Publications

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 (Kremen1 2A-Cre, Nr4a1-GFP, and Pdyn IRES-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:patchy 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.

BACKGROUND: RBC distribution width is a key variable in complete blood counts, associated with immature RBC release into circulation due to various processes, including systemic inflammation. RDW correlates with elevated acute inflammatory markers like ESR, CRP, and interleukin-6, and is a biomarker in conditions like kidney disease and multiple myelomas. It independently predicts disease severity in critically ill adults and is associated with morbidity, mortality and length of stay in pediatric intensive care unit, though its potential as an early biomarker for detecting pediatric patients with multiple organ dysfunction (MODS) remains unknown.

METHODS: The study retrospectively reviewed PICU patients admitted to Aga Khan University Hospital from September 2018 to December 2022, excluding those admitted for less than 48 h for elective procedures, received recent RBC transfusions, or were anemic. RDW > 14.0% was considered elevated. MODS, defined as dysfunction in two or more organs, was the primary outcome. Data included demographics, PRISM III scores, laboratory values (RDW, BUN, creatinine, CRP, etc.), and clinical outcomes. Patients were stratified into three RDW groups: <13.4%, 13.4-14.3%, and > 14.4%. Analysis focused on associations between RDW levels and MODS within the first 7 days of PICU admission.

RESULTS: The study included 680 patients. Higher RDW was associated with younger age and higher PRISM III scores, but not with sex. RDW Group III had longer hospital stays, higher mortality, and higher incidence of MODS, but not significant. Hemoglobin and MCHC levels were lower in Group III, whereas BUN and creatinine levels showed no significant differences across groups. The OR for MODS was highest for Group II.

CONCLUSIONS: This retrospective study evaluated the prognostic value of RDW in predicting length of stay, mortality, and early identification of MODS within seven days. Among 680 pediatric patients, higher RDW levels were associated with increased mortality, longer LOS, and higher rates of sepsis and MODS, though these findings lacked statistical significance. Elevated RDW was linked to inflammation and critical illness severity but did not correlate well with pediatric severity scores or MODS trends. Future multicenter studies are recommended to explore RDW's utility in predicting early organ dysfunction and critical illness outcomes.

The free fibula flap has transformed mandibular reconstruction, evolving from simply for bone defect reconstruction to including immediate dental rehabilitation and from a staged to a simultaneous procedure. This paper chronicles the progression from delayed implant placement to the modern-day single-stage "jaw in a day" (JIAD) procedure, enabled by advances in CAD/CAM (computer aided design/computer aided manufacturing) technology, virtual surgical planning, and digital prosthesis. Pioneering work contributing to fibula-jaw reconstruction and rehabilitation from Chang Gung Memorial Hospital is also highlighted. The anatomical study of the fibula osteoseptocutaneous flap makes its clinical application also possible when simultaneous skin/mucosal coverage is needed. The early and vast experience of secondary and primary dental implantation has allowed us to develop and advocate for the "jaw during admission" after several initial attempts at JIAD reconstruction. In this approach, the dental prosthesis is delayed to the day before discharge from the hospital after confirming the success of the transferred fibula. It not only avoids an unnecessary step in complicated fibula flap transfer procedures, but in case of failure, it also mitigates logistical and technical challenges of prosthesis conversion, while maintaining the benefits of immediate dental implant restoration. This review also examines current evidence surrounding implant success, complications like osteoradionecrosis, and outcomes in malignant versus benign cases.

Three uncommon rearranged pregnane steroids, namely, sclerogroids A-C (1-3), along with seven known related ones 4-10, have been isolated from the soft coral Scleronephthya gracillimum collected off Ximao Island. The photoreactions of four α,β-unsaturated ketosteroids (8, 11-13) have been successfully performed, leading to the generation of two novel carbon skeleton pregnane steroids with an unprecedented 5/3/6/6/5 pentacyclic ring scaffold, namely, sclerogranes A (8b) and B (11f), together with a series of rearranged steroids and oxidation products. The structures of the new compounds were elucidated by a combination of spectroscopic analyses, time dependent density functional theory (TDDFT)-electronic circular dichroism (ECD) calculations, and comparison of the NMR data with those of known analogues. Bioassays demonstrated that compounds 1-4 and 8a exhibit significant antibacterial activity against various strains of vancomycin-resistant enterococci, as well as other pathogenic bacteria in humans and fish with minimum inhibitory concentration (MIC) values ranging from 1.9 to 29.6 μg/mL. In addition, compound 11c showed antineoplastic activity against HT-29 with an IC50 value of 27.24 ± 2.87 μM, while compounds 8d and 11f exhibited anti-inflammatory activity by inhibiting the release of NO in RAW264.7 cells with IC50 values of 15.4 ± 0.53 and 7.56 ± 0.93 μM, respectively.

Lymphedema is a chronic, progressive condition characterized by the accumulation of protein-rich interstitial fluid due to impaired lymphatic transport. It significantly impairs quality of life and presents complex diagnostic and therapeutic challenges. Despite its prevalence, lymphedema remains underdiagnosed and undertreated, in part due to limited provider education and a lack of access to coordinated care. For this reason, a multidisciplinary approach to lymphedema management is crucial. Early diagnosis is critical and requires collaboration across primary care, oncology, vascular medicine, radiology, lymphatic therapy, and surgery. There are increasing imaging techniques available, but require unique skill sets to perform and interpret. Similarly, there are growing surgical treatment options, but conservative therapy remains the mainstay for most patients. A structured, collaborative model is essential for high-quality, patient-centered lymphedema care. Establishing multidisciplinary lymphedema centers can enhance outcomes, reduce delays, and promote innovation in treatment strategies.

Background/Objectives: This study aimed to assess the effectiveness of a combination therapy comprising eyelid hygiene, intense pulsed light (IPL), and meibomian gland expression in patients with meibomian gland dysfunction (MGD). Methods: This retrospective study included MGD patients who completed at least three sessions of combination therapy administered at 4-week intervals, with a minimum follow-up period of 6 months. Ocular surface parameters were evaluated at baseline and at 1, 3, and 6 months after treatment initiation. Based on the clinical response following the initial three sessions, patients were categorized into either the standard treatment group (3 sessions) or the extended treatment group, who received three additional sessions of the same combination therapy. Results: A total of 107 patients (77 females; 30 males) were enrolled. 74 patients received standard treatment, and 33 received extended treatment. In the standard group, significant improvements compared with baseline were observed in the Ocular Surface Disease Index score, non-invasive tear break-up time, corneal staining, lid margin plugging, telangiectasia, and the meibomian gland expressibility score. Conversely, in the extended group, only the meibomian gland expressibility score showed significant improvements at the 3-month follow-up. Conclusions: The standard combination therapy resulted in significant and durable improvements in approximately 70% of MGD patients, with effects persisting for at least 3 months post-treatment. These findings support the clinical utility of this multimodal approach and highlight the need for biomarkers to predict treatment response.

In this paper, we designed, built, characterized and demonstrated a cost-effective diffuse optical tomographic (DOT) system for imaging absorbing and fluorescent targets and fluorescence alteration induced by temperature change in a scattering medium. DOT based imaging in a scattering media (such as biological tissue) is highly desired because of its high sensitivity and non-invasive nature. Unfortunately, conventional methods require expensive devices, such as lasers, optical switches, scientific cameras or photon detectors and advanced electronic controlling systems and data acquisition tools. To lower the cost and provide a simple system that can be used by researchers, teachers, and students who have a limited budget, we investigated and tested a method that uses light-emitting diodes (LEDs), a mobile phone-based camera, and a low-cost microcontroller (an Uno R3 board) to achieve the goal with reasonable accuracy. This method includes a hardware system, a software system for hardware controlling, data acquisition and processing, and an imaging reconstruction algorithm. By combining these subsystems, we demonstrated the feasibility of 3-dimensional imaging of absorbing and fluorescence targets and temperature change-induced fluorescence in a scattering medium using a temperature-sensitive fluorophore.

PURPOSE: To evaluate whether left-sided transjugular intrahepatic portosystemic shunt (L-TIPS) placement offers an advantage over conventional right-sided transjugular intrahepatic portosystemic shunt (R-TIPS) in cirrhotic patients with a history of Grade 1 hepatic encephalopathy (HE), specifically in lowering the incidence and progression of HE.

MATERIALS AND METHODS: This institutional review board (IRB)-approved, single-center retrospective study analyzed 25 consecutive patients who underwent L-TIPS creation between January 2016 and March 2023 who had a history of Grade 1 HE. Using 1:2 matching for 5 variables (pre-transjugular intrahepatic portosystemic shunt HE grades, albumin levels, stent size, Model for End-stage Liver Disease [MELD] score, and age), 50 patients who received R-TIPS were selected for comparison of procedural and clinical outcomes.

RESULTS: Of the 75 patients, there were 25 in the L-TIPS group (age, 58.4 years [SD ± 6.8]; 72% male) and 50 in R-TIPS group (age, 58.8 years [SD ± 8.4]; 66% male; P = .828 for age; P = .600 for sex). Rates of HE stage escalation after transjugular intrahepatic portosystemic shunt placement were not significantly different between groups (48% L-TIPS vs 38% R-TIPS; P = .562). The rate of medically refractory HE was 4% in the L-TIPS group and 0% in the R-TIPS group. There was no significant difference in the number of adverse events between the 2 groups (P = .802).

CONCLUSIONS: L-TIPS demonstrates a similar safety profile and similar rates of HE as R-TIPS in patients with pre-existing Grade 1 HE.

Background: Adrenal incidentalomas are common findings at contrast-enhanced CT, yet their management remains controversial. Objective: The purpose of this study was to determine the prevalence of malignancy among incidental indeterminate adrenal nodules detected on contrast-enhanced CT in patients without known cancer. Methods: We performed a 12-institution retrospective cohort study of adult patients without known cancer who underwent contrast-enhanced CT of the abdomen from January 1, 2010, to April 2, 2016. Consecutive reports from 10,646 cases were reviewed. CT images were reviewed for 2603 cases with reports describing an adrenal nodule measuring 1 cm or larger. Malignancy or benignity was determined using the following reference standards: pathology, diagnostic imaging (attenuation on unenhanced CT < 10 HU or signal-intensity loss at chemical shift MRI), imaging stability for at least 1 year, or clinical follow-up of at least 5 years. Descriptive statistics were performed using the binomial exact method and chi-square test. Results: The final cohort included 1320 patients (813 women, 507 men; mean age, 63.1 ± 15.2 years) with 1506 adrenal nodules. Mean nodule size was 2.1 cm ± 0.7 cm (range, 1.0-10.7 cm; IQR, 1.6-2.5 cm). The prevalence of malignancy among all nodules, nodules measuring 1-2 cm, nodules measuring 2-4 cm, and nodules measuring more than 4 cm was 0.07% (1/1506; 95% CI, 0.0-0.37%), 0.0% (0/773; 95% CI, 0.0-0.39%), 0.14% (1/694; 95% CI, 0.0-0.80%), and 0.0% (0/39; 95% CI, 0.0-7.4%). respectively. The one malignant nodule was an adrenocortical carcinoma diagnosed 9 years after initial detection. A total of 940 nodules underwent unenhanced CT after the index CT; all were benign. Of these, 654 were less than 10 HU, 157 were 10-20 HU, and 129 were more than 20 HU. Conclusion: The prevalence of malignancy among incidental indeterminate adrenal nodules on contrast-enhanced CT in patients without known cancer was exceedingly low. Clinical Impact: Follow-up imaging is not warranted for small (1-2 cm) incidental indeterminate adrenal nodules detected on contrast-enhanced CT in patients without known cancer.