Reversal of Tetracycline Resistance in Escherichia coli by Noncytotoxic bis(Tryptophan)s.

Nine bis(tryptophan) derivatives (BTs) and two control compounds were synthesized and tested for antimicrobial activity against two Escherichia coli strains and a Staphylococcus aureus strain. The effects of linker type, shape, and conformational rigidity were manifested in dramatic differences in altering tetracycline potency when coadministered with that antibiotic. A reversal of resistance was observed for an E. coli strain having a TetA efflux pump. Survival of mammalian cells was assayed with good result.

Antibiotic Potency against E.†coli Is Enhanced by Channel-Forming Alkyl Lariat Ethers.

Several N,N'-bis(n-alkyl-4,13-diaza[18]crown-6) lariat ethers were found to significantly enhance the potency of rifampicin and tetracycline, but not erythromycin and kanamycin, against the non-pathogenic DH5α and K-12 strains of Escherichia coli when administered at levels below their minimum inhibitory concentrations (MICs). The enhancements in antibiotic potency observed for the lariat ethers ranged from three- to 20-fold, depending on the strain of E. coli, the antibiotic, and the lengths of the alkyl chains attached at the macroring nitrogen atoms. The dialkyl lariat ethers, previously thought to only be cation carriers, formed well-behaved, ion-conducting pores in soybean asolectin membranes, as judged by planar bilayer conductance measurements. The ability of lariat ethers to form stable pores, which appeared to be aggregated, depended in part on alkyl chain length and in part on the composition of the bilayer membrane in which they were studied.

Hydraphiles enhance antimicrobial potency against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis.

Hydraphiles are synthetic amphiphiles that form ion-conducting pores in liposomal membranes. These pores exhibit open-close behavior when studied by planar bilayer conductance techniques. In previous work, we showed that when co-administered with various antibiotics to the DH5α strain of Escherichia coli, they enhanced the drug's potency. We report here potency enhancements at low concentrations of hydraphiles for the structurally and mechanistically unrelated antibiotics erythromycin, kanamycin, rifampicin, and tetracycline against Gram negative E. coli (DH5α and K-12) and Pseudomonas aeruginosa, as well as Gram positive Bacillus subtilis. Earlier work suggested that potency increases correlated to ion transport function. The data presented here comport with the function of hydraphiles to enhance membrane permeability in addition to, or instead of, their known function as ion conductors.

Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers.

Lariat ethers are macrocyclic polyethers-crown ethers-to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter's potency is often strongly enhanced. Potency enhancements and resistance reversals have been documented in vitro for a range of Gram-negative and Gram-positive bacteria with a variety of antimicrobials. Strains of E. coli and Staphylococcus aureus having resistance to a range of drugs have been studied and the potency enhancements (checkerboards) are reported here. Drugs included in the present study are ampicillin, cefepime, chlortetracycline, ciprofloxacin, doxycycline, kanamycin, minocycline, norfloxacin, oxycycline, penicillin G, and tetracycline. Enhancements of norfloxacin potency against S. aureus 1199B of up to 128-fold were observed. The properties of these lariat ethers have been studied to determine solubility, their membrane penetration, cytotoxicity and mammalian cell survival, and their effect on bacterial efflux pumps. It is shown that in some cases, the lariat ethers have complex antimicrobials with considerable selectivity. Based on these observations, including 1:1 complexation between lariat ethers and antimicrobials and the cytotoxicity of the MeI salts showing a separation index of 32-fold, they hold significant potential for further development.

Anion complexation and transport by isophthalamide and dipicolinamide derivatives: DNA plasmid transformation in E. coli.

Tris-arenes based on either isophthalic acid or 2,6-dipicolinic acid have been known for more than a decade to bind anions. Recent studies have also demonstrated their ability to transport various ions through membranes. In this report, we demonstrate two important properties of these simple diamides. First, they transport plasmid DNA into Escherichia coli about 2-fold over controls, where the ampicillin resistance gene is expressed in the bacteria. These studies were done with plasmid DNA (~2.6 kilobase (kb)) in JM109 E. coli cells. Second, known methods do not typically transport large plasmids (>15 kb). We demonstrate here that transformation of large pVIB plasmids (i.e., >20 kb) were enhanced over water controls by ~10-fold. These results are in striking contrast to the normal decrease in transformation with increasing plasmid size.

Posterior-only approach for the treatment of symptomatic central thoracic disc herniation regardless of calcification: A consecutive case series of 30 cases over five years.

PURPOSE: To report the safety and efficacy of posterolateral approach for thoracic disc herniation (TDH) via a consecutive clinical case series of 30 central thoracic disc herniations that were all operated through a posterolateral approach. METHODS: A retrospective review was conducted of all patients with symptomatic TDH who underwent surgical intervention from 2016 to 2021. A total of 23 patients comprising 30 central TDH were included in the study. Age, gender, location of the lesion, preoperative and post-operative Frankel and Nurick scores, surgical approach and instrumented vertebrae, and length of stay were recorded. FINDINGS: 23 patients with an average age of 62 were included in the study. 30 of the 32 symptomatic TDH were centrally located. 8/32 TDH were calcified while 24/32 TDH were non-calcified. Unilateral and bilateral transpedicular approach was used in the treatment of 12/32 and 10/32 disc herniations respectively. A transfacet-pedicle sparing approach was used in 10/32 disc herniations. 19/23 (82.6%) of the patients had improvement in Nurick score while 12/23 (52.2%) patients had improvement in their Frankel scores. The average length of stay was 4.5 days. No major complications were encountered. All patients underwent a short-segment instrumented construct with no need for revision surgery for thoracic disc herniation, worsening myelopathy, or instrumentation failure. CONCLUSIONS: 83% of the patients who underwent a transfacet or transpedicular decompression for the treatment of symptomatic TDH had improvement in their myelopathy with no neurological deterioration in any of the patients. Given the familiarity and low morbidity associated with a transfacet or transpedicular approach, posterolateral-based approaches remains an excellent alternative for surgical management of majority of the patients with thoracic disc herniations.

Presentation and management of nervous system cavernous malformations in children: A systematic review and case report.

Cerebral cavernous malformations (CMs) are slow-flow vascular lesions that affect up to 0.5% of the pediatric population. These lesions are at risk for hemorrhage, causing seizures, and leading to neurological deficits. Here, we conduct a literature review and then present a report of a supratentorial CM in a 2-year-old patient with no significant past medical history who presented at our institution with 1 month of eye twitching. We performed a literature search of five databases of all articles published before 2020. Our inclusion criteria included cohort and case series of children with mean age under 12 years. Our search yielded 497 unique articles, of which 16 met our inclusion criteria. In our pooled literature analysis, a total of 558 children were included, 8.3% of which had a positive family history and 15.9% had multiple CMs. About 46.1% of the children had seizures, and 88.4% of those who underwent surgery had a total resection. About 85.1% of those with epilepsy were Engel Class 1 postsurgery. Over a mean follow-up of 4.1 years, 3.4% of patients had additional neurological deficits, including paresis and speech deficits. Our analysis of published literature shows surgical intervention should be considered first-line therapy for patients who are symptomatic from CM, present with seizure, and have surgically accessible lesions. Additional work is needed on outcomes and long-term effects of minimally invasive treatments, including radiosurgery and laser ablation, in pediatric populations.

Assessment of a host-guest interaction in a bilayer membrane model.

Supramolecular interactions are well recognized and many of them have been extensively studied in chemistry. The formation of supramolecular complexes that rely on weak force interactions are less well studied in bilayer membranes. Herein, a supported bilayer membrane is used to probe the penetration of a complex between tetracycline and a macrocyclic polyether. In a number of bacterial systems, the presence of the macrocycle has been found to significantly enhance the potency of the antimicrobial in vitro. The crown·tetracycline complex has been characterized in solution, neutron reflectometry has probed complex penetration, and the phenomena have been modeled by computational methods.

Cervical schwannoma with acute worsening and intratumoral hemorrhage.

BACKGROUND: Primary spinal tumors are rare and include schwannomas. In the cervical region, these lesions can cause pain, radiculopathy, and/or myelopathy. CASE DESCRIPTION: A 53-year-old male presented with 9 months of chronic neck pain and left upper extremity radiculopathy/myelopathy. The MRI revealed an intradural extramedullary C6-C7 left-sided mass with foraminal extension. Following a C5-C7 laminectomy with C5-T2 instrumented fusion, the diagnosis of schwannoma with evidence of recent hemorrhage was confirmed by biopsy. Three weeks postoperatively, the patient was pain free, no longer taking opioids, and neurologically intact. Although the MRI 6 months later showed no tumor, the MRI 15 months later documented a recurrent enhancing C6-C7 lesion. The patient elected to be treated with external beam radiotherapy and remained asymptomatic. CONCLUSION: A 53-year-old underwent resection of a cervical C6-C7 schwannoma with intratumoral hemorrhage. Fifteen months following C5-C7 laminectomy with C5-T2 fusion, the tumor recurred and required external beam radiation therapy.

Management of giant prolactinoma causing craniocervical instability: illustrative case.

BACKGROUND: Giant prolactinomas (>4 cm) are a rare entity, constituting less than 1% of all pituitary tumors. Diagnosis can usually be achieved through endocrinological analysis, but biopsy may be considered when trying to differentiate between invasive nonfunctioning pituitary adenomas and primary clival tumors such as chordomas. OBSERVATIONS: The authors presented a rare case of a giant prolactinoma causing significant clival and occipital condyle erosion, which led to craniocervical instability. They provided a review of the multimodal management. Management involved medical therapy with dopamine agonists, and surgery was reserved for acute neural compression or dopamine agonist resistance, with the caveat that surgery was extremely unlikely to lead to normalization of serum prolactin in dopamine agonist-resistant tumors. LESSONS: Adjunctive surgical therapy may be necessary in cases of skull base erosion, particularly when erosion or pathological fractures involve the occipital condyles. Modern posterior occipital-cervical fusion techniques have high rates of arthrodesis and can lead to symptomatic improvement. This procedure should be considered early in the multimodal approach to giant prolactinomas because of the often dramatic response to medical therapy and potential for further craniocervical instability.

Bis(Tryptophan) Amphiphiles Form Ion Conducting Pores and Enhance Antimicrobial Activity against Resistant Bacteria.

The compounds referred to as bis(tryptophan)s (BTs) have shown activity as antimicrobials. The hypothesis that the activity of these novel amphiphiles results from insertion in bilayer membranes and transport of cations is supported by planar bilayer voltage-clamp studies reported herein. In addition, fluorescence studies of propidium iodide penetration of vital bacteria confirmed enhanced permeability. It was also found that BTs having either meta-phenylene or n-dodecylene linkers function as effective adjuvants to enhance the properties of FDA-approved antimicrobials against organisms such as S. aureus. In one example, a BT-mediated synergistic effect enhanced the potency of norfloxacin against S. aureus by 128-fold. In order to determine if related compounds in which tryptophan was replaced by other common amino acids (H2N-Aaa-linker-Aaa-NH2) we active, a family of analogs have been prepared, characterized, and tested as controls for both antimicrobial activity and as adjuvants for other antimicrobials against both Gram-negative and Gram-positive bacteria. The most active of the compounds surveyed remain the bis(tryptophan) derivatives.

Use of C7 Slope as a Surrogate Marker for T1 Slope: A Radiographic Study in Patients with and without Cervical Deformity.

BACKGROUND: T1 slope has emerged as an important radiographic parameter in the evaluation and surgical management of adult cervical spinal deformity. Given the high rates of nonvisualization of T1 slope on upright cervical radiographs, however, this study examined the evaluation of C7 slope as a potential surrogate marker. METHODS: This is a retrospective review in adult patients with and without cervical deformity to examine the correlation of C7 and T1 slopes on routine upright cervical radiographs. In secondary analysis, correlations of C7 and T1 slopes were made amongst various demographic variables, different surgical groups, and various measures of cervical alignment. Cervical deformity was defined as sagittal vertical axis >40 mm, coronal Cobb angle >10°, and sagittal Cobb >10° in kyphosis. RESULTS: C7 slope was visualized in 93% of patients as opposed to T1 slope in 68% of patients, leading to a final study population of 129 patients. Mean values of C7 and T1 slopes were 26.5° and 28.1°, respectively. Significant correlation was found in patients with and without cervical deformity (r = 0.9, P < 0.01). This correlation remained significant amongst demographics, surgical groups, and measures of cervical alignment. CONCLUSIONS: Results demonstrated that C7 and T1 were in direct correlation in a variety of different cohorts regardless of deformity status or prior fusion. This study indicates that C7 slope may be reliably used a surrogate marker especially when visualization of T1 slope is not possible.

Synthetic ionophores as non-resistant antibiotic adjuvants.

Antimicrobial resistance is a world-wide health care crisis. New antimicrobials must both exhibit potency and thwart the ability of bacteria to develop resistance to them. We report the use of synthetic ionophores as a new approach to developing non-resistant antimicrobials and adjuvants. Most studies involving amphiphilic antimicrobials have focused on either developing synthetic amphiphiles that show ion transport, or developing non-cytotoxic analogs of such peptidic amphiphiles as colistin. We have rationally designed, prepared, and evaluated crown ether-based synthetic ionophores ('hydraphiles') that show selective ion transport through bilayer membranes and are toxic to bacteria. We report here that hydraphiles exhibit a broad range of antimicrobial properties and that they function as adjuvants in concert with FDA-approved antibiotics against multi-drug resistant (MDR) bacteria. Studies described herein demonstrate that benzyl C14 hydraphile (BC14H) shows high efficacy as an antimicrobial. BC14H, at sub-MIC concentrations, forms aggregates of ∼200 nm that interact with the surface of bacteria. Surface-active BC14H then localizes in the bacterial membranes, which increases their permeability. As a result, antibiotic influx into the bacterial cytosol increases in the presence of BC n Hs. Efflux pump inhibition and accumulation of substrate was also observed, likely due to disruption of the cation gradient. As a result, BC14H recovers the activity of norfloxacin by 128-fold against resistant Staphylococcus aureus. BC14H shows extremely low resistance development and is less cytotoxic than colistin. Overall, synthetic ionophores represent a new scaffold for developing efficient and non-resistant antimicrobial-adjuvants.

Wrap-Around Appearance: Underrecognized Radiologic Feature of Spinal Lymphoma.

A 71-year-old man presented with neck and upper back pain to the emergency department. Magnetic resonance imaging of the thoracic demonstrated a T2 vertebral lesion with epidural spinal cord compression. Considering the degree of severe spinal cord compression and the absence of a pathologic diagnosis, an urgent separation surgery was planned. A frozen section of the tumor from the paraspinal mass during initial exposure confirmed the presence of lymphoma, and hence only a T2 laminectomy and decompression were performed. Final pathology was non-Hodgkin lymphoma. Careful evaluation of the magnetic resonance image shows the presence of circumferential epidural spinal cord compression along with involvement of the posterior elements in a characteristic "wrap-around" fashion. Recognition of this finding may steer the surgeon toward a differential of spinal lymphoma, and its clinical importance cannot be overemphasized.

Radiodensity of intraventricular hemorrhage associated with aneurysmal subarachnoid hemorrhage may be a negative predictor of outcome.

OBJECTIVE The presence, extent, and distribution of intraventricular hemorrhage (IVH) have been associated with negative outcomes in aneurysmal subarachnoid hemorrhage (SAH). Several qualitative scores (Fisher grade, LeRoux score, and Graeb score) have been established for evaluating SAH and IVH. However, no study has assessed the radiodensity within the ventricular system in aneurysmal SAH patients with IVH. Prior studies have suggested that hemorrhage with a higher radiodensity, as measured by CT Hounsfield units, can cause more irritation to brain parenchyma. Therefore, the authors set out to investigate the relationship between the overall radiodensity of the ventricular system in aneurysmal SAH patients with IVH and their clinical outcome scores. METHODS The authors reviewed the records of 101 patients who were admitted to their institution with aneurysmal SAH and IVH between January 2011 and July 2015. The following data were collected: age, sex, Glasgow Coma Scale (GCS) score, Hunt and Hess grade, extent of SAH (none, thin, or thick/localized), aneurysm location, and Glasgow Outcome Scale (GOS) score. To evaluate the ventricular radiodensity, the initial head CT scan was loaded into OsiriX MD. The ventricular system was manually selected as the region of interest (ROI) through all pertinent axial slices. After this, an averaged ventricular radiodensity was calculated from the ROI by the software. GOS scores were dichotomized as 1-3 and 4-5 subgroups for analysis. RESULTS On univariate analysis, younger age, higher GCS score, lower Hunt and Hess grade, and lower ventricular radiodensity significantly correlated with better GOS scores (all p < 0.05). Subsequent multivariate analysis yielded age (OR 0.936, 95% CI 0.895-0.979), GCS score (OR 3.422, 95% CI 1.9-6.164), and ventricular density (OR 0.937, 95% CI 0.878-0.999) as significant independent predictors (p < 0.05). A receiver operating characteristic curve yielded 12.7 HU (area under the curve 0.625, p = 0.032, sensitivity = 0.591, specificity = 0.596) as threshold between GOS scores of 1-3 and 4-5. CONCLUSIONS This study suggests that the ventricular radiodensity in aneurysmal SAH patients with IVH, along with GCS score and age, may serve as a predictor of clinical outcome.

Repeated recurrence of thoracic spine stenosis following decompression alone for ossification of the ligamentum flavum: case report.

Ossification of the ligamentum flavum (OLF) is a well-recognized but rare cause of thoracic myelopathy. Its subtle and variable clinical presentation often makes the diagnosis challenging. The treatment of symptomatic OLF requires surgical intervention, with the most common surgical procedure being a posterior decompression with or without instrumentation. Recurrence of ossification and stenosis after surgery is rare and usually occurs at the same intervertebral level. Multiple recurrences of ossification and stenosis are exceptionally rare. The authors report the case of OLF in a 60-year-old man who experienced recurrence of ossification and stenosis twice after posterior decompression surgeries alone. The patient was ultimately treated with revision decompression and instrumented fusion. The authors also present a pertinent review of the literature.

A Rare Extra-Axial Midline Tentorial Adult Medulloblastoma with Dural-Tail Sign Mimicking a Meningioma.

Medulloblastomas are categorized as the World Health Organization Grade IV neoplasms. Only 33 cases have been reported of extra-axial, mostly in the cerebellar pontine angle and lateral cerebellar hemisphere, medulloblastomas in the current literature. Our study showcases the first case of an extremely rare presentation of an extra-axial midline tentorial adult medulloblastoma with the dural-tail sign mimicking a meningioma. To achieve the best possible outcome, a high index of suspicion for medulloblastoma is critical especially in young patient with an atypical posterior fossa mass as treatment regimens drastically different between a medulloblastoma and a meningioma.

Safe Use of Tissue Plasminogen Activator in Conjunction with the Integra Camino Bolt for the Drainage of Chronic Subdural Hematoma.

Chronic subdural hematoma (CSDH) is a relatively common condition encountered in a neurosurgical practice. There have been increased efforts in creating different treatment regimens for CSDH to improve patients' outcomes, including the addition of tissue plasminogen activator (tPA) in drains to reduce recurrences. Here, we present the first case report of the safe use of tPA in conjunction with an Integra Camino bolt for maximized drainage of CSDH with a successful neurological recovery and the complete resolution of the hematoma.

Methotrexate-induced Leukoencephalopathy without Typical Restricted Diffusion on Diffusion-weighted Imaging and the Utility of Magnetic Resonance Spectroscopy to Support the Diagnosis.

Methotrexate (MTX) is a common antimetabolite agent that is widely used today in treating leukemia, lymphoma, and osteosarcoma. Its use has been associated with leukoencephalopathy causing seizures, paralysis, and even coma. To achieve the best possible outcome, it is important to be able to make a prompt diagnosis. Studies reported restricted diffusion on diffusion-weighted imaging (DWI) which is a reliable early sign of acute MTX-induced leukoencephalopathy. However, we report here the first case of MTX-induced leukoencephalopathy without typical restricted diffusion on DWI and the utility magnetic resonance spectroscopy to support this diagnosis in the difficult case such as the one being presented here.