocktail was associated with a decreased stool output in all patients. Bacteriological analysis of the duodenal flora after this treatment showed a statistically significant decrease in the total microbial count, the aerobic microbial fraction and the Enterobacteriaceal fraction. On analysis of the bacterial genera a significant decrease was noted in Neisseria, Haemophilus, and aerobic lactobacilli. Analysis of individual patients' duodenal fluid bacteriology in conjunction with the stool bacteriology results before administration of the bowel cocktail often provided an explanation as to the possible aetiology of the diarrhoea and its resolution by therapy. Conclusions: Small intestinal bacterial overgrowth, in the accepted sense of a luxuriant flora teeming with faecal organisms, did not appear to be a feature of the patients in this study. The total bacterial count was only slightly above the accepted upper limit of normal. Although the decrease in the number of Enterobacteriaceae could possibly be interpreted in the context of bacterial overgrowth, a study of the individual patients' duodenal flora shows that these microorganisms were more likely to be acting as specific enteric pathogens. It is concluded that small intestinal bacterial overgrowth, as currently defined, is not an important cause of persistent diarrhoea. The efficacy of the bowel cocktail is more likely to reside in its ability to eradicate specific enteric pathogens. The author ends by questioning the validity of the whole concept of small intestinal bacterial overgrowth.

No description available.

Schizophrenia is a disabling psychiatric and neurodevelopmental disorder that represents a tremendous public health burden. Despite the inroads made in the treatment of its symptoms, understanding its etiology and pathophysiology remains challenging due to the genetic heterogeneity of the disease and the corresponding complexity of the neural systems which it affects. In recent years, the development of next generation sequencing and substantial progress in the field of psychiatric genetics have revealed the important role of individually rare but collectively common heritable and de novo mutations (DNMs) in the complex genetic architecture of schizophrenia. Previously, we had identified SETD1A encoding a histone methyltransferase, as a high-risk gene for schizophrenia, which has been confirmed extensively through follow-up meta-analyses. This discovery emphasized the important role that neural gene regulation plays in the coordination of complex cognitive processes. However, it is unclear how to translate a ubiquitous molecular process such as chromatin modification into a mechanistic and disease-specific insight. Our previous comprehensive analysis of mutant mice carrying a loss of function (LoF) allele in the Setd1a orthologue uncovered the role of SETD1A in gene regulation, neuronal architecture, synaptic plasticity, neuronal ensemble activity and cognitive function and showed that neurocognitive deficits that derive from Setd1a deficiency can be reversed by pharmacological interventions during adulthood. Our previous ChIP-Seq analysis showed a striking overlap between SETD1A, MEF2, and LSD1 targets at enhancers in the prefrontal cortex (PFC). Since MEF2 is an activity dependent transcription factor, we hypothesized that SETD1A may also modulate activity-dependent gene expression in the brain. To elucidate the effects of Setd1a deficiency on activity-dependent transcription, we established an in vitro neuronal activity dependent gene (ADG) expression assay and identified genes modulated by neuronal activity using ChIP-Seq and RNA-Seq assays. We found a remarkable overlap of a dynamic pattern of activity-dependent recruitment of SETD1A, LSD1 and MEF2 to enhancers of ADGs. Our results showed Setd1a deficiency affects transcription in an activity-dependent manner and transcriptional alteration induced by Setd1a deficiency under neuronal activation can be attenuated by inhibition of LSD1 activity. In addition, we investigated how SETD1A modulates MEF2 transactivation activity by performing luciferase assays. Our results suggest that SETD1A represses MEF2 activity but the repression is unlikely to be mediated by lysine methylation. We also performed behavioral analyses of Setd1a+/- mice and found that the social behavior and social memory were impaired in female Setd1a+/- mice but remained intact in male Setd1a+/- mice. Ultimately, future work is underway to analyze the targets of SETD1A, which in turn could lead to the development of therapeutic strategies to reverse the progression of schizophrenia.

During the last ten years, several patients have presented to the Renal Unit of Groote Schuur Hospital with acute renal failure following the use of traditional (N'anga or Gqirha) medication. The history together with abnormal liver-function tests and renal failure was thought to be suggestive of a toxic aetiology. The specific toxin however remained unknown, until during the admission of one patient, a relative brought in the medication, analysis of which revealed a high concentration of potassium dichromate. Subsequently elevated levels of chromium were demonstrated by atomic absorption spectrometry in the blood and urine of this patient. Following this case there have been six further cases of acute renal failure resulting from use of dichromate containing traditional remedies. These remedies were obtained from a variety of sources including street-hawkers, herbal chemists, and traditional healers. Clinical and laboratory data relating to these seven patients will be presented.

AIMS OF STUDY: 1. To analyse the patients . who have been treated at Groote Schuur Hospital over the last seven years for Pseudotumor Cerebri. 2. To document the clinical features of this group of patients. 3. To determine the visual prognosis of this group. 4. To assess the forms of treatment that have been used in this group. 5. To review the literature with regard to: a) a comparison of the results of other studies with the present one. b) the pathophysiology of the condition. c) treatment of the syndrome. d) the visual prognosis of the syndrome.