Publications

Adult, symptomatic Chiari malformation Type I (CMI) is a painful, often debilitating, neurological condition which is defined by the herniation, or extension, of the cerebellar tonsils below the skull. Research has shown that Chiari patients on average exhibit a number of anatomical variations, or morphometric differences, from healthy controls in the cranio-vertebral region; however the potential contribution of these differences to CMI's pathophysiology is not clear. This case-control study looked at nine representative morphometric measures (MM) in 432 adult, female CMI subjects and 148 adult, female controls. Each measure was dichotomized at three increasing distances from the control mean to represent exposures in an odds ratio analysis with CMI as the outcome. In addition, logistic regression modeling was used to determine the overall predictive ability of the MMs. Finally, disease severity was compared across three CMI subgroups with varying degrees of morphometric severity. We found that a reduced fastigium height demonstrated the largest increase in both crude and adjusted odds ratios at every level with an exposure-response pattern. Logistic regression correctly identified 87% of the CMI subjects as CMI based on the MMs. On average, CMI subjects had more than 3 MMs that were at least one standard deviation from the control mean, but there was no association between morphological and disease severity. These results suggest that further studies into anatomical variations such as fastigium height in CMI patients are warranted.

Delta lactones are fatty acid-derived aroma compounds that hold tremendous commercial value. As consumer demand for natural flavours continues to rise, the bioproduction of δ-lactones, including δ-decalactone and δ-dodecalactone, is attracting substantial interest. Our study brings forth a novel approach to the bioproduction of δ-lactones from glucose, deviating from existing methods that primarily rely on the biotransformation of fatty acids. The high cost of fatty acid raw material constrains the commercial viability of this traditional approach. We engineered surface-lipid producing type I polyketide synthase (PKS) from Mycobacterium smegmatis by incorporating macrolactone thioesterase (TE) domain. Two out of three fusion constructs produced an appropriately engineered PKS-TE fusion protein that facilitated the synthesis of δ-lactones. When grown on glucose as the sole carbon source, recombinant E. coli expressing the engineered PKS-TE fusion protein successfully made δ-lactones ranging from C8-C18 acyl chains. Our research further highlights the potential of Mycobacterium smegmatis as a cell factory for producing fatty acid-based δ-lactones. By genetically designing and engineering Mycobacterium smegmatis to express PKS-TE fusion protein, we achieved bioproduction of various δ-lactones. Batch fermentation of the engineered E. coli strain fed with 2 % glucose produced 786 mg/L of δ-dodecalactone and 444 mg/L of δ-decalactone at 120 h, underscoring the efficacy of our approach. Thus, this study is the first to demonstrate a methodology for redirecting primary metabolic intermediates towards δ-lactone biosynthesis in engineered bacteria, enabling the use of inexpensive and renewable feedstocks.

Interventional oncology has gained a lot of traction as an attractive alternative treatment for various musculoskeletal tumours by offering minimally invasive image-guided therapies. In this domain, thermal ablation is increasingly being used malignant tumours, including bone metastatic disease. Thermal ablation therapies such as radiofrequency ablation, microwave ablation, cryoablation and high intensity focused ultrasound therapy achieve excellent local tumour control and pain palliation, whilst structural stability is ensured through the combination with bone augmentation techniques such as standard or reinforced osteoplasty. Many factors are affecting the results including the biology of the disease the treatment intent (curative or palliative) as well as the potential for complications, like thermal injury to surrounding tissues, highlight the need for meticulous procedural planning. This review highlights the pathophysiology, the current repertoire of thermal ablation techniques, clinical outcomes and the future directions for the treatment of metastatic bone disease.

PURPOSE: This study investigated the effect of bone metastasis on the biomechanical environment of human vertebrae in patients with metastatic spine disease through the metric of load-to-strength ratio (LSR). Specifically, we compared the patients' LSRs to age and sex-similar noncancer controls from the Framingham Heart Study.

METHODS: Derived from clinical CT data of 135 metastatic spine disease patients planned for radiotherapy and 246 normative controls from the Framingham Heart Study, individualized spinal musculoskeletal models and vertebral strength estimates were used to compute level-specific LSR under natural standing and three weight-holding conditions (standing + weight, flexion + weight, and lateral bending + weight).

RESULTS: Adjusted for age, BMI, and spinal region, osteosclerotic and mixed lesion vertebrae had higher strength than osteolytic and control vertebrae. The musculoskeletal models suggested breast, prostate, and male lung cancer patients had higher compressive vertebral loading, and female lung cancer patients had lower compressive vertebral loading than controls. Male patients had higher standardized LSRs in natural standing, while female patients had lower LSRs for all activities than controls. Independent of sex, vertebrae with osteosclerotic and mixed bone metastasis had lower LSRs than controls, while, for osteolytic bone lesions, males had higher and females lower LSRs than controls. Vertebrae with no observed lesion on CT had higher LSRs than controls in males and lower LSRs in females.

DISCUSSION: Our findings highlighted that primary cancer and lesion type differentially affected task-specific vertebral loading and strength, thus modifying the vertebral LSRs. Sex-mediated differences in LSRs between FHS controls and vertebrae with no observed metastatic lesions suggest that considering the latter as "normal" should be taken with care. Our initial assessment supports further examination of whether vertebral LSR measurements are associated with vertebral risk and, if so, what threshold values indicate risk.

LEVEL OF EVIDENCE: 3.

OBJECTIVE: This study aims to assess the diagnostic value of the coronary artery calcium score (CACS) to predict significant coronary artery stenosis (SCAS) in presolid organ transplant patients with a moderate and high risk of coronary artery disease.

METHODS: In this retrospective HIPAA-compliant study, all pre-liver/kidney transplant patients with intermediate or high risk of coronary artery disease who underwent cardiac CT angiogram (CCTA) and CACS between January 1, 2018 and December 31, 2022 were reviewed. CACS was assessed according to the Agatston score. SCAS was defined as ≥50% diameter stenosis on CCTA. The potential to predict SCAS was assessed by computing the area under the receiver curve (AUC), and the sensitivity and specificity of CACS in diagnosing SCAS were calculated at various CACS thresholds.

RESULTS: A total of 291 patients (81; 28% female) with a mean age of 57.7±9.9 years, were included. The median CACS was 772 (IQR: 320 to 1892) in patients with SCAS versus 23 (IQR: 0 to 187) in those without SCAS (P<0.01). CACS demonstrated efficacy in predicting SCAS, with an AUC of 0.88. In the subgroup analysis, mean CACS differed significantly between pre-liver and pre-kidney solid organ transplant patients, but the difference between AUC curves was not significant. With the use of traditional CACS thresholds, the sensitivity dropped below 95%, but with optimized thresholds of CACS ≤62 or ≥869 for 95% sensitivity and specificity, 63% of pretransplant patients could be attributed either to a low-risk or high-risk for SCAS, respectively.

CONCLUSIONS: Our study shows that CACS can accurately predict SCAS in a large proportion of pre-kidney and liver transplant patients with intermediate or high risk of coronary artery disease. CACS can be considered as a screening tool to identify patients with low likelihood of SCAS, who might not require CCTA, as well as those with a high likelihood in whom a proactive approach should be considered.

BACKGROUND: Preliminary work suggests that glymphatic transit is abnormal and dynamic in idiopathic intracranial hypertension (IIH), although its incomplete characterization across the disease course has led to debate as to its pathophysiologic relevance. We seek to clarify whether glymphatic transit varies across IIH's disease course, correlates with intracranial pressure, and might be measured radiographically to aid diagnosis.

METHODS: Diffusion tensor imaging along the perivascular space (ALPS) was used to measure perivascular diffusivity and generate indices of glymphatic transit (ALPS-indices). We studied healthy controls and participants with IIH cross-sectionally, the latter stratified into untreated, treated, or cured IIH. Participants with untreated IIH were substratified as "acute" if imaged <6 months from onset or "chronic" if imaged ≥6 months from onset.

RESULTS: Forty participants were studied. We identified a positive, nonlinear correlation between ALPS-indices and disease duration in patients with untreated IIH. ALPS-indices differed between participants with chronic, treated, and acute IIH, in descending order. Healthy controls exhibited lower ALPS-indices than participants with chronic IIH and higher ALPS-indices than participants with acute IIH. ALPS-indices correlated positively with lumbar puncture opening pressures in participants with chronic IIH. Receiver-operating-characteristic curves demonstrated high areas-under-the curve in distinguishing between participants with untreated IIH and controls.

CONCLUSIONS: These data support the hypothesis that changes in glymphatic transit are likely a result rather than a cause of IIH, that radiographic indices of glymphatic transit may be leveraged diagnostically, and that ALPS-indices measuring perivascular diffusivity are likely a physiologically valid reflection of glymphatic transit in humans.

BACKGROUND: Information derived from lumbar puncture (LP) remains fundamental in the diagnosis of idiopathic intracranial hypertension (IIH). However, almost all patients with IIH are obese, rendering LPs technically difficult. The number of attempts required to achieve success and the likelihood of post-LP headache due to cerebrospinal fluid (CSF) leak has not been well characterized in this specific patient population or by LP modality.

METHODS: We conducted a retrospective chart review of IIH patients seen at a single neuro-ophthalmology clinic who underwent LP, either guided by conventional anatomic landmarks or via fluoroscopy. Chi-squared analysis was performed to assess differences in the likelihood of post-LP CSF leak by LP method. Unpaired t-tests were performed to assess between differences in the number of attempts required, BMI, and opening pressure.

RESULTS: 49 patients underwent 74 LPs. 31 (42%) were performed at the bedside, while 43 (58%) were performed fluoroscopically. Incidence of post-LP CSF leak was 14% in patients who underwent fluoroscopically-guided LPs and 45% in patients receiving bedside LPs (p-value = .0029). 8 bedside LPs (26%) required multiple attempts to complete, while only 1 fluoroscopically guided procedure required more than 1 attempt (2%).

CONCLUSION: Fluoroscopically-guided LPs required fewer attempts and were less likely to be complicated by CSF leak compared to bedside LPs. Body mass index and opening pressure were not associated with the risk of a post-LP CSF leak. The information derived from this study may help to avoid excess time, cost, and morbidity in the evaluation of patients with suspected IIH.

BACKGROUND: Motor symptoms of Parkinson’s disease (PD) primarily result from the degeneration of nigrostriatal dopaminergic neurons (DANs), particularly the Aldehyde Dehydrogenase 1A1-positive (ALDH1A1⁺) subpopulation. Pitx3-deficient mice exhibit selective developmental loss of ALDH1A1⁺ DANs but paradoxically display hyperlocomotion, suggesting compensatory changes in striatal circuitry. The dorsal striatum contains four main types of spiny projection neurons (SPNs): patch (or striosome) and matrix subtypes of both direct-pathway (dSPNs) and indirect-pathway (iSPNs). Activation of patch dSPNs suppresses locomotion by inhibiting ALDH1A1⁺ DANs.

METHODS: We combined RNAscope in situ hybridization with SPN subtype-specific reporter mice to quantify patch and total dSPNs and iSPNs in Pitx3-deficient and control mice. Three patch SPN reporter lines (Kremen12A − Cre, Nr4a1-GFP, and PdynIRES−Cre) were used to map projections. Optogenetic stimulation was performed in freely moving mice to assess the behavioral effects of activating patch dSPNs and iSPNs.

RESULTS: Pitx3-deficient mice showed no change in the overall dSPN: iSPN ratio but exhibited a marked shift in the patch dSPN: patch iSPN ratio, which decreased from 1.7 in control mice to 0.7 in the Pitx3-deficient group. Accordingly, patch dSPN projections to the substantia nigra pars reticulata (SNr) were reduced, whereas patch iSPN projections to the globus pallidus externus (GPe) were enhanced. Notably, while optogenetic stimulation of patch dSPNs and iSPNs suppressed locomotion in control mice, the same stimulation promoted locomotion in Pitx3-deficient mice.

CONCLUSIONS: Our findings reveal a selective reorganization of patch SPNs in response to developmental loss of ALDH1A1⁺ DANs, characterized by reduced patch dSPN and enhanced patch iSPN influence. This shift may underlie the paradoxical hyperlocomotion observed in Pitx3-deficient mice and provides insight into circuit-level adaptations with potential therapeutic relevance for PD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00920-2.