Differential Effect of Light and Dark Period Sleep Fragmentation on Composition of Gut Microbiome and Inflammation in Mice.

Bi-directional interactions amongst the gut microbiota, immune system, and brain function are thought to be critical mediators of health and disease. The role sleep plays in mediating these interactions is not known. We assessed the effects of sleep fragmentation (SF) on the microbiota-gut-brain axis. Male C57BL/6NCrl mice (4 to 5 per cage, fed standard lab chow) experienced SF via mechanical stimulation at 2 min intervals during the light (SF) and dark (DD, dark disturbances) periods. Home cage (HC) controls were undisturbed. After 10 days, fecal samples were collected at light onset, midday, light offset, and midnight. Samples were also collected after 10 days without SF. Subsequently, the mice were randomized across groups and allowed 20 additional days of recovery followed by 10 days of SF or DD. To assess effects on the microbiota, 16S rRNA sequencing was used, and mesenteric lymph nodes (MLNs) and cortex and medial prefrontal cortex were analyzed using cytokine arrays. SF and DD produced significant alterations in the microbiota compared to HC, and DD had greater impact than SF on some organisms. SF produced marked suppression in MLNs of chemokines that regulate inflammation (CCL3, CCL4 and their receptor CCR5) and maintain the immune mucosal barrier (Cxcl13) at the same time that cortical cytokines (IL-33) indicated neuroinflammation. DD effects on immune responses were similar to HC. These data suggest that SF alters the microbiome and suppresses mucosal immunity at the same time that mediators of brain inflammation are upregulated. The translational implications for potential application to clinical care are compelling.

Comparison of central-line-associated bloodstream infections between central venous catheters lined by combined chlorhexidine and silver sulfadiazine versus silver ionotrophes alone: A before-after-before retrospective study.

A before-after-before direct comparison between catheters lined with chlorhexidine and silver sulfadiazine (CHSS) versus silver ionotrophes (SI) with a primary objective of comparison of rate of central-line-associated infection (CLABSI) in three 10-month windows. The CHSS catheters were associated with a lower rate of CLABSI.

Origin of Syrinx Fluid in Syringomyelia: A Physiological Study.

BACKGROUND: The origin of syrinx fluid is controversial. OBJECTIVE: To elucidate the mechanisms of syringomyelia associated with cerebrospinal fluid pathway obstruction and with intramedullary tumors, contrast transport from the spinal subarachnoid space (SAS) to syrinx was evaluated in syringomyelia patients. METHODS: We prospectively studied patients with syringomyelia: 22 with Chiari I malformation and 16 with SAS obstruction-related syringomyelia before and 1 wk after surgery, and 9 with tumor-related syringomyelia before surgery only. Computed tomography-myelography quantified dye transport into the syrinx before and 0.5, 2, 4, 6, 8, 10, and 22 h after contrast injection by measuring contrast density in Hounsfield units (HU). RESULTS: Before surgery, more contrast passed into the syrinx in Chiari I malformation-related syringomyelia and spinal obstruction-related syringomyelia than in tumor-related syringomyelia, as measured by (1) maximum syrinx HU, (2) area under the syrinx concentration-time curve (HU AUC), (3) ratio of syrinx HU to subarachnoid cerebrospinal fluid (CSF; SAS) HU, and (4) AUC syrinx/AUC SAS. More contrast (AUC) accumulated in the syrinx and subarachnoid space before than after surgery. CONCLUSION: Transparenchymal bulk flow of CSF from the subarachnoid space to syrinx occurs in Chiari I malformation-related syringomyelia and spinal obstruction-related syringomyelia. Before surgery, more subarachnoid contrast entered syringes associated with CSF pathway obstruction than with tumor, consistent with syrinx fluid originating from the subarachnoid space in Chiari I malformation and spinal obstruction-related syringomyelia and not from the subarachnoid space in tumor-related syringomyelia. Decompressive surgery opened subarachnoid CSF pathways and reduced contrast entry into syringes associated with CSF pathway obstruction.

Bowel preparation for colonoscopy: what is best and necessary for quality?

PURPOSE OF REVIEW: Colonoscopy is recognizably, the best colon cancer prevention test, provided the quality of the preparation is adequate for detection of precancerous polyps but also allowing for accurate identification of margins, thereby facilitating complete endoscopic resection. As there are many aspects effecting colon prep outcomes, it is timely to review new standards for optimizing outcomes, including product selection based on patient demographics. RECENT FINDINGS: New national guidelines have set a minimum quality threshold for adequacy and also defined a split day delivery for oral options as the "standard of care". Several new prep options have been recently released and these data are discussed. SUMMARY: Optimizing the quality of colon preps has major implications for clinical practice. Clinicians must recognize new targets for standard of care, providing the best approach for each individual patient, considering variable factors which may otherwise compromise success.

Variable response of CNS hemangioblastomas to Pazopanib in a single patient with von Hippel-Lindau disease: Case report.

Von Hippel-Lindau (VHL) disease is a multisystem genetic disease, the cardinal manifestations of which include central nervous system hemangioblastomas (CNS HB), renal cell carcinomas (RCC), and pheochromocytoma. Tumorigenesis in VHL of both RCC and CNS HB occurs secondary to downstream effects of a mutated or absent VHL protein. Treatment of RCCs with tyrosine kinase inhibitors (TKIs) such as Pazopanib is now first line therapy, but their effect on VHL-associated CNS HBs remains unknown. We report the use of Pazopanib in a patient with VHL disease for treatment of RCC who also harbored multiple CNS HBs. Following initiation of treatment, a large cervical and a lumbar spinal HB regressed in size while the remaining CNS HBs exhibited stable or progressive disease. These findings highlight the multiplicity of factors contributing to hemangioblastoma development, even among tumors with a common germline mutation, and the potential limitations of TKIs, but additionally this report supports the conservative management of asymptomatic VHL patients with spinal HBs whereby tumor response to TKI treatment may alleviate or postpone the need for surgery.

Central Nervous System Germinomas Express Programmed Death Ligand 1.

Immunomodulation and tumor-induced tolerance is one of the central mechanisms in the oncogenesis of malignant and benign neoplasms. While numerous pathways have been described, signaling through the programmed death receptor 1 (PD-1) on T lymphocytes, via activation through its ligand, programmed death ligand 1 (PD-L1) expressed on tumor cells is one of the central pathways involved in tumor-induced tolerance. While the neoplastic component of germinomas of the CNS is the germ cell, these tumors also exhibit an abundance of quiescent tumor-infiltrating lymphocytes. We therefore investigated whether PD-L1 expression may be responsible for germinoma-induced T cell anergy, and if these tumors may be susceptible to immunotherapy. Pathologic specimens obtained from 21 cases of CNS germinomas between 2000 and 2016 were analyzed for the presence of PD-L1 and PD-1 expression by immunohistochemistry. Nineteen of 21 germinomas (90%) harbored germ cell components that stained positively for PD-L1. Positive lymphocyte staining for PD-L1 was evident in 16 cases. PD-1 expression was largely confined to lymphocytes; PD-L1 therefore may contribute to lymphocyte quiescence observed in these tumors. These results raise the possibility that immune checkpoint inhibitors such as nivolumab may have a therapeutic role in future treatment of germinomas.

Resection of pituitary macroadenomas via the pseudocapsule along the posterior tumor margin: a cohort study and technical note.

OBJECTIVE Extracapsular resection of pituitary microadenomas improves remission rates, but the application of pseudocapsular techniques for macroadenomas has not been well described. In larger tumors, the extremely thin, compressed normal gland or its complete absence along the tumor's anterior surface limits the application of the traditional pseudocapsular technique that can be used for microadenomas. However, in the authors' experience, the interface between the pseudocapsule at the posterior margin of the adenoma and the compressed normal gland behind it is universally present, providing a surgical dissection plane. In mid-2010, the authors began using a new surgical technique to identify and use this interface for the resection of larger macroadenomas, a technique that can be used with the microscope or the endoscope. METHODS The authors performed a cohort study using prospectively collected preoperative imaging reports and operative details and retrospectively reviewed postoperative images and clinical follow-up of patients with a pituitary macroadenoma 20-40 mm in maximum diameter undergoing microscopic transsphenoidal resection. Since dissection of the tumor capsule only pertains to encapsulated tumor within the sella and not to tumor invading the cavernous sinus, assessment of tumor removal of noninvasive tumors emphasized the entire tumor, while that of invasive tumors emphasized the intrasellar component only. The incidence of residual tumor on postoperative imaging, new-onset endocrinopathy, and recovery of preoperative pituitary deficits was compared between patients who underwent surgery before (Group A) and after (Group B) implementation of the new technique. RESULTS There were 34 consecutive patients in Group A and 74 consecutive patients in Group B. Tumors in 18 (53%) Group A and 40 (54%) Group B patients had no evidence of cavernous sinus invasion on MRI. Use of the posterior pseudocapsule technique reduced the incidence of intrasellar residual tumor on postoperative MRI for tumors without cavernous sinus invasion (39% [Group A] vs 10%, p < 0.05) and in all tumors regardless of invasion (50% vs 18%, p < 0.005). The incidence of new endocrinopathy was less likely (25% vs 12%, p = 0.098) and the recovery of prior deficits more likely (13% vs 27%, p = 0.199) among patients treated using the pseudocapsule approach, although the differences are not statistically significant. CONCLUSIONS Use of the posterior pseudocapsule dissection plane can enhance the resection of pituitary macroadenomas.

Comparison of MRI techniques for detecting microadenomas in Cushing's disease.

OBJECTIVE Many centers use conventional and dynamic contrast-enhanced MRI (DMRI) sequences in patients with Cushing's disease. The authors assessed the utility of the 3D volumetric interpolated breath-hold examination, a spoiled-gradient echo 3D T1 sequence (SGE) characterized by superior soft tissue contrast and improved resolution, compared with DMRI and conventional MRI (CMRI) for detecting microadenomas in patients with Cushing's disease. METHODS This study was a blinded assessment of pituitary MRI in patients with proven Cushing's disease. Fifty-seven patients who had undergone surgery for Cushing's disease (10 male, 47 female; age range 13-69 years), whose surgical findings were considered to represent a microadenoma, and who had been examined with all 3 imaging techniques were included. Thus, selection emphasized patients with prior negative or equivocal MRI on referral. The MRI annotations were anonymized and 4 separate imaging sets were independently read by 3 blinded, experienced clinicians: a neuroradiologist and 2 pituitary surgeons. RESULTS Forty-eight surgical specimens contained an adenoma (46 ACTH-staining adenomas, 1 prolactinoma, and 1 nonfunctioning microadenoma). DMRI detected 5 adenomas that were not evident on CMRI, SGE detected 8 adenomas not evident on CMRI, including 3 that were not evident on DMRI. One adenoma was detected on DMRI that was not detected on SGE. McNemar's test for efficacy between the different MRI sets for tumor detection showed that the addition of SGE to CMRI increased the number of tumors detected from 18 to 26 (p = 0.02) based on agreement of at least 2 of 3 readers. CONCLUSIONS SGE shows higher sensitivity than DMRI for detecting and localizing pituitary microadenomas, although rarely an adenoma is detected exclusively by DMRI. SGE should be part of the standard MRI protocol for patients with Cushing's disease.

Agenesis of Anterior Falx Cerebri in Patient with Planned Interhemispheric Approach to Third Ventricle Mass.

BACKGROUND: Complete or partial agenesis of the falx cerebri may occur in pediatric patients with developmental anomalies. However, isolated agenesis of the falx in a developmentally normal adult is exceptionally rare. We describe the first reported case of a patient with a third ventricular mass associated with partial agenesis of the anterior falx cerebri, a circumstance that influenced surgical access to a third ventricular epidermoid cyst. CASE DESCRIPTION: A 60-year-old developmentally normal woman presented with progressively worsening aphasia and altered mental status. Brain magnetic resonance imaging showed obstructive hydrocephalus from a third ventricular mass. An anterior interhemispheric transcallosal approach was planned to remove the tumor. However, upon dural opening there was no evidence of a falx cerebri, an anomaly visible but not reported on the prior imaging studies. An interhemispheric fissure was present, but the medial frontal lobes were densely adherent, with multiple traversing veins within the superficial arachnoid of the fissure. Therefore, a left frontal transcortical approach was performed for microsurgical resection of the tumor. Histopathologic analysis identified the lesion to be an epidermoid cyst. CONCLUSIONS: Partial agenesis of the falx cerebri is exceedingly rare in a developmentally normal adult, particularly in the presence of an anatomically normal superior sagittal sinus. If present, however, it is important to note this association preoperatively because partial agenesis of the falx cerebri precludes an interhemispheric transcallosal approach to the lateral and third ventricles.

Wake-up Call to Clinicians: The Impact of Sleep Dysfunction on Gastrointestinal Health and Disease.

Sleep dysfunction is an epidemic affecting a large portion of the adult population. Recent studies have linked sleep dysfunction with an upregulation of proinflammatory cytokines (eg, tumor necrosis factor-α, interleukin-1 and interleukin-6), the implications of which can have a profound impact on a variety of gastrointestinal disease. In particular, sleep dysfunction seems to accelerate disease states characterized by inflammation (eg, gastroesophageal reflux disease, irritable bowel syndrome and functional dyspepsia, chronic liver disease, inflammatory bowel disease, and colorectal cancer). This article evaluates the complex interplay between sleep dysfunction and gastrointestinal health and disease.

The Effects of Sleep on the Commensal Microbiota: Eyes Wide Open?

Sleep dysfunction is an epidemic, the implications of which have a profound impact on a variety of gastrointestinal disease. Recent data suggests a relationship between sleep dysfunction and intestinal dysbiosis, a known proinflammatory driver. This article evaluates the interplay between sleep dysfunction and gastrointestinal health and disease, with a focus on the impact of circadian rhythm disruption on the commensal microbiota.

Functional Outcome After Resection of Von Hippel-Lindau Disease-Associated Cauda Equina Hemangioblastomas: An Observational Cohort Study.

BACKGROUND: Cauda equina hemangioblastomas in von Hippel-Lindau (VHL) disease can cause significant neurological signs and symptoms. Despite their associated morbidity, the management of these tumors remains incompletely defined. OBJECTIVE: To determine optimal management, we analyzed the functional outcomes after resection of these tumors. METHODS: VHL patients who underwent surgical resection of cauda equina hemangioblastomas at the National Institutes of Health and the University of Virginia were included. Clinical and radiological follow-up was performed at 6- to 12-month intervals after surgery. RESULTS: Fifteen patients underwent 18 operations for 21 cauda equina hemangioblastomas (median follow-up 5.9 years). Patients often presented with multiple symptoms, including pain (67%), numbness (50%), urinary complaints (33%), and weakness (11%). Median preoperative tumor volume was 1.2 cm 3 . Four tumors at 3 operations were not resected due to a motor nerve root origin. Gross total resection was achieved in 14 surgeries (93% of operations when resection was attempted). New mild (non-function limiting) neurological symptoms were noted after 11 operations (61%), which most often (64%) resolved within 2 weeks of surgery. At 6-month follow-up, 15 patients (83%) were stable, 2 (11%) were improved, and 1 (6%) was worse. Histological analysis revealed that all tumors originated from within the involved nerve fascicle. CONCLUSIONS: VHL-associated cauda equina hemangioblastomas have an intrafascicular origin and require interruption of the rootlet of origin for complete resection. Motor nerve root involvement may preclude complete resection but strategies including bony decompression and/or interruption of vascular supply may provide a therapeutic option. Nevertheless, most VHL patients with symptom-producing lesions improve with resection.

Normalized Early Postoperative Cortisol and ACTH Values Predict Nonremission After Surgery for Cushing Disease.

Context: Perioperative increases in adrenocorticotropic hormone (ACTH) and cortisol mimic results of corticotropin-releasing hormone (CRH) stimulation testing. This phenomenon may help identify patients with residual adenoma after transsphenoidal surgery (TSS) for Cushing disease (CD). Objective: To predict nonremission after TSS for CD. Design: Retrospective case-control study of patients treated at a single center from December 2003 until July 2016. Early and medium-term remission were assessed at 10 days and 11 months. Patients and Setting: Two hundred and ninety-one consecutive TSS cases from 257 patients with biochemical evidence of CD seen at a clinical center. Interventions: Normalized early postoperative values (NEPVs) for cortisol and ACTH were calculated as immediate postoperative cortisol or ACTH levels minus preoperative post-CRH-stimulation test levels. Main Outcome Measures: Prediction of early nonremission was evaluated using logistic regression. Prediction of medium-term remission was assessed using Cox regression. Predictive ability was quantified by area under the receiver operating characteristic curve (AUROC). Results: NEPVs for cortisol and ACTH predicted early nonremission [adjusted odds ratio (OR): 1.1; 95% confidence interval (CI): 1.0, 1.1; P = 0.016 and adjusted OR: 1.0; 95% CI: 1.0, 1.0; P = 0.048, respectively]. AUROC for NEPV of cortisol was 0.78 (95% CI: 0.61, 0.95); for NEPV of ACTH, it was 0.80 (95% CI: 0.61, 0.98). NEPVs for cortisol and ACTH predicted medium-term nonremission [hazard ratio (HR): 1.1; 95% CI: 1.0, 1.1; P = 0.023 and HR: 1.0; 95% CI: 1.0, 1.0; P = 0.025, respectively]. Conclusions: NEPVs for cortisol and ACTH predicted nonremission after TSS for CD.

Cushing's disease: pathobiology, diagnosis, and management.

Cushing's disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of CD is critical for effective surgical management and optimal prognosis. The authors review the current pathophysiological principles, diagnostic methods, and management of CD.