Editorial Board

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Meetings Calendar

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Show me the evidence: Dealing with bias in the medical literature

Taking care of patients with spine related pain and disability is challenging. Diagnosis is an imprecise art and there are a multitude of competing treatment modalities for any given pain syndrome. Interventions may be expensive and dangerous, and measuring objective outcomes is difficult and time consuming. Those of us who accept the challenge of treating this patient population need not only to be armed with the best available evidence but also need to understand the limits of the available evidence when making treatment decisions.

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Table of Contents

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Physical function computer adaptive test outcomes in diabetic lumbar spine surgical patients

Diabetes is a highly prevalent comorbid condition among patients undergoing spine surgery. Several studies have used legacy patient-reported outcome measures to implicate diabetes as a predictor of increased disability, pain, and decreased physical function and quality of life following spine surgery. The effect of diabetes on postoperative physical function has not yet been studied using the PROMIS Physical Function Computer Adaptive Test (PF CAT).

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Expressional and functional analyses of epididymal SPINKs in mice

Publication date: Available online 25 December 2018

Source: Gene Expression Patterns

Author(s): Juri Jeong, Boyeon Lee, Jihye Kim, Jaehwan Kim, Seong Hyeon Hong, Donghyun Kim, Seungho Choi, Byung-Nam Cho, Chunghee Cho

Abstract

Epididymal maturation is critical for acquisition of motility and fertilizing capacity by sperm. During epididymal transit, the surface of sperm undergoes prominent sequential changes through interactions with secreted proteins, including protease inhibitors. In the present study, we characterized three epididymis-specific SPINKs (serine protease inhibitors, Kazal-type): SPINK8, SPINK11, and SPINK12. We found that these epididymal SPINKs are expressed in an epididymal region-specific manner and their expression is developmentally regulated. Remarkably, cellular analyses revealed that SPINK8 and SPINK12 are transferred to the sperm. To investigate the in vivo properties of SPINK12, we analyzed knockout mice generated by CRISPR/Cas9-mediated genome editing. Loss of SPINK12 did not alter epididymal tubule structure or sperm phenotypes. Spink12 mutant mice exhibited normal fertility, suggesting that SPINK12 is functionally redundant in the epididymis.

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Herbal Medicine in the Management of Tinnitus

AbstractTinnitus, which is commonly defined as "ringing in the ears" by the patients, is a perception of an auditory sensation without any accompanying external stimulation. It accounts for a notable part of visits in otolaryngology clinics and has been estimated to involve about 5–15% of adult population making serious problems in 3–5% of patients. Tinnitus causes a lot of problems for patients, their family, and guardians and significantly decreases quality of life of patients. Many treatment methods have been proposed and presented for Tinnitus since the first year of diagnosis. These methods range from conservative management and chemical medications to surgical methods. As the other diseases and conditions, herbal medicine has been trying to treat Tinnitus and a variety of medications have been proposed. In this chapter, we aimed to have a comprehensive review on the current herbal medications of Tinnitus from all over the world.
Keywordstinnitus herbal medicine treatment epidemiology Ginkgo bilobaChapter and author infoShow +1. Tinnitus: definition, etiology, and epidemiologyTinnitus, which is commonly defined as "ringing in the ears" by the patients, is a perception of an auditory sensation without any accompanying external stimulation [1, 2]. It accounts for a notable part of visit in otolaryngology clinics and has been estimated to involve about 5–15% of adult population making serious problems in 3–5% of patients [1, 2, 3, 4, 5].
Tinnitus causes a lot of problems for patients, their family, and guardians and significantly decreases quality of life of patients. Most of the patients have complaints with sleep disorders, depression, decreased self-confidence, and altered social communications as well as difficulties in quotidian activities [2].
Tinnitus is generally categorized into two types: subjective and objective. A majority of patients suffer from a subjective tinnitus, which means perception of an auditory sensation without any evident stimulus. In some patients, a kind of organic measurable stimulus such as glomus tumor, by making turbulence of blood flow, is the cause for tinnitus, which is called objective tinnitus [1, 2]. This type of tinnitus can be found by examiner using an ear-canal microphone or stethoscope [6].
A variety of risk factors have been reported for subjective tinnitus so far; hearing loss, depression, head trauma, and medication-related ototoxicity [7, 8, 9]. Some other conditions may have a role in predisposing patients to tinnitus such as acoustic trauma and presbycusis, and it may be associated with temporomandibular joint (TMJ) or cervical spine dysfunctions (somatic tinnitus) as well as depression and anxiety [10, 11, 12, 13, 14].
2. Current treatmentsCurrently, United States Food and Drug Administration (FDA) or the European Medicine Agency has not approved any drug for the treatment of tinnitus [15]. The complex mechanism and innate diversity in etiology of tinnitus have made its treatment a dilemma for physicians and specially otolaryngologists. Despite considerable number of researches, none of the so far presented medications and treatments has resulted in a sustained reduction in perception of tinnitus [16]. No appropriately controlled clinical trials have been successful to prove efficacy of a single drug. Thus, pharmacological treatment of tinnitus seems to be ineffective [17, 18]. Antidepressants are more frequently prescribed for tinnitus and seem to be effective but with a notable number of side effects. Anticonvulsants, benzodiazepines, lidocaine, and antispasmodics are also among commonly prescribed medications [19]. Voice therapy, using hearing aids, adjuvant therapies as well as environmental sound enrichment are the most common nonmedical approaches to Tinnitus [20].
Regarding the abovementioned issues, there are varieties of complementary and alternative medicine (CAM) treatments, which have been experimented in clinical stage for tinnitus. Herbal medicine or acupuncture, as the most popular types of CAMs therapy among people, have been shown to be effective in management of tinnitus when prescribed solely or in combination [21, 22]. Most of the CAM studies have a small sample size and few methodological pitfalls make it difficult to decide firmly about these treatments.
Some of medicinal herbs and their derivates have been evaluated in various phases of studies: in vitro, in vivo, and even in small to large scale clinical trials [23, 24, 25, 26, 27, 28, 29, 30]. In fact, people in different regions of the world have different approaches to medicinal plants and use a variety of herbal medications for treating different diseases and conditions, which have not yet been scientifically assessed [31, 32]. In this chapter, we will discuss and review current traditional and herbal medicine treatments with approved or possible effects on management of Tinnitus.
3. Ginkgo biloba (Jinko)Ginkgo biloba from the Ginkgoaceae family is a Chinese traditional medicine herb, which is being used for the treatment of asthma and bronchitis for a long time [22, 33]. It has gotten popular also in western countries as well as in Asian ones [34]. Ginkgo biloba is widely available as easily accessible, inexpensive, and relatively safe leaf extracts with various reported therapeutic benefits such as improved cognition and memory as well as sexual function [35, 36]. These improvements beside other biological effects of Jinko extracts such as improvement of microcirculation and neuroprotection are attributable to flavonoid glycosides and terpene lactones, active pharmacologic gradients of Ginkgo biloba. It should be pointed that seeds play a remarkable role in Chinese traditional medicine and they are the most commonly used parts of plants for herbal medications, while Ginkgo biloba is processed from the plants' leaves.
Jinko has been proposed for management of various central nervous system pathologies including tinnitus; however, some previous researches have reported no beneficial effects for Ginkgo biloba in treatment of tinnitus [36, 37, 38, 39, 40, 41]. Nevertheless, no certain decide can be made regarding effects of Ginkgo biloba on management of tinnitus according to its complex pharmacological profile, which shows need for further accurate researches [42].
4. Bojungikgitang and banhabaekchulchonmatang (traditional Korean medicine)Bojungikgitang and banhabaekchulchonmatang have been approved by Korea Food and Drug Administration and are being widely used in Korea for treatment of Tinnitus because of their very low rate of adverse effects [16]. These two herbal medications have found their places among Korean people and physicians. Traditional Korean medicine (TKM) believes that Tinnitus is mainly caused from irregularities in bowel and visceral (zang-fu) functioning [16]. According to TKM, gallbladder deficiency associated with tinnitus is managed by banhabaekchulchonmatang, and bojungikgitang is used to manage the pattern of qi-deficiency [21]. Both of these drugs are now fully covered by Korean National Health Insurance (KNHI).
5. Gushen PianasGushen Pianas is a novel Chinese medicinal herb, which is being used in the treatment of sensorineural hearing loss and Tinnitus. Phlegm-accumulation stasis and splenonephric hypofunction are the two main proposed mechanisms of action for Gushen Pianas in treatment of Tinnitus [43]. This medication has been developed by Institute of Otorhinolaryngology of Chinese PLA General Hospital and Wuhan Kexing Biomedical Development Co.
Effectiveness of the drug was evaluated in a phase 2 double-blind randomized clinical trial on 120 patients with sensorineural deafness associated with tinnitus. Patients received five tablets of Gushen Pianas every 8 hours and the effect was assessed after 4 weeks. The findings suggested Gushen Pianas as a suitable treatment for hearing loss with no evident adverse effects [43].
6. Panax ginseng (Jinseng)Root of the Panax ginseng, with local name of Jinseng, a Chinese medicinal plant from the Araliaceae family has been being used for treatment of Tinnitus since dawn of traditional medicine [44]. Korean red ginseng (KRG) is a traditional Korean herbal medication, which has been used for more than 2000 years, believed to have several benefits for human body [45]. It is considered that oxidative stress is the cause for idiopathic tinnitus and patients may take benefits from oral antioxidant therapy [46, 47]. So, KRG has been proposed for treatment of tinnitus as it inhibits production of reactive oxygen species (ROS) and also attenuates hydrogen peroxide-induced oxidative stress in human neuroblastoma cells [48, 49]. The effect of KRG (3000 mg/day) was evaluated in a randomized clinical trial in which the patients showed a significant reduction in tinnitus handicap inventory (THI) score and increased quality of life. Also some adverse effects have been reported for Jinseng and specially KRG in literature. Deficiency of vital energy (DE), known as qi-deficiency, is a traditional Chinese medicine syndrome, which indicates the disease emerging identity. Some studies believe that Ginseng, especially Korean Red Ginseng, might cause some adverse effects if the patient's body constitution does not match the qi-deficiency. However, others have reported the Ginseng as the treatment of qi-deficiency caused by any reasons [50].
Further researches are needed to assess beneficial and adverse effects of KRG more accurately.
7. GarlicPrevious conducted researches have reported a lipid-lowering effect for garlic and some others have counted fibrinolytic activity and lowering blood pressure as therapeutic roles of garlic. Few studies have also reported garlic to be beneficial for treatment of tinnitus [6]. Garlic's effect on tinnitus is attributable to improve blood flow of cochlea as a result of its antiplaque formation ability, stabilizing blood pressure, and augmentation in antioxidant capability of the blood. No scientific studies have been conducted for approving these effects and all of them are theoretical [51].
8. Yoku-kan-sanThere are more than 120 plants approved by Japanese ministry of health, labor, and welfare, which are now being used in practice as traditional medications [52]. Yoku-kan-san, a traditional Japanese herbal medication, is one of these approved herbal medications composed from seven plants (Angelicae Radix, Atractylodis Lanceae Rhizoma, Bupleuri Radix, Poria, Glycyrrhizae Radix, Cnidii Rhizoma, and Uncariae Uncis Cum Ramlus). This combination is more frequently used as treatment of psychological conditions such as irritability, insomnia, night terrors, and hypnic myoclonia, especially in infant patients [53]. Although, there are not enough clinical investigation and convincing data for beneficial effect of Yoku-kan-san on tinnitus, but it has been shown to be effective for tinnitus resulted from undifferentiated somatoform disorder in a 44-year-old woman [54]. There is an obvious need for more clinical researches to support such kind of case reports.
Today's world is going toward the use of medicinal plants and herbal medicines, which are now finding their place among people. Conditions with no precise pharmacologic treatment, such as tinnitus, are more probable to be resolved by herbal medications. In this chapter, we tried to review current medicinal plants for treatment of tinnitus; however, currently, there is a lack of clinical research in this issue. The effect of herbal medications on tinnitus should be investigated in more future clinical researches.
https://www.intechopen.com/online-first/herbal-medicine-in-the-management-of-tinnitus/

Association of low‐frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts

Genome‐wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low‐frequency variants may account for some of the "missing" heritability. Therefore, we scanned low‐frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP‐Seq studies in craniofacial tissues or cell lines contained multiple low‐frequency (0.01–1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low‐frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p‐value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p‐value = .001). These findings suggest that low‐frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.

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Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships

The most frequent cause of isolated complex III deficits is mutations to the nuclear‐encoded ATPase BCS1L. Disease phenotypes are varied and can be as mild as Björnstad syndrome, characterized by pili torti and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. BCS1L mutations are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving low birth weight, renal and hepatic pathologies, hypotonia, and developmental delays. We analyzed all published patient cases of mutations to BCS1L and modeled the tertiary and quaternary structure of the BCS1L protein to map the location of disease‐causing BCS1L mutations. We show that higher order structural analysis can be used to understand the phenotype observed in a patient with the novel compound heterozygous c.550C>T(p.Arg184Cys) and c.838C>T(p.Leu280Phe) mutations. More broadly, higher order structural analysis reveals genotype–phenotype relationships within the intermediate complex III deficiency category that help to make sense of the spectrum of observed phenotypes. We propose a change in nomenclature that unifies the intermediate phenotype under "BCS1L Mitopathies". Patterns in genotype–phenotype correlations within these BCS1L Mitopathies are evident in the context of the tertiary and quaternary structure of BCS1L.

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Parents' perceptions of functional abilities in people with Down syndrome

Abstract

A realistic assessment of the range of functional abilities found in people with Down syndrome (DS) may assist in counseling expectant parents. This study asked parents from the United States and the Netherlands to assess 11 functional skills of their sons and daughters with DS: walking, eating, speaking, grooming/personal hygiene, reading, writing, preparing meals, working at a job, going on dates, traveling independently, and living independently. We analyzed responses from 2,658 parents who have sons/daughters with DS of all ages. The majority of people with DS in the United States could walk by 25 months of age, speak reasonably well by 12 years, maintain their own personal hygiene by 13 years, and work independently by 20 years. By 31 years of age, 49% were reading reasonably well, and 46% were writing reasonably well. Approximately 30% could travel independently, and 34% were living independently. The results from parents in the Netherlands were similar for most measures. This normative data on function may contribute to anticipatory guidance and decision‐making. Furthermore, as parents and clinicians seek to assess the relative strengths and weakness of people with DS, resources and supports can be marshaled for those not meeting milestones at expected times.

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Quantitative Tests Reveal that Microtubules Tune the Healthy Heart but Underlie Arrhythmias in Pathology

Key points

Our group previously discovered and characterized the microtubule mechanotransduction pathway linking diastolic stretch to NADPH oxidase 2 derived reactive oxygen species signals that regulate calcium sparks and calcium influx pathways. Here we used focused experimental tests to constrain and expand our existing computational models of calcium signaling in heart. Mechanistic and quantitative modeling revealed new insights in disease including: changes in microtubule network density and properties, elevated NOX2 expression, altered calcium release dynamics, how NADPH Oxidase 2 is activated by and responds to stretch, and finally the degree to which normalizing mechano‐activated reactive oxygen species signals can prevent calcium dependent arrhythmias.

Abstract

Microtubule (MT) mechanotransduction links diastolic stretch to generation of NADPH oxidase 2 (NOX2) dependent reactive oxygen species (ROS), signals we term X‐ROS. While stretch elicited X‐ROS primes intracellular calcium (Ca²⁺) channels for synchronized activation in the healthy heart, the dysregulated excess in this pathway underscores asynchronous Ca²⁺ release and arrhythmia. Here, we expanded our existing computational models of Ca²⁺ signaling in heart to include MT‐dependent mechanotransduction through X‐ROS. Informed by new focused experimental tests to properly constrain our model, we quantitate the role of X‐ROS on excitation‐contraction coupling in healthy and pathological conditions. This approach allowed for a mechanistic investigation that revealed new insights into X‐ROS signaling in disease including: changes in MT network density and PTMs, elevated NOX2 expression, altered Ca²⁺ release dynamics (i.e., Ca²⁺ sparks and Ca²⁺ waves), how NOX2 is activated by and responds to stretch, and finally the degree to which normalizing X‐ROS can prevent Ca²⁺‐dependent arrhythmias.

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The whole cell Ca2+ release‐activated Ca2+ current ICRAC is regulated by the mitochondrial Ca2+ uniporter channel and is independent of extracellular and cytosolic Na+

Key points

Ca²⁺ entry through Ca²⁺ release‐activated Ca²⁺ channels activates numerous cellular responses. Under physiological conditions of weak intracellular Ca²⁺ buffering, mitochondrial Ca²⁺ uptake regulates CRAC channel activity. Knockdown of the mitochondrial Ca²⁺ uniporter channel prevented the development of I_CRAC in weak buffer but not when strong buffer was used instead. Removal of either extracellular or intra‐pipette Na⁺ had no effect on the selectivity, kinetics, amplitude, rectification or reversal potential of whole cell CRAC current Knockdown of the mitochondrial Na⁺‐Ca²⁺ exchanger did not prevent the development of I_CRAC in strong or weak Ca²⁺ buffer. Whole cell CRAC current is Ca²⁺‐selective Mitochondrial Ca²⁺ channel and not Na⁺‐dependent transport regulates CRAC channels under physiological conditions. Ca²⁺ entry through store‐operated Ca²⁺ release‐activated Ca²⁺ (CRAC) channels plays a central role in activation of a range of cellular responses over broad spatial and temporal bandwidths. Mitochondria, through their ability to take up cytosolic Ca²⁺, are important regulators of CRAC channel activity under physiological conditions of weak intracellular Ca²⁺ buffering. The mitochondrial Ca²⁺ transporter(s) that regulates CRAC channels is unclear and could involve the 40 KDa mitochondrial Ca²⁺ uptake channel MCU or the Na⁺‐Ca²⁺‐Li⁺ exchanger (NCLX). Here, we have investigated the involvement of these mitochondrial Ca²⁺ transporters in supporting the CRAC current I_CRAC under a range of conditions in RBL mast cells. Knockdown of the MCU impaired the activation of I_CRAC under physiological conditions of weak intracellular Ca²⁺ buffering. In strong Ca²⁺ buffer, knockdown of the MCU channel did not inhibit I_CRAC development demonstrating that mitochondria regulate CRAC channels under physiological conditions by buffering of cytosolic Ca²⁺ via the MCU channel. Surprisingly, manipulations that altered extracellular Na⁺, cytosolic Na⁺ or both failed to inhibit the development of I_CRAC in either strong or weak intracellular Ca²⁺ buffer. Knockdown of NCLX also did not affect I_CRAC. Prolonged removal of external Na⁺ also had no significant effect on store‐operated Ca²⁺ entry, on cytosolic Ca²⁺ oscillations generated by receptor stimulation or on CRAC channel‐driven gene expression. In the RBL mast cell, Ca²⁺ flux through the MCU but not NCLX is indispensable for activation of I_CRAC.

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Comparison of pulse contour, aortic Doppler ultrasound and bioelectrical impedance estimates of stroke volume during rapid changes in blood pressure

New Findings

What is the central question of this study?

Pulse contour analysis of the finger arterial pressure by Windkessel modeling is commonly used to continuously estimate stroke volume; but, is it valid during dynamic changes in blood pressure?

What is the main finding and its importance?

Second‐by‐second analysis revealed that pulse contour analysis underestimated stroke volume by up to 25% after standing from a squat, and 16% after standing thigh cuff release when compared to aortic Doppler ultrasound estimates. These results reveal that pulse contour analysis of stroke volume should be interpreted with caution during rapid changes in physiological state.

Abstract

Dynamic measurements of stroke volume (SV) and cardiac output (Q̇) provide an index of central hemodynamics during transitional states, such as posture changes and onset of exercise. The most widely used method to assess dynamic fluctuations in SV is the Modelflow method, which uses the arterial blood pressure waveform along with age and sex specific aortic properties to compute beat‐to‐beat estimates of aortic flow. Modelflow has been validated against more direct methods in steady state conditions, but not during dynamic changes in physiological state, such as active orthostatic stress testing. The present study compared the dynamic SV responses from Modelflow (SV_MF), aortic Doppler ultrasound (SV_U/S), and bioelectrical impedance analysis (SV_BIA) during two different orthostatic stress tests, a squat‐to‐stand (S‐S) transition, and standing bilateral thigh cuff release (TCR) in 15 adults (6 females). Second‐by‐second analysis revealed that when compared to estimates of SV by aortic Doppler ultrasound, Modelflow underestimated SV by up to 25% from 3 – 11 seconds after standing from the squat position and by up to 16% from 3 – 7 seconds following TCR (P < 0.05). SV_MF and SV_BIA were similar during the first minute of the S‐S transition but were different 3 seconds after TCR, and at intermittent time points between 34 and 44 seconds (P < 0.05). These findings indicate that the physiological conditions elicited by orthostatic stress testing violate some of the inherent assumptions of Modelflow and challenge models used to interpret bioelectrical impedance responses resulting in an underestimation in SV during rapid changes in physiological state.

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Paravascular spaces, entry or exit from the brain?

New Findings

What is the topic of this review?

In this symposium report we review the glymphatic clearance from the brain.

What advances does it highlight?

Evaluation of the evidence indicates that cerebrospinal fluid flows along paravascular spaces at the surface of the brain. However, bulk flow along penetrating arteries into the brain, followed by exit along veins, requires further confirmation. Clearance from the brain, based on mixing, may provide an alternative explanation for experimental findings.

Abstract

The interstitial fluid (ISF) of the brain provides the environment for proper neuronal function. Maintenance of volume and composition of ISF requires regulation of influx and removal of water, ions, nutritive and waste products. The recently described glymphatic pathway may contribute to some of these functions. It proposes that cerebrospinal fluid (CSF) enters the brain via paravascular spaces along arteries, mixes with ISF, and leaves the brain via paravascular spaces along veins. In this symposium report we review the glymphatic concept, its concerns, and alternative views on ISF‐CSF exchange.

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Dynamic heart rate response to multi‐day unsupported ultra‐endurance cycle racing: A case report

New Findings

What is the main observation in this case?

Ultra‐endurance cycle racing is known to lead to suppressed heart rates as a product of time spent racing. This case report identifies a racer who experienced this phenomenon initially, but then uniquely experienced an overall increase in heart rate late in the race.

What insight does it reveal?

In this case, unique chronotropic disturbances to heart rate occurred as a result of the many extreme demands of ultra‐endurance racing. Work should now focus on identifying the frequency of this response in other racers and whether the causes are physiological, environmental or genetic in nature.

Abstract

Participation in ultra‐endurance cycling events such as the Transcontinental Race is increasing. These extremely demanding races provide a unique opportunity for field observation as to the limits of human endurance physiology and importantly, when these limits might be exceeded, and crossover into pathology. The heart is of special interest in this field and previous data suggest 'reverse drift' of heart rate occurs as a product of time and load in races of 24 ‐ 48 hrs, whilst transient structural abnormalities have been observed upon completion of running ultramarathons. Here, we report a unique case of a male cyclist racing in the Transcontinental Race over an extended period of 14 days characterised by extreme workloads and low quantity and quality of sleep. Heart rate response was dynamic over the course of the race and defined by a U‐shaped quadratic relationship. Larger scale study is required to determine the relevance of this information to the ultra‐endurance cycling community.

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