Faculty Bibliography

In addition to redefining essential tremor (ET), the 2018 consensus statement of the Movement Disorder Society on tremor coined a new term: essential tremor-plus (ET-plus). This term is uncertainly defined as tremor with the characteristics of ET, with additional neurological signs of uncertain clinical significance. If ET-plus had been defined on the basis of a difference in underlying pathology or an appreciable difference in prognosis, it would have a valid, scientific rationale, as does the term Parkinson-plus. However, there is no such evidence, so the basis for the term is questionable. In fact, ET-plus might only represent a state condition (ie, patients with ET might develop these additional clinical features when the disease is at a more advanced stage). We caution against coining new terms that are not supported by a firm scientific basis and encourage research into the creation of essential tremor subsets that are defined with respect to differences in underlying causes or pathophysiology.

The production of pore-forming toxins that disrupt the plasma membrane of host cells is a common virulence strategy for bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA)^1-3. It is unclear, however, whether host species possess innate immune mechanisms that can neutralize pore-forming toxins during infection. We previously showed that the autophagy protein ATG16L1 is necessary for protection against MRSA strains encoding α-toxin⁴-a pore-forming toxin that binds the metalloprotease ADAM10 on the surface of a broad range of target cells and tissues^2,5,6. Autophagy typically involves the targeting of cytosolic material to the lysosome for degradation. Here we demonstrate that ATG16L1 and other ATG proteins mediate protection against α-toxin through the release of ADAM10 on exosomes-extracellular vesicles of endosomal origin. Bacterial DNA and CpG DNA induce the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protect host cells in vitro by serving as scavengers that can bind multiple toxins, and improve the survival of mice infected with MRSA in vivo. These findings indicate that ATG proteins mediate a previously unknown form of defence in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.

OBJECTIVE:To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ. METHODS:-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints. RESULTS:Trough serum concentration was above the "therapeutic" concentration of 2.0 μg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ. CONCLUSIONS:Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.

Over 115 000 people are waiting for life-saving organ transplants, of whom a small fraction will receive transplants and many others will die while waiting. Existing efforts to expand the number of available organs, including increasing the number of registered donors and procuring organs in uncontrolled environments, are crucial but unlikely to address the shortage in the near future and will not improve donor/recipient compatibility or organ quality. If successful, organ bioengineering can solve the shortage and improve functional outcomes. Studying manufactured organs in animal models has produced valuable data, but is not sufficient to understand viability in humans. Before risking manufactured organ experimentation in living humans, study of bioengineered organs in recently deceased humans would facilitate evaluation of the function of engineered tissues and the complex interactions between the host and the transplanted tissue. Although such studies do not pose risk to human subjects, they pose unique ethical challenges concerning the previous wishes of the deceased, rights of surviving family members, effective operation and fair distribution of medical services, and public transparency. This article investigates the ethical, legal and social considerations in performing engineered organ research on the recently deceased.

BACKGROUND:Endovascular therapy (EVT) for stroke improves outcomes but is time sensitive. OBJECTIVE:To compare times to treatment and outcomes between patients taken to the closest primary stroke center (PSC) with those triaged in the field to a more distant comprehensive stroke center (CSC). METHODS:During the study, a portion of our region allowed field triage of patients who met severity criteria to a more distant CSC than the closest PSC. The remaining patients were transported to the closest PSC. We compared times to treatment and clinical outcomes between those two groups. Additionally, we performed a matched-pairs analysis of patients from both groups on stroke severity and distance to CSC. RESULTS:Over 2 years, 232 patients met inclusion criteria and were closest from the field to a PSC; 144 were taken to the closest PSC and 88 to the more distant CSC. The median additional transport time to the CSC was 7 min. Times from scene departure to alteplase and arterial puncture were faster in the direct group (50 vs 62 min; 93 vs 152 min; p<0.001 for both). Among patients who were independent before the stroke, the OR for less disability in the direct group was 1.47 (95% CI 1.13 to 1.93, p=0.003), and 2.06 (95% CI 1.10 to 3.89, p=0.01) for the matched pairs. CONCLUSIONS:In a densely populated setting, for patients with stroke who are EVT candidates and closest to a PSC from the field, triage to a slightly more distant CSC is associated with faster time to EVT, no delay to alteplase, and less disability at 90 days.

Tuberculous Meningitis (TBM) is the most common form of central nervous system Tuberculosis (TB), accounting for 5-6% of extrapulmonary TB cases. Nowadays, TBM continues to be a major topic in public health because of its high prevalence worldwide. This retrospective study aimed to describe the clinical, laboratory, and imaging characteristics at admission; and in-hospital outcome of adult Mexican patients with TBM. We collected data from medical records of patients aged ≥18 years diagnosed with TBM according to the uniform case definition for clinical research who were treated at Tijuana General Hospital between January 2015 and March 2018 and compared them according to the subtype of diagnosis. We included 41 cases (26 males, median age 28 years, range 18-57 years), 13 (31.7%) patients were HIV positive, and 21 (51.2%) were illicit drug users. At admission, 7 (17.1%) patients were in stage I, 22 (53.6%) in stage II, and 12 (29.3%) in stage III. A definitive diagnosis was established in 23 (56.1%) patients, probable in 14 (34.1%), and possible in four (9.8%). Molecular testing was positive in 83% of the cases, yielding significantly higher positive results than other microbiological studies. There were eight (19.5%) deaths, without statistical difference between mortality and not having a definitive diagnosis (p = 0.109). We found that the baseline characteristics of our population were similar to those described by other authors worldwide. In this series, molecular testing showed to be very useful when used in the early stages, particularly in subjects with subacute onset of headache, fever, weight loss, and altered mental status.