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Survivors of acute lymphoblastic leukemia (ALL), the most common childhood cancer, are at increased risk for long-term cognitive problems, including executive function deficits. The chemotherapeutic agent methotrexate (MTX) is used to treat most ALL patients and is closely associated with cognitive deficits. To address how early life cancer chemotherapy leads to cognitive deficits, we developed a translationally relevant mouse model of leukemia survival that exposed mice to leukemic cells and chemotherapeutic drugs (vincristine and MTX, with leucovorin rescue) in early life. Male and female mice were tested several weeks later using novel object recognition (recognition memory) and 5-choice serial reaction time task (executive function). Gene expression of proinflammatory, white matter and synapse-associated molecules was assessed in the prefrontal cortex and small intestine both acutely after chemotherapy and chronically after cognitive testing. Early life cancer-chemotherapy exposure resulted in recognition memory and executive function deficits in adult male mice. Prefrontal cortex expression of the chemokine Ccl2 was increased acutely, while small intestine expression of the proinflammatory cytokine tumor necrosis factor-alpha was elevated both acutely (both sexes) and chronically (males only). Inflammation in the small intestine was correlated with prefrontal cortical proinflammatory and synaptic gene expression changes, as well as to executive function deficits. Collectively, these data indicate that the current protocol results in a robust mouse model in which to study cognitive deficits in leukemia survivors, and suggest that small intestine inflammation may represent a novel contributor to adverse CNS consequences of early life chemotherapy.

The standard of care for idiopathic normal pressure hydrocephalus (iNPH) is placement of a ventriculoperitoneal (VP) shunt. However, VP shunts require intracranial intervention and are associated with notable postoperative complications, with some groups reporting complication rates for VP shunts ranging from 17 to 33%, along with failure rates up to 17.7%. Lumboperitoneal (LP) shunts are an alternative for cerebrospinal fluid diversion that do not require intracranial surgery, thus providing utility in patients where intracranial surgery is not possible or preferred. Here we retrospectively reviewed our 25 patients with LP horizontal-vertical (LP-HV) shunts placement for initial treatment for iNPH from 2014 to 2019. All patients had preoperative gait dysfunction, 16 (64%) had urinary incontinence, and 21 (84%) exhibited cognitive insufficiency. Two weeks post-shunt placement, 23/25 (92%) patients demonstrated improvement in gait, 11/16 (68%) had improvement in incontinence, and 14/21 (66%) had improvement cognitive insufficiency. At six months or greater follow up 13/20 (65%) had improvement in gait, 7/15 (47%) showed improvement in incontinence, and 11/15 (73%) demonstrated improvement in cognitive function. Six patients (24%) required at least one revision of the LP shunt. Shunt malfunctions resulted from CSF leak in one patient, shunt catheter migration in two patients, peritoneal catheter pain in one patient, and clinical symptoms for overdrainage in two patients. Thus, we demonstrate that LP-HV shunt placement is safe and efficacious alternative to VP shunting for iNPH, resulting in notable symptomatic improvement and low risk of overdrainage, and may be considered for patients where cranial approaches should be avoided.

Background The incidence of primary hyperparathyroidism has increased 300% in the United States in the past 30 years, and secondary hyperparathyroidism is almost universal in patients with end-stage renal disease. We assessed the presence of environmental chemicals in human hyperplastic parathyroid tumors as possible contributing factors to this increase. Methods Cryopreserved hyperplastic parathyroid tumors and normal human parathyroids were analyzed by gas chromatography and liquid chromatography coupled to ultra-high-resolution mass spectrometry, bioinformatics, and biostatistics. Results Detected environmental chemicals included polychlorinated biphenyls, polybrominated diphenyl ethers, dichloro-diphenyl-trichloroethane derivatives, and other insecticides. A total of 99% had p,p’-dichlorodiphenyldichloroethylene. More than 50% contained other environmental chemicals, and many classified as endocrine disruptors. Polychlorinated biphenyl-28 and polychlorinated biphenyl-49 levels correlated positively with parathyroid tumor mass. Polybrominated diphenyl ether-47 concentrations in tumors were inversely correlated with patients’ serum calcium levels. Cellular metabolites in pathways of purine and pyrimidine synthesis and mitochondrial energy production were associated with tumor growth and with p,p’-dichlorodiphenyldichloroethylene in primary hyperparathyroidism tumors. In normal parathyroids, p,p'-dichlorodiphenyldichloroethylene , polychlorinated biphenyl-28, polychlorinated biphenyl-74, and polychlorinated biphenyl-153, but not p,p'-dichlorodiphenyldichloroethylene or polychlorinated biphenyl-49, were detected. Conclusion Environmental chemicals are present in human parathyroid tumors and warrant detailed epidemiologic and mechanistic studies to test for causal links to the growth of human parathyroid tumors.

The impact of parathyroidectomy on neuropsychiatric symptoms in primary hyperparathyroidism remains poorly defined. The validated scales Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 can be used to assess depression and anxiety, respectively. Our aim was to prospectively characterize the changes in neuropsychiatric symptoms after parathyroidectomy.Patients undergoing parathyroidectomy and thyroidectomy (control) from two institutions between 2014 and 2019 were prospectively administered a questionnaire assessing neuropsychiatric symptoms before and after surgery. Paired t tests compared preoperative with postoperative neuropsychiatric symptoms and t tests compared differences in neuropsychiatric symptoms between parathyroidectomy and thyroidectomy.A total of 244 patients underwent parathyroidectomy and 161 underwent thyroidectomy. We observed improvement in neuropsychiatric symptoms after parathyroidectomy (6.2 [5.0-7.4], P.01). Preoperatively, neuropsychiatric symptoms were more prevalent in patients undergoing parathyroidectomy when compared with thyroidectomy (11.2 ± 11.5 vs 7.5 ± 8.2, P.01); however, after surgery there was no difference between the two groups (5.1 ± 7.1 vs 5.4 ± 7.2, P = .59). Preoperatively, 27.5% and 18.0% of patients endorsed moderate to severe depression and anxiety, which fell to 8.2% and 5.3%, respectively, (P.01) after surgery.Patients undergoing parathyroidectomy showed significant improvement in neuropsychiatric symptoms after surgery. Neuropsychiatric symptoms are more prevalent in patients with primary hyperparathyroidism. Neuropsychiatric symptoms should be assessed in all patients with primary hyperparathyroidism and should be considered a relative indication for parathyroidectomy.

Background Achieving deep brain stimulation (DBS) dose equivalence is challenging, especially with pulse width tuning and directional contacts. Further, the precise effects of pulse width tuning are unknown, and recent reports of the effects of pulse width tuning on neural selectivity are at odds with classic biophysical studies. Methods We created multicompartment neuron models for two axon diameters and used finite element modeling to determine extracellular influence from standard and segmented electrodes. We analyzed axon activation profiles and calculated volumes of tissue activated. Results We find that long pulse widths focus the stimulation effect on small, nearby fibers, suppressing distant white matter tract activation (responsible for some DBS side effects) and improving battery utilization when equivalent activation is maintained for small axons. Directional leads enable similar benefits to a greater degree. Reexamining previous reports of short pulse stimulation reducing side effects, we explore a possible alternate explanation: non-dose equivalent stimulation may have resulted in reduced spread of neural activation. Finally, using internal capsule avoidance as an example in the context of subthalamic stimulation, we present a patient-specific model to show how long pulse widths could help increase the biophysical therapeutic window. Discussion We find agreement with classic studies and predict that long pulse widths may focus the stimulation effect on small, nearby fibers and improve power consumption. While future pre-clinical and clinical work is necessary regarding pulse width tuning, it is clear that future studies must ensure dose equivalence, noting that energy- and charge-equivalent amplitudes do not result in equivalent spread of neural activation when changing pulse width.

In humans, excessive gestational weight gain during pregnancy is associated with an increased risk for executive function deficits in the offspring. Our previous work has confirmed this finding in mice, as offspring from dams fed a 60% high fat (HF) diet during breeding, gestation, and lactation demonstrate impulsive-like behavior in the 5 choice serial reaction time task (5CSRTT). Because the prefrontal cortex (PFC), which plays a key role in executive function, undergoes substantial postnatal adolescent pruning and microglia are actively involved in synaptic refinement, we hypothesized that microglia may play a role in mediating changes in brain development after maternal HF diet, with a specific focus on microglial activity during adolescence. Therefore, we treated male and female offspring from HF or control diet (CD) dams with PLX3397-formulated diet (PLX) to ablate microglia during postnatal days 23-45. After PLX removal and microglial repopulation, adult mice underwent testing to evaluate executive function. Adolescent PLX treatment did increase the control male dropout rate in learning the basic FR1 task, but otherwise had a minimal effect on behavior in control offspring. In males, HF offspring learned faster and performed better on a simple operant task (fixed ratio 1) without an effect of PLX. However, in HF offspring this increase in FR1 responding was associated with more impulsive errors in the 5CSRTT while PLX eliminated this association and decreased impulsive errors specifically in HF offspring. This suggests that adolescent PLX treatment improves executive function and particularly impulsive behavior in adult male HF offspring, without an overall effect of perinatal diet. In females, maternal HF diet impaired reversal learning but PLX had no effect on performance. We then measured gene expression in adult male PFC, nucleus accumbens (NAC), and amygdala (AMG), examining targets related to synaptic function, reward, and inflammation. Maternal HF diet increased PFC synaptophysin and AMG psd95 expression. PFC synaptophysin expression was correlated with more impulsive errors in the 5CSRTT in the HF offspring only and PLX treatment eliminated this correlation. These data suggest that adolescent microglia may play a critical role in mediating executive function after perinatal high fat diet in males.

BackgroundPyramidal neurons throughout hippocampal CA3 are diverse in their dendritic morphology, and CA3 is not homogenous in its structure or function. Nonetheless, few structural studies have captured the precise 3D somatic position and the 3D dendritic morphology of CA3 pyramidal neurons simultaneously.New methodHere, we present a simple approach to reconstruct the apical dendritic morphology of CA3 pyramidal neurons using the transgenic fluorescentThy1-GFP-M line. The approach simultaneously tracks the dorsoventral, tangential, and radial positions of reconstructed neurons within the hippocampus. It is especially designed for use with transgenic fluorescent mouse lines, which are commonly used in genetic studies of neuronal morphology and development.ResultsWe demonstrate how topographic and morphological data are captured from transgenic fluorescent mouse CA3 pyramidal neurons.Comparison with existing methodsThere is no need to select and label CA3 pyramidal neurons with the transgenic fluorescentThy1-GFP-M line. By taking transverse (not coronal) serial sections, we preserve fine dorsoventral, tangential, and radial somatic positioning of 3D-reconstructed neurons. Because CA2 is well defined by PCP4 immunohistochemistry, we use that technique here to to increase precision in defining tangential position along CA3.ConclusionsWe developed a method for simultaneously collecting precise somatic positioning as well as 3D morphological data among transgenic fluorescent mouse hippocampal pyramidal neurons. This fluorescent method should be compatible with many other transgenic fluorescent reporter lines and immunohistochemical methods, facilitating the capture of topographic and morphological data from a wide variety of genetic experiments in mouse hippocampus.HighlightsSimultaneous capture of 3D location and pyramidal dendritic morphology in CA3Method utilizes replicable techniques and reagents available to most laboratoriesMethod is adaptable to other transgenic mouse lines and immunohistochemical studies

Sociodemographic factors may play a role in incidence and treatment of metastatic spinal tumors, as there is a delay in diagnosis and increased incidence of relevant primaries. There has yet to be a detailed analysis of the impact of sociodemographic factors on surgical outcomes for spinal metastases. We sought to examine the influence of socioeconomic factors on outcomes for patients with metastatic spinal tumors.Two hundred and sixty-three patients who underwent surgery for metastatic spinal tumors were identified. Sociodemographic characteristics were then collected and assigned to patients based on their ZIP code. The Chi-square test and the Mann-Whitney-U test were used for binary and continuous variables, respectively. Multivariate regression models were also used to control for age, smoking status, body mass index, and Charlson Comorbidity Index.Males had significantly lower rates of post-treatment complication compared to females (22.7 % vs 39.3 %, p = 0.0052), and those in high educational attainment ZIP codes had significantly shorter length of stay (LOS) compared to low educational attainment ZIP codes (9.3 days vs 12.2 days, p = 0.0058). Multivariate regression revealed that living in a high percentage white ZIP code and being male significantly decreased risk of post-treatment complication by 19 % (p = 0.042) and 14 % (p = 0.032), respectively. Living in a high educational attainment ZIP code decreased LOS by 3 days (p = 0.019).Males had significantly lower rates of post-treatment complication. Patients in high percentage white areas also had decreased rate of post-treatment complications. Patients living in areas with high educational attainment had shorter length of stay.