Case report: Rare skeletal manifestations in a child with primary hyperparathyroidism

Background: Primary hyperparathyroidism (PHPT) is uncommon among children with an incidence of 1:300,000. This diagnosis is often missed in children in contrast to adults where it is detected at a pre symptomatic stage due to routine blood investigations. Etiology of PHPT can be due to adenoma, hyperplasia or rarely carcinoma. Case presentation: A 12year old Sri Lankan girl presented with progressive difficulty in walking since 1year. On examination she had bilateral genu valgum. Skeletal survey revealed valgus deformity of knee joints, bilateral subluxation of upper femoral epiphysis(SUFE), epiphyseal displacement of bilateral humeri, rugger jersey spine and subperiosteal bone resorptions in lateral aspects of 2nd and 3rd middle phalanges. There were no radiological manifestations of rickets. Metabolic profile revealed hypercalcemia with hypophosphatemia. Intact parathyroid hormone levels were elevated at 790pg/ml. Vitamin D levels were deficient. She had low bone mineral density with Z score of -3.4. Vitamin D supplementation resulted in worsening of hypercalcemia without reduction in PTH levels. Tc 99 Sestamibi uptake scan showed abnormal tracer retention in left inferior pole of thyroid. A large parathyroid gland was removed with histology favoring parathyroid adenoma. Post operatively she developed hypocalcemia. Bilateral osteotomy was done for SUFE and further surgeries for correction of limb deformities planned. Conclusion: PHPT in children is usually diagnosed late when irreversible organ damage has occurred. Children can present with non specific symptoms involving gastrointestinal, musculoskeletal, renal and neurological systems. PHPT can cause disarray in bone and epiphysis in children during pubertal growth spurt. Genu valgum and SUFE are rare skeletal manifestations in PHPT and only 10 cases of genu valgum and 9 cases of SUFE have been reported up to now. So far no cases have been reported on epiphyseal displacement of humeri. Awareness regarding the occurrence of these rare skeletal manifestations especially during puberty is important for early diagnosis to prevent irreversible outcomes

Dopaminergic Modulation of Auditory Cortex-Dependent Memory Consolidation through mTOR

Previous studies in the auditory cortex of Mongolian gerbils on discrimination learning of the direction of frequency-modulated tones (FMs) revealed that long-term memory formation involves activation of the dopaminergic system, activity of the protein kinase mammalian target of rapamycin (mTOR), and protein synthesis. This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control. Here, we report that the D1/D5 dopamine receptor agonist SKF-38393 substantially improved gerbils’ FM discrimination learning when administered systemically or locally into the auditory cortex shortly before, shortly after, or 1 day before conditioning. Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls. The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect. By immunohistochemistry, D1 dopamine receptors were identified in the gerbil auditory cortex predominantly in the infragranular layers. Together, these findings suggest that in the gerbil auditory cortex dopaminergic inputs regulate mTOR-mediated, protein synthesis-dependent mechanisms, thus controlling for hours or days the consolidation of memory required for the discrimination of complex auditory stimuli

Toxoplasma gondii Actively Inhibits Neuronal Function in Chronically Infected Mice

Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii–infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca2+) imaging studies revealed that tachyzoites actively manipulated Ca2+ signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca2+ uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca2+ stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host

Species-Specific Diversity of a Fixed Motor Pattern: The Electric Organ Discharge of Gymnotus

Understanding fixed motor pattern diversity across related species provides a window for exploring the evolution of their underlying neural mechanisms. The electric organ discharges of weakly electric fishes offer several advantages as paradigmatic models for investigating how a neural decision is transformed into a spatiotemporal pattern of action. Here, we compared the far fields, the near fields and the electromotive force patterns generated by three species of the pulse generating New World gymnotiform genus Gymnotus. We found a common pattern in electromotive force, with the far field and near field diversity determined by variations in amplitude, duration, and the degree of synchronization of the different components of the electric organ discharges. While the rostral regions of the three species generate similar profiles of electromotive force and local fields, most of the species-specific differences are generated in the main body and tail regions of the fish. This causes that the waveform of the field is highly site dependant in all the studied species. These findings support a hypothesis of the relative separation of the electrolocation and communication carriers. The presence of early head negative waves in the rostral region, a species-dependent early positive wave at the caudal region, and the different relationship between the late negative peak and the main positive peak suggest three points of lability in the evolution of the electrogenic system: a) the variously timed neuronal inputs to different groups of electrocytes; b) the appearance of both rostrally and caudally innervated electrocytes, and c) changes in the responsiveness of the electrocyte membrane

History-Dependent Excitability as a Single-Cell Substrate of Transient Memory for Information Discrimination

Neurons react differently to incoming stimuli depending upon their previous history of stimulation. This property can be considered as a single-cell substrate for transient memory, or context-dependent information processing: depending upon the current context that the neuron “sees” through the subset of the network impinging on it in the immediate past, the same synaptic event can evoke a postsynaptic spike or just a subthreshold depolarization. We propose a formal definition of History-Dependent Excitability (HDE) as a measure of the propensity to firing in any moment in time, linking the subthreshold history-dependent dynamics with spike generation. This definition allows the quantitative assessment of the intrinsic memory for different single-neuron dynamics and input statistics. We illustrate the concept of HDE by considering two general dynamical mechanisms: the passive behavior of an Integrate and Fire (IF) neuron, and the inductive behavior of a Generalized Integrate and Fire (GIF) neuron with subthreshold damped oscillations. This framework allows us to characterize the sensitivity of different model neurons to the detailed temporal structure of incoming stimuli. While a neuron with intrinsic oscillations discriminates equally well between input trains with the same or different frequency, a passive neuron discriminates better between inputs with different frequencies. This suggests that passive neurons are better suited to rate-based computation, while neurons with subthreshold oscillations are advantageous in a temporal coding scheme. We also address the influence of intrinsic properties in single-cell processing as a function of input statistics, and show that intrinsic oscillations enhance discrimination sensitivity at high input rates. Finally, we discuss how the recognition of these cell-specific discrimination properties might further our understanding of neuronal network computations and their relationships to the distribution and functional connectivity of different neuronal types

Impact of BMI on patient outcome in acute myeloid leukaemia patients receiving intensive induction therapy: a real-world registry experience

Background Acute myeloid leukaemia (AML) is treated with intensive induction chemotherapy (IT) in medically fit patients. In general, obesity was identified as a risk factor for all-cause mortality, and there is an ongoing debate on its impact on outcome and optimal dosing strategy in obese AML patients. Methods We conducted a registry study screening 7632 patients and assessed the impact of obesity in 1677 equally IT treated, newly diagnosed AML patients on the outcome (OS, EFS, CR1), comorbidities, toxicities and used dosing strategies. Results Obese patients (BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, P  = 0.015) and CR1 rate (78.7% vs. 84.3%, P  = 0.015) without differences in median EFS (7.8 vs. 9.89 months, P  = 0.3) compared to non-obese patients (BMI < 30). The effect was predominantly observed in older (≥60 years) patients. Obesity was identified as an independent risk factor for death, and obese patients demonstrated higher rates of cardiovascular or metabolic comorbidities. No differences for OS, EFS, CR1 or treatment-related toxicities were observed by stratification according to used dosing strategy or dose reduction. Conclusions In conclusion, this study identifies obesity as an independent risk factor for worse OS in older AML patients undergoing curative IT most likely due to obesity-related comorbidities and not to dosing strategy

Activity patterns of cochlear ganglion neurones in the starling

1. Spontaneous activity and responses to simple tonal stimuli were studied in cochlear ganglion neurones of the starling. 2. Both regular and irregular spontaneous activity were recorded (Figs. I to 5). Non-auditory cells have their origin in the macula lagenae. Mean spontaneous rate for auditory cells (all irregularly spiking) was 45 spikes s-1. 3. In half the units having characteristic frequencies (CFs) <1.5 kHz, time-interval histograms (TIHs) of spontaneous activity showed regularly-spaced peaks or 'preferred' intervals. The spacing of the peak intervals was, on average, 15% greater than the CF-period interval of the respective units (Fig. 11). 4. In TIH of lower-frequency cells without preferred intervals, the modal interval was also on average about 15% longer than the CF-period interval (Fig. 11). Apparently, the resting oscillation frequency of these cells lies below their CF. 5. Tuning curves (TCs) of neurones to short tone bursts show no systematic asymmetry as in mammals. Below CF 1 kHz, the low-frequency flanks of the TCs are, on average, steeper than the high-frequency flanks. Above CF 1 kHz, the reverse is true (Fig. 15). 6. The cochlear ganglion and nerve are tonotopically organized. Low-frequency fibres arise apically in the papilla basilaris and are found near non-auditory (lagenar) fibres (Figs. 2 and 19). 7. Discharge rates to short tones were monotonically related to sound presure level (Fig. 20). Saturation rates often exceeded 300 spikes s- 1. 8. 'On-off' responses and primary suppression of spontaneous activity were observed (Figs. 22 and 23). 9. A direct comparison of spontaneous activity and tuning-curve symmetry (Fig. 15b) revealed that, apart from quantative differences, fundamental qualitative differences exist between starling and guinea-pig primary afferents