Supplemental oxygen requirement after tonsillectomy in children >3 years of age.

INTRODUCTION: The indications for postoperative admission after tonsillectomy in children >3 years of age are less well defined than for children <3 years old, and typically include severe obstructive sleep apnea (OSA), obesity, comorbidities, or behavioral factors. Inpatient care after tonsillectomy typically consists of respiratory monitoring and support, as respiratory compromise is the most common complication after pediatric tonsillectomy. We aim to evaluate risk factors associated with postoperative oxygen supplementation and to identify high risk populations within the admitted population who use additional resources or require additional interventions. METHODS: Retrospective chart review of patients between the ages of 3 and 18 years old who underwent tonsillectomy by four surgeons at a tertiary care children's hospital was performed. Data including demographics, comorbidities, surgical intervention, pre- and postoperative AHI, admission, postoperative oxygen requirement, and postoperative complications was collected and analyzed. RESULTS: There were 401 patients included in the analysis. Of the patients in this study, 65.59% were male, 43.39% were Latino, and 53.87% were ages 3 to 7. Of the 397 patients with a record for supplemental oxygen, 36 (9.07%) received supplemental oxygen. The LASSO regression odds ratios (OR) found to be important for modeling supplemental oxygen use (in decreasing order of magnitude) are BMI ≥35 (OR = 2.30), pre-op AHI >30 (OR = 2.28), gastrointestinal comorbidities (OR = 2.20), musculoskeletal comorbidities (OR = 1.91), cardiac comorbidities (OR = 1.20), pulmonary comorbidities (OR = 1.14), and BMI 30 to <35 (OR = 1.07). Female gender was found to be negatively associated with risk of supplemental oxygen use (OR = 0.84). Age, race, AHI ≥15-30, neurologic comorbidities, syndromic patients, admission reason, and undergoing other procedures concomitantly were not found to be associated with increased postoperative oxygen requirement. CONCLUSION: BMI ≥30, pre-op AHI >30, male gender, and gastrointestinal, musculoskeletal, cardiac, and pulmonary comorbidities are all associated with postoperative supplemental oxygen use. Age, race, AHI ≥15-30, neurologic comorbidities, syndromic patients, admission reason, and undergoing other procedures concomitantly were not found to be associated with increased postoperative oxygen requirement.

Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex.

The glutamate delta family of receptors is composed of GluD1 and GluD2 and serve as synaptic organizers. We have previously demonstrated several autism-like molecular and behavioral phenotypes including an increase in dendritic spines in GluD1 knockout mice. Based on previous reports we evaluated whether disruption of autophagy mechanisms may account for these phenotypes. Mouse model with conditional deletion of GluD1 from excitatory neurons in the corticolimbic regions was utilized. GluD1 loss led to overactive Akt-mTOR pathway, higher p62 and a lower LC3-II/LC3-I ratio in the somatosensory cortex suggesting reduced autophagy. Excitatory elements were increased in number but had immature phenotype based on puncta size, lower AMPA subunit GluA1 expression and impaired development switch from predominantly GluN2B to mixed GluN2A/GluN2B subunit expression. Overactive Akt-mTOR signaling and impaired autophagy was also observed in dorsal striatum upon conditional ablation of GluD1 and in the prefrontal cortex and hippocampus in constitutive knockout. Finally, cognitive deficits in novel object recognition test and fear conditioning were observed in mice with conditional ablation of GluD1 from the corticolimbic regions. Together, these results demonstrate a novel function of GluD1 in the regulation of autophagy pathway which may underlie autism phenotypes and is relevant to the genetic association of GluD1 coding, GRID1 gene with autism and other developmental disorders.

Cost-Effectiveness of Outreach Strategies for Stool-Based Colorectal Cancer Screening in a Medicaid Population.

Outreach, including patient navigation, has been shown to increase the uptake of colorectal cancer (CRC) screening in underserved populations. This analysis evaluates the cost-effectiveness of triennial multi-target stool DNA (mt-sDNA) versus outreach, with or without a mailed annual fecal immunochemical test (FIT), in a Medicaid population. A microsimulation model estimated the incremental cost-effectiveness ratio using quality-adjusted life years (QALY), direct costs, and clinical outcomes in a cohort of Medicaid beneficiaries aged 50-64 years, over a lifetime time horizon. The base case model explored scenarios of either 100% adherence or real-world reported adherence (51.3% for mt-sDNA, 21.1% for outreach with FIT and 12.3% for outreach without FIT) with or without real-world adherence for follow-up colonoscopy (66.7% for all). Costs and outcomes were discounted at 3.0%. At 100% adherence to both screening tests and follow-up colonoscopy, mt-sDNA costed more and was less effective compared with outreach with or without FIT. When real-world adherence rates were considered for screening strategies (with 100% adherence for follow-up colonoscopy), mt-sDNA resulted in the greatest reduction in incidence and mortality from CRC (41.5% and 45.8%, respectively) compared with outreach with or without FIT; mt-sDNA also was cost-effective versus outreach with and without FIT ($32,150/QALY and $22,707/QALY, respectively). mt-sDNA remained cost-effective versus FIT, with or without outreach, under real-world adherence rates for follow-up colonoscopy. Outreach or navigation interventions, with associated real-world adherence rates to screening tests, should be considered when evaluating the cost-effectiveness of CRC screening strategies in underserved populations.

Rhinosinusitis in Pediatric Primary Ciliary Dyskinesia: Impact of Disease.

OBJECTIVES: Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by abnormal respiratory cilia ultrastructure and/or function causing defective mucociliary clearance. We investigated the extent and severity of rhinosinusitis in a large cohort of children with PCD and explored associations among risk factors, including genotype and sinus disease. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic children's hospital. SUBJECTS AND METHODS: A review was conducted with a patient registry at the PCD Foundation Center at our institution. Demographic, imaging, clinical, and operative data were reviewed through the institutional electronic health record system. RESULTS: Fifty-four subjects were identified with mean and median age at diagnosis of 5.2 and 4.0 years. The male:female ratio was 35%:65%. Sinus symptoms were present in 46 (85%) subjects, 22 of whom had chronic rhinosinusitis. Nineteen (35%) subjects underwent operative intervention, consisting of endoscopic sinus surgery (ESS; 16 patients) and maxillary lavage (3 patients). Nineteen subjects underwent adenoidectomy for PCD-related indications. Five sinus-related admissions in 3 subjects were noted during the study period, and no complication of rhinosinusitis occurred in the cohort. Genetic test results were available in 27 subjects, in whom 23 (85%) had biallelic mutations in a PCD gene. Demographic factors, Lund-Mackay score, and PCD genotype were not found to be predictors for ESS or hospitalization in our cohort. CONCLUSION: While rhinosinusitis was common in our PCD cohort, most patients did not require ESS. Since complications of rhinosinusitis were uncommon, we recommend judicious surgical management tailored to the patient's symptoms.

Mobile Health Application and e-Health Literacy: Opportunities and Concerns for Cancer Patients and Caregivers.

Health literacy is critical for cancer patients as they must understand complex procedures or treatment options. Caregivers' health literacy also plays a crucial role in caring for cancer patients. Low health literacy is associated with low adherence to medications, poor health status, and increased health care costs. There is a growing interest in the use of mobile health applications (apps) to improve health literacy. Mobile health apps can empower underserved cancer patients and their caregivers by providing features or functionalities to enhance interactive patient-provider communication and to understand medical information more readily. Despite the potentiality of improving health literacy through mobile health apps, there exist several related concerns: no equal access to mobile technology, no familiarity or knowledge of using mobile health apps, and privacy and security concerns. These elements should be taken into account for health policy making and mobile apps design and development. Importantly, mobile apps should be developed with the goal of achieving a high range of user access by considering all health literacy level and various cultural and linguistic needs.

Neonatal Stridor: Diagnosis and Management.

Stridor, a common presenting sign of respiratory distress in a newborn, has many systemic causes. It may arise from the larynx or the tracheobronchial airway. This article presents the most common pathologic conditions in this anatomic region, with highlights on management.

Early clinical outcomes after small incision lenticule extraction surgery (SMILE).

PURPOSE: Dry eye is known to impact on clinical outcomes after laser vision correction and the use of a newer 'all femtosecond laser' surgical approach may be associated with less impact on the ocular surface post-operatively. The purpose of this study was to evaluate the early clinical outcomes and tear instability after the first small incision lenticule extraction (SMILE) cases undertaken by three surgeons at a single site in the UK. METHODS: Retrospective audit. Seventy-one eyes of 37 patients underwent SMILE surgery using the Zeiss VisuMax laser system (Carl Zeiss Meditec, Germany). Uncorrected and corrected distance visual acuity, spherical equivalent refraction, fluorescein enhanced tear break up time, simulated keratometry and complications were evaluated pre- and post-operatively where applicable. RESULTS: The study population consisted of 21 males and 16 females. The mean±standard deviation age was 33±8years. The results showed that 100% of eyes achieved 20/40 or better and 88% achieved 20/20 or better uncorrected distance visual acuity. The spherical equivalent refraction after surgery was within ±0.50D in 82% of eyes at three months. There was no significant difference in tear break up time from pre-operative levels at three months. Complications were infrequent. CONCLUSIONS: This early data from surgeons' first SMILE procedures suggest SMILE provides good outcomes in terms of refractive predictability and visual acuity with minimal impact on the tear film. Longitudinal research will further improve our understanding of the longer-term impact of SMILE on clinical outcomes, ocular surface metrics and patient reported outcomes.

The human mitochondrial Hsp60 in the APO conformation forms a stable tetradecameric complex.

The human mitochondrial chaperonin is a macromolecular machine that catalyzes the proper folding of mitochondrial proteins and is of vital importance to all cells. This chaperonin is composed of 2 distinct proteins, Hsp60 and Hsp10, that assemble into large oligomeric complexes that mediate the folding of non-native polypeptides in an ATP dependent manner. Here, we report the bacterial expression and purification of fully assembled human Hsp60 and Hsp10 recombinant proteins and that Hsp60 forms a stable tetradecameric double-ring conformation in the absence of co-chaperonin and nucleotide. Evidence of the stable double-ring conformation is illustrated by the 15 Å resolution electron microscopy reconstruction presented here. Furthermore, our biochemical analyses reveal that the presence of a non-native substrate initiates ATP-hydrolysis within the Hsp60/10 chaperonin to commence protein folding. Collectively, these data provide insight into the architecture of the intermediates used by the human mitochondrial chaperonin along its protein folding pathway and lay a foundation for subsequent high resolution structural investigations into the conformational changes of the mitochondrial chaperonin.

Dosimetric Analysis of Neural and Vascular Structures in Skull Base Tumors Treated with Stereotactic Radiosurgery.

Objective To examine the relationship between the prescribed target dose and the dose to healthy neurovascular structures in patients with vestibular schwannomas treated with stereotactic radiosurgery (SRS). Study Design Case series with chart review. Setting SRS center from 2011 to 2013. Subjects Twenty patients with vestibular schwannomas treated at the center from 2011 to 2013. Methods Twenty patients with vestibular schwannomas were included. The average radiation dose delivered to healthy neurovascular structures (eg, carotid artery, basilar artery, facial nerve, trigeminal nerve, and cochlea) was analyzed. Results Twenty patients with vestibular schwannomas who were treated with fused computed tomography/magnetic resonance imaging-guided SRS were included in the study. The prescribed dose ranged from 10.58 to 17.40 Gy over 1 to 3 hypofractions to cover 95% of the target tumor volume. The mean dose to the carotid artery was 5.66 Gy (95% confidence interval [CI], 4.53-6.80 Gy), anterior inferior cerebellar artery was 8.70 Gy (95% CI, 4.54-12.86 Gy), intratemporal facial nerve was 3.76 Gy (95% CI, 3.04-4.08 Gy), trigeminal nerve was 5.21 Gy (95% CI, 3.31-7.11 Gy), and the cochlea was 8.70 Gy (95% CI, 7.81-9.59 Gy). Conclusions SRS for certain vestibular schwannomas can expose the anterior inferior cerebellar artery (AICA) and carotid artery to radiation doses that can potentially initiate atherosclerotic processes. The higher doses to the AICA and carotid artery correlated with increasing tumor volume. The dose delivered to other structures such as the cochlea and intratemporal facial nerve appears to be lower and much less likely to cause immediate complications when shielded.

Prevalence, Severity, Exposures, and Treatment Patterns of Tinnitus in the United States.

Importance: Tinnitus is a common problem for millions of individuals and can cause substantial negative effects on their quality of life. A large epidemiologic study of tinnitus and its management patterns in the US adult population is lacking. Objectives: To quantify the epidemiologic features and effect of tinnitus and to analyze the management of tinnitus in the United States relative to the 2014 American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) clinical practice guidelines. Design, Methods, and Participants: This cross-sectional analysis of the representative 2007 National Health Interview Survey (raw data, 75 764 respondents) identified a weighted national sample of adults (age, ≥18 years) who reported tinnitus in the preceding 12 months. Data were collected in November 2014 at the University of California, Irvine, and Harvard Medical School. Main Outcomes and Measures: In addition to quantifying prevalence, severity, duration, and regularity of tinnitus, specific data regarding noise exposure and tinnitus management patterns during health care visits were analyzed. Results: Among an estimated (SE) 222.1 (3.4) million US adults, 21.4 (3.4) million (9.6% [0.3%]) experienced tinnitus in the past 12 months. Among those who reported tinnitus, 27% had symptoms for longer than 15 years, and 36% had nearly constant symptoms. Higher rates of tinnitus were reported in those with consistent exposure to loud noises at work (odds ratio, 3.3; 95% CI, 2.9-3.7) and during recreational time (odds ratio, 2.6; 95% CI, 2.3-2.9). Years of work-related noise exposure correlated with increasing prevalence of tinnitus (r = 0.13; 95% CI, 0.10-0.16). In terms of subjective severity, 7.2% reported their tinnitus as a big or a very big problem compared with 41.6% who reported it as a small problem. Only 49.4% had discussed their tinnitus with a physician, and medications were the most frequently discussed recommendation (45.4%). Other interventions, such as hearing aids (9.2%), wearable (2.6%) and nonwearable (2.3%) masking devices, and cognitive behavioral therapy (0.2%), were less frequently discussed. Conclusions and Relevance: The prevalence of tinnitus in the United States is approximately 1 in 10 adults. Durations of occupational and leisure time noise exposures correlated with rates of tinnitus and are likely targetable risk factors. Management options suggested by the recently published AAO-HNSF guidelines were followed infrequently.

Use of Mobile Health Applications for Health-Seeking Behavior Among US Adults.

This study explores the use of mobile health applications (mHealth apps) on smartphones or tablets for health-seeking behavior among US adults. Data was obtained from cycle 4 of the 4th edition of the Health Information National Trends Survey (HINTS 4). Weighted multivariate logistic regression models examined predictors of 1) having mHealth apps, 2) usefulness of mHealth apps in achieving health behavior goals, 3) helpfulness in medical care decision-making, and 4) asking a physician new questions or seeking a second opinion. Using the Andersen Model of health services utilization, independent variables of interest were grouped under predisposing factors (age, gender, race, ethnicity, and marital status), enabling factors (education, employment, income, regular provider, health insurance, and rural/urban location of residence), and need factors (general health, confidence in their ability to take care of health, Body Mass Index, smoking status, and number of comorbidities). In a national sample of adults who had smartphones or tablets, 36 % had mHealth apps on their devices. Among those with apps, 60 % reported the usefulness of mHealth apps in achieving health behavior goals, 35 % reported their helpfulness for medical care decision-making, and 38 % reported their usefulness in asking their physicians new questions or seeking a second opinion. The multivariate models revealed that respondents were more likely to have mHealth apps if they had more education, health insurance, were confident in their ability to take good care of themselves, or had comorbidities, and were less likely to have them if they were older, had higher income, or lived in rural areas. In terms of usefulness of mHealth apps, those who were older and had higher income were less likely to report their usefulness in achieving health behavior goals. Those who were older, African American, and had confidence in their ability to take care of their health were more likely to respond that the mHealth apps were helpful in making a medical care decision and asking their physicians new questions or for a second opinion. Potentially, mHealth apps may reduce the burden on primary care, reduce costs, and improve the quality of care. However, several personal-level factors were associated with having mHealth apps and their perceived helpfulness among their users, indicating a multidimensional digital divide in the population of US adults.

Oligomerization of the Sec7 domain Arf guanine nucleotide exchange factor GBF1 is dispensable for Golgi localization and function but regulates degradation.

Members of the large Sec7 domain-containing Arf guanine nucleotide exchange factor (GEF) family have been shown to dimerize through their NH2-terminal dimerization and cyclophilin binding (DCB) and homology upstream of Sec7 (HUS) domains. However, the importance of dimerization in GEF localization and function has not been assessed. We generated a GBF1 mutant (91/130) in which two residues required for oligomerization (K91 and E130 within the DCB domain) were replaced with A and assessed the effects of these mutations on GBF1 localization and cellular functions. We show that 91/130 is compromised in oligomerization but that it targets to the Golgi in a manner indistinguishable from wild-type GBF1 and that it rapidly exchanges between the cytosolic and membrane-bound pools. The 91/130 mutant appears active as it integrates within the functional network at the Golgi, supports Arf activation and COPI recruitment, and sustains Golgi homeostasis and cargo secretion when provided as a sole copy of functional GBF1 in cells. In addition, like wild-type GBF1, the 91/130 mutant supports poliovirus RNA replication, a process requiring GBF1 but believed to be independent of GBF1 catalytic activity. However, oligomerization appears to stabilize GBF1 in cells, and the 91/130 mutant is degraded faster than the wild-type GBF1. Our data support a model in which oligomerization is not a key regulator of GBF1 activity but impacts its function by regulating the cellular levels of GBF1.

Transcanal Micro-Osteotome Only Technique for Excision of Exostoses.

OBJECTIVES: To evaluate the outcomes and complications of transcanal excision of exostoses using micro-osteotomes, without a postauricular incision or the use of the drill. STUDY DESIGN: A retrospective chart review of patients undergoing exostoses excision. SETTING: Tertiary Care Medical Center. SUBJECTS AND METHODS: All of the patients underwent surgical removal of the exostoses using only a 1 or 2 mm micro-osteotomes. Patients were followed postoperatively and associated complications were evaluated. RESULTS: One-hundred thirty-eight ears in 106 patients were treated for obstructive exostosis. The average age of patients was 43 ± 16 years. Of these, 99 were man (93%) and 7 were woman (7%). A majority of the patients (84%, n = 89) had 90 to 100% obstruction of the ear canal. Complete ear canal healing was observed in 80% of patients by 3 weeks. All but one patient had healed by 6 weeks postoperatively. There were 9 (6.5%) slit tympanic membrane perforations that healed with intraoperative gelfoam or fascia myringoplasty. One patient had an anterior canal mobilization which required Xeroform packing for 3 weeks for stabilization. There were no postoperative vertigo, facial paresis, conductive/sensorineural hearing loss, soft tissue stenoses, and no skin grafting required. CONCLUSIONS: This is the first study to report a series of patients performing solely a transcanal approach using micro-osteotomes for removing exostoses. Results indicate that it is a safe procedure with low complication rate and expeditious healing. Patients with 100% obstruction can have this procedure performed with no significant increase in morbidity.

Microbiological sampling of the forgotten components of a flexible fiberoptic laryngoscope: what lessons can we learn?

The effectiveness of a Cidex-based decontamination protocol was analyzed for its effectiveness in cleaning various components of a flexible fiberoptic laryngoscope (FFL), including the handle, eyepiece, and detachable light cable. A random microbiological sampling and aerobic bacterial culture analysis of 6 FFL eyepieces, 6 FFL driver handles, and 5 light cables prior to patient use was performed. Of 17 samples collected, 7 (41%) were contaminated with bacterial organisms. Organisms recovered represented both environmental organisms from skin and oral flora origin. This study demonstrates that potential contaminants may be present on FFL eyepieces and light cables, which are commonly overlooked in the cleaning protocols of a standard otolaryngology clinic.

Role of mTOR downstream effector signaling molecules in Francisella tularensis internalization by murine macrophages.

Francisella tularensis is an infectious, gram-negative, intracellular microorganism, and the cause of tularemia. Invasion of host cells by intracellular pathogens like Francisella is initiated by their interaction with different host cell membrane receptors and the rapid phosphorylation of different downstream signaling molecules. PI3K and Syk have been shown to be involved in F. tularensis host cell entry, and both of these signaling molecules are associated with the master regulator serine/threonine kinase mTOR; yet the involvement of mTOR in F. tularensis invasion of host cells has not been assessed. Here, we report that infection of macrophages with F. tularensis triggers the phosphorylation of mTOR downstream effector molecules, and that signaling via TLR2 is necessary for these events. Inhibition of mTOR or of PI3K, ERK, or p38, but not Akt signaling, downregulates the levels of phosphorylation of mTOR downstream targets, and significantly reduces the number of F. tularensis cells invading macrophages. Moreover, while phosphorylation of mTOR downstream effectors occurs via the PI3K pathway, it also involves PLCγ1 and Ca(2+) signaling. Furthermore, abrogation of PLC or Ca(2+) signaling revealed their important role in the ability of F. tularensis to invade host cells. Together, these findings suggest that F. tularensis invasion of primary macrophages utilize a myriad of host signaling pathways to ensure effective cell entry.

Hemilingual spasm: defining a new entity, its electrophysiological correlates and surgical treatment through microvascular decompression.

OBJECTIVE: We report on vascular compression syndrome of the 12th cranial nerve (hypoglossal), an occurrence not previously reported, and demonstrate, through corresponding objective electrophysiological evidence, that microvascular decompression of the hypoglossal nerve root can cure hemilingual spasm. CLINICAL PRESENTATION: A 52-year-old man had lower face muscle twitching and tongue spasms, which worsened with talking, chewing, or emotional stress. Carbamazepine offered only temporary relief, and relief from injections of botulinum toxin was insignificant. He was referred for surgical treatment. High-resolution magnetic resonance imaging of his posterior fossa contents revealed no obvious evidence of any compressive vessel along the facial nerve, but a compressive vessel along the hypoglossal nerve was apparent. INTERVENTION: The presence of preoperative tongue spasms encouraged interoperative monitoring of tongue motor responses. The facial nerve exit zone was explored, but microsurgical inspection of the seventh/eighth cranial nerve complex did not reveal any compressive vessel. However, at the anterolateral aspect of the medulla oblongata, the hypoglossal nerve was clearly compressed and distorted laterally by a large tortuous vertebral artery. When the artery was mobilized away from the nerve, the abnormal late electromyographic response to transcranial electrical stimulation disappeared; immediately after shredded Teflon was interpositioned between the artery and the nerve, the abnormal spontaneous tongue fasciculation also disappeared. The patient has remained spasm free 6 months after surgery. CONCLUSION: Hemilingual spasm may be caused by vascular contact/compression along cranial nerve XII at the lower brainstem and belong to the same family of cranial nerve hyperactivity disorders as hemifacial spasm.

Video assisted thoracic surgery sublobar resection of intralobar pulmonary sequestration after preoperative embolization of systemic blood supply.

Intralobar pulmonary sequestration is abnormal lung tissue of embryonic origin that receives arterial blood supply from the systemic arterial circulation from the abdominal aorta. The arterial blood supply traverses the diaphragm and courses through the inferior pulmonary ligament. Intralobar pulmonary sequestrations are usually treated by anatomic lobar or sublobar resections via an open thoracotomy. Recent reports suggest the utility of a video assisted thoracic surgery (VATS) pulmonary resection. However, the presence of the feeding systemic artery often makes VATS resection difficult or impossible, due to the risk of injury to the feeding vessel, and subsequent retraction below the diaphragm. We present procedural video recordings describing a multidisciplinary procedure, where precedent coil embolization of the feeding systemic vessel allows for relative risk-free VATS sublobar resection of the intralobar pulmonary sequestration.

Getting into the brain: approaches to enhance brain drug delivery.

Being the most delicate organ of the body, the brain is protected against potentially toxic substances by the blood-brain barrier (BBB), which restricts the entry of most pharmaceuticals into the brain. The developmental process for new drugs for the treatment of CNS disorders has not kept pace with progress in molecular neurosciences because most of the new drugs discovered are unable to cross the BBB. The clinical failure of CNS drug delivery may be attributed largely to a lack of appropriate drug delivery systems. Localized and controlled delivery of drugs at their desired site of action is preferred because it reduces toxicity and increases treatment efficiency. The present review provides an insight into some of the recent advances made in the field of brain drug delivery.The various strategies that have been explored to increase drug delivery into the brain include (i) chemical delivery systems, such as lipid-mediated transport, the prodrug approach and the lock-in system; (ii) biological delivery systems, in which pharmaceuticals are re-engineered to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium; (iii) disruption of the BBB, for example by modification of tight junctions, which causes a controlled and transient increase in the permeability of brain capillaries; (iv) the use of molecular Trojan horses, such as peptidomimetic monoclonal antibodies to transport large molecules (e.g. antibodies, recombinant proteins, nonviral gene medicines or RNA interference drugs) across the BBB; and (v) particulate drug carrier systems. Receptor-mediated transport systems exist for certain endogenous peptides, such as insulin and transferrin, enabling these molecules to cross the BBB in vivo.The use of polymers for local drug delivery has greatly expanded the spectrum of drugs available for the treatment of brain diseases, such as malignant tumours and Alzheimer's disease. In addition, various drug delivery systems (e.g. liposomes, microspheres, nanoparticles, nanogels and bionanocapsules) have been used to enhance drug delivery to the brain. Recently, microchips and biodegradable polymers have become important in brain tumour therapy.The intense search for alternative routes of drug delivery (e.g. intranasal drug delivery, convection-enhanced diffusion and intrathecal/intraventricular drug delivery systems) has been driven by the need to overcome the physiological barriers of the brain and to achieve high drug concentrations within the brain. For more than 30 years, considerable efforts have been made to enhance the delivery of therapeutic molecules across the vascular barriers of the CNS. The current challenge is to develop drug delivery strategies that will allow the passage of drug molecules through the BBB in a safe and effective manner.

Neuromuscular disorders in clinical practice: case studies.

Neuromuscular disorders represent a large group of highly varied and interesting clinical disorders, many of which have major general medical manifestations. These disorders can be diagnosed largely based on the patient's history and physical examination with a little help from modern technology. Despite the outdated belief that neurologic conditions are diagnosed but rarely treatable, all cases discussed herein represent disorders for which there are extensive options and opportunities for meaningful management. These 16 brief case overviews challenge and refresh diagnostic skills and provide the framework for selected comments regarding management options.