This continuing series gathers and presents original research results on the leading edge of medicine and biology. Each article has been carefully selected in an attempt to present substantial topical data across a broad spectrum. Topics discussed in this book include gastroesophageal reflux disease and sleep disorders; soybean-derived thyroglobulin as an analyte specific reagent for in vitro diagnostic tests and devices; optic neuritis and sarcoidosis; radiculotherapy; impact of betaine HCl on the absorption of orally administered drugs; relationships between disease activity, work-home conflict, and burnout among Crohn's disease patients; global challenges in the identification and management of pre-eclampsia; management of fibromialgia symptoms; acid indigestion; environmental factors stimulating the manifestation of iodine deficiency disorders; preoperative serum thyroglobulin concentration as a predictive factor of malignancy in follicular and hurthle cell neoplasms of the thyroid gland; thyroglobulin antibodies in patients with skin disorders; and financing health care.
Chapter 1 - Sleep disorders place an immense burden on the lives of 50-70 million Americans every year leading to impairments in a multitude of categories, including health, quality of life, and work productivity. With advances in sleep research technology, the authors now have a more comprehensive understanding of the mechanisms behind these sleep disorders allowing them to focus on the interactions of sleep with numerous disease processes. In particular, the relationship between gastroesophageal reflux disease (GERD) and sleep disorders has been studied, revealing an increased prevalence of sleep disorders in patients with GERD compared to the general population. This chapter reviews the consequences of these sleep disorders, the clinical evidence on the relationship between GERD and sleep disturbances, and the impact these disorders have on health related quality of life. Finally, a review of available medical intervention trials offers encouraging results that pharmacological therapy for GERD may improve the associated sleep disturbances. A broader awareness of the prevalence and impact of GERD-related sleep disorders may prove to increase early interventions, improving not only quality of life but also long term outcomes.
Chapter 2 - Presently, human thyroglobulin is extracted from cadaver or surgically resected thyroid tissue. Such reliance on human organs for recovery and purification of proteins required for diagnostic applications complicates the manufacturing process from acquisition, to purification and quality control. These limitations have defeated efforts to establish a universally recognized standard, preventing normalization of assays to detect circulating thyroglobulin or antibodies against this protein.
Unfortunately, producing intact, recombinant human thyroglobulin in protein expression systems is a daunting task that, until recently, has not been successful. The authors have achieved expression of full-length human thyroglobulin in stable lines of soy, and have been able to purify this protein from transgenic soybean seeds.
This accomplishment provides several manufacturing advantages, as well as some potential solutions for the problems encountered when using thyroid-extracted thyroglobulin.
The uniformity of recombinant protein is especially attractive when one considers the numerous post-translational modifications occurring in thyroid cells.
The ease of production and purification of soybean-derived thyroglobulin is cost effective, but also allows for manufacturing flexibility in that protein expression can be separated in time and geography from the final purification of this protein in soy powders. Taken together, soybean-derived thyroglobulin has characteristics consistent with those necessary and desired for an industry standard.
The availability of a renewable source of recombinant human thyroglobulin also has implications for solving some of the open-ended problems in diagnostic assays which employ this protein. Immobilization or radiolabeling heterogeneous lots of thyroid-derived thyroglobulin are variables which should be minimized with more homogenous starting material. Furthermore, the ability to remove interfering anti-thyroglobulin antibodies from patients' sera or tissue homogenates could also be accomplished using devices constructed from a plentiful source of renewable thyroglobulin.
Our ability to express full length human thyroglobulin in transgenic soybean seeds provides, for the first time, a practical solution for the many limitations inherent in present day diagnostic assays that currently must rely on a protein isolated from primary thyroid tissue.
Chapter 3 - Optic neuritis is one of the most common manifestations of neurosarcoidosis. It may occur alone or in association with other neurologic manifestations. It may be confused with other causes of optic neuritis, including multiple sarcoidosis. Since neurosarcoidosis responds to anti-inflammatory therapy, it is an important disease to diagnose or exclude in a patient who presents with optic neuritis. In this review, the author will discuss when to consider the diagnosis of sarcoidosis and the treatment of optic neuritis due to sarcodoisis. There are an increasing number of treatment options for sarcoidosis. The authors' review will allow the clinician to apply an evidence based approach to therapy.
Chapter 4 - Radiculopathy is a clinical condition commonly characterized by symptoms including numbness, tingling, pain and/or loss of strength in a region that corresponds to compression of a nerve in the spine. Loss of strength in particular is more suggestive of damage to the involved nerves and may present more often in situations where the symptoms were experienced for an extended period of time prior to presentation and/or there was related trauma or additional cause. Additionally, increased sensitivity can also be noted in a particular area or region (hypersensitivity). This can occur all along the spinal cord where an anatomic compression of a nerve root results from items such as a mechanical disturbance, injury, mass effect from a lesion, infection, medication effect or congenital issue. The most common region for radiculopathy is in the lumbar region and the cervical region, but it can also occur in the thoracic or middle portion of the spine.
The distribution of the specific nerve roots involved typically correlate with the signs and symptoms on patient presentation. Sensation and muscular signals in the upper extremities, neck involve the nerve roots of the cervical spine. The sensation and muscle innervation of the thoracic area, the chest and back correlate with the nerves of the thoracic spine and the more common region of the lumbar spine involves nerves supplying and receiving nerve impulses of the lower extremities, lower back and buttocks. The signs and symptoms typically seen include localized numbness, tingling pain and/or loss of strength in the involved areas. Lower back and extremity pain may be described by patients as radiating from the lower back to the extremities, which is also referred to as sciatic pain.
Chapter 5 - For drugs given orally in a solid dosage form (i.e. tablets, capsules, etc.), drug absorption is heavily dependent on the stomach for drug dissolution and solubilization. One of the main factors to influence these processes is the presence of hydrogen ions, which are secreted into the lumen of the stomach by parietal cells and are responsible for the high acidity (low pH) of the gastric environment. Though gastric pH has been recognized by many previous publications for its importance in food digestion and the absorption of nutrients, it is especially important from a pharmacologic standpoint, as perturbations in gastric pH can have a significant impact on oral drug absorption and exposures, particularly for those drugs that display a pH-dependent solubility. Furthermore, with the wide availability and usage of acid reducing agents such as proton-pump inhibitors or H_2-receptor antagonists, it is not unlikely that a drug would be co-administered at an elevated gastric pH, otherwise known as pharmacologically-induced hypochlorhydria. In this short communication, the authors evaluate the effects of betaine HCL a natural supplement found in over-the-counter digestive aids, on gastric pH and the potential impact it may have on the absorption of orally administered drugs co-administered with acid reducing agents.
Chapter 6 - Objective: Crohn's disease (CD) is a chronic inflammatory disease characterized by periods of exacerbation and remission. Periods with increased disease activity influence daily life management. The aim of this study was to examine the relationships between work-home conflict, occupational exhaustion and disease activity.
Method: eighty-eight patients with active (n=27) or inactive (n=61) CD were included in the study. Disease activity was determined by the Harvey Bradshaw index, work-home conflict, and occupational exhaustion was measured. Patients were compared with healthy controls (n = 88).
Results: data's showed that: 1) patients with high disease activity reported more work-home interference and occupational exhaustion than patients with low disease activity; 2) the predictive power of disease activity on work-home interference and occupational exhaustion, accounting for significant amounts of variance (24%-12%); 3) work-home interference partially mediated the relationship between disease activity and occupational exhaustion. An indirect effect test indicated that the inclusion of work-home interference in the statistical models was statistically meaningful.
Conclusions: Gastroenterology care programs should pay special attention to work-home conflict in order to decrease the negative impact of CD activity on occupational exhaustion. Patients' work experiences should be included in their clinical treatment.
Chapter 7 - Although maternal mortality is thought to be declining, it is estimated that around 800 women die daily as a result of complications of pregnancy. 85% of this burden lies with Sub-Saharan Africa and Southern Asia and all ten of the countries with the highest maternal mortality ratios are in Africa. Pre-eclampsia (defined as hypertension and proteinuria occurring after 20 weeks' gestation of pregnancy) is a leading cause of maternal morbidity and mortality in the developing world, and is also associated with poor fetal outcomes, including fetal growth restriction, and intrauterine fetal death. The World Health Organisation estimates that around 26% of severe maternal pregnancy outcomes are associated with pre-eclampsia, and it is thought to be responsible for approximately 40,000 maternal deaths annually. 99% of these deaths occur in developing countries.
There are a number of factors and challenges contributing to the stark disparity in pre-eclampsia related morbidity and mortality in the developing world, compared to the developed world. Restricted or under-staffed maternity services, particularly in rural areas with poor transport systems, mean that women in low and middle-income countries may present late or infrequently to antenatal care where pre-eclampsia (a frequently asymptomatic condition) may be diagnosed. However, even when uptake of antenatal healthcare is high, pre-eclampsia remains under-diagnosed. Early and accurate identification of at-risk women depends on regular and accurate blood pressure monitoring. However, training in the use of the technically challenging sphygmanometer may be insufficient, and equipment may be lacking or defective. Detection of proteinuria by dipstick has low specificity and depends on a regular supply of accurate urine dipsticks.
Once pre-eclampsia is diagnosed (often at a late stage), skilled management is essential (timely delivery of the infant with skilled attendance, preceded by blood pressure control and seizure prevention). However, access to such care may be restricted by transport limitations and referral options, particularly for poor women in rural settings. Once care has been accessed, the quality may be sub-standard. For example, although magnesium sulphate has been shown to be effective for the prevention and control of eclamptic seizures it is yet to be widely used in many low and middle income countries.
Efforts to reduce maternal morbidity and mortality due to the complications of pre-eclampsia in low and middle income countries must be based around improving detection of pre-eclampsia in community and primary care settings, accompanied by improved access to higher-level facilities which can safely induce labour or deliver by caesarean section, with the availability of appropriate high quality medications for blood pressure control and seizure prophylaxis.
Chapter 8 - Fibromialgia is a rheumatologic condition characterized by generalized pain and the presence of multiple trigger points. Most of the patients also present with a complex symptomatology that can include other clinical manifestations such as fatigue, sleep disturbances, joint stiffness, deteriorated functional capacity, cognitive alterations and balance impairment. In particular, balance impairments are one of the 10 most debilitating symptoms in Fibromialgia. Balance and functionality alterations can have consequences such as falls, anxiety and decreased confidence. They also have a significant impact in the subject's quality of life and in society due to the associated physical, psychological, social and economic complications.
Physiotherapy is a non-pharmacological treatment approach that is recommended in the clinical guidelines for the general management of Fibromialgia. Diverse authors have analysed the effects of Physiotherapy on Fibromialgia symptoms. However, they did not analyse the specific effects on balance and functional capacity.
A systematic review of the most recent studies was carried out focusing on the clinical effectiveness of Physiotherapy on postural balance and functionality in subjects diagnosed with Fibromyalgia. The treatment techniques that were used in the interventions were: Whole body vibration, miofascial release, balneotherapy and physical exercise. The treatment modalities that showed better results on postural balance were whole body vibration, balance exercises and water based exercises. The treatment techniques that showed significant improvements on functional capacity were whole body vibration, miofascial release, balneotherapy and physical exercise.
Considering the reported benefits of Physiotherapy in the management of Fibromiaigia symptoms, and the impact that balance alterations and functionality deficits have in the quality of life of these patients, the objective of this chapter is to analyse the results achieved by different authors on different Physiotherapy techniques in relation to these specific symptoms.
Chapter 9 - Acid indigestion is a term commonly used by patients and physicians to indicate some form of gastrointestinal tract upset. It includes a wide variety of symptoms, such as early satiety, nausea, bloating and abdominal discomfort. These vague upper gastrointestinal symptoms have been termed dyspepsia. Functional dyspepsia, which is characterized by persistent or recurrent pain or discomfort centered in the upper abdomen based on Rome criteria, is accounted to be approximately 20% in the general population.
Occasionally, patients use the term indigestion, to describe heartburn. However, it is defined more specifically as a burning sensation in the retroesternal area of variable intensity. Likewise, this retroesternal burning, is the mainly symptom associated with gastroesophageal reflux disease (GERD).
The epidemiological aspects of heartburn and GERD have been object of growing interest in the last decade because its increasing prevalence and the complications of the disease. Population-based studies suggest that GERD is a common condition with a prevalence ranging between 10-20% in North America. The impact of GERD extends beyond its economic burden, as it significantly impaired health-related quality of life. Both dyspepsia and GERD are frequent chronic, often need long term treatment. Moreover, several studies have reported a higher prevalence of dyspeptic symptoms in patients with GERD. In this chapter, the authors will review the cause, identify the symptoms and discuss treatment of patients with heartburn and acid indigestion.
Chapter 10 - Pregnancy induces several major changes to thyroid physiology. Women with inadequate iodine nutrition in pregnancy may be particularly vulnerable to the effects of environmental thyroid disruptors (thiocyanates released from tobacco smoke, high nitrate levels in drinking water and food products, selenium deficiency). The aim of this study was to evaluate the association between iodine deficiency and some environmental factors, stimulating the manifestation of iodine deficiency in pregnant women.
Subjects of study were 128 pregnant women aged 27.97 ± 5.94 years from the town and district of Plovdiv, South Bulgaria. For the purpose of the study were measured the indicators: urinary iodine and thiocyanate concentrations, serum nitrate and selenium levels.
The median urinary iodine of the inspected pregnant women was 123 μg/L, which is an indicator for insufficient iodine intake in pregnancy; 58.6% of the women had iodine deficiency.
The mean urinary thiocyanate concentration was 3.94 ± 1.93mg/L. Almost 2/3 of smokers and passive smokers had higher urinary thiocyanate levels compared to the mean value. Association between tobacco smoke exposure and frequency of iodine deficiency of the inspected pregnant women was statistically significant (OR=2.250, 95% CI 1.046-4.841, P=0.0397).
The mean serum nitrate concentration of the pregnant women was 22.7±10.21 μmol/ L. The term of pregnancy exerts an influence on the nitrate serum level (p=0.002) during the trimesters. The nitrate serum level in the third trimester was significantly higher than those in the second trimester (p<0.0001). The association between serum nitrate level and frequency of iodine deficiency was statistically significant (OR=4.266; 95%CI 1.589-11.452; χ2= 9.08, p=0.0029).
The mean serum selenium level of the studied women was 794.58±193.59 nmol/L. Approximately half (46.7%) of the inspected pregnant women were with low serum selenium levels. The risk about iodine deficiency by low serum selenium levels in pregnant women was increased (OR=2.994, 95%CI 1.136-7.894; χ2=5.01, p=0.0316).
These findings demonstrate the necessity for more adequate prophylactic steps for improvement of iodine status during pregnancy. Thiocyanate levels should be carefully controlled in cases of severe iodine deficiency to avoid a competitive inhibition of iodine intake. The results confirm the potential role of high nitrate level as an environmental factor stimulating the manifestation of iodine deficiency. Selenium as essential trace element plays a key role in the thyroid hormone metabolism. Combined selenium and iodine deficiency have negative influence on the thyroid hormone regulative functions, especially during pregnancy.
Chapter 11 - Background: Preoperative distinction between benign and malignant follicular or Hurthle cell neoplasms based on cytologic examination of a fine-needle aspiration biopsy specimen is not possible. Preoperative measurement of serum thyroglobulin (Tg) is not recommended for initial evaluation of thyroid nodules, even though Tg concentrations are higher in follicular as well as Hiirthle cell carcinomas than in benign follicular or Hurthle cell tumors. The aim of this study was to establish the cut-off value of the preoperative serum Tg concentration as a predictive factor of malignant disease in patients with a follicular or Hurthle cell neoplasm.
Methods: In total, 667 patients (555 females, 112 males, age range 9-86 years, median age 52 years) with follicular or Hurthle cell neoplasm were surgically treated at out Institute from 1988 to 2009. Patients with distant and/or regional metastases were excluded from the authors' study. The risk factors for malignancy were identified by the chi-square test and multivariate logistic regression.
Results: Altogether, 634 patients (523 females, 111 males, age range 9-86 years, median age 53 years) had negative Tg-autoantibodies and were included in the authors' study. The median tumor size was 3 cm (range 0.4-12 cm). The histopathological diagnoses were carcinoma, adenoma and benign goiter in 189 (30%), 253 (40%) and 192 (30%) patients, respectively. The predictive factors for carcinoma shown by the chi-square test were: age of the patients, tumor size, volume of the thyroid gland and preoperative Tg concentration. The independent predictors of malignancy as shown by multivariate logistic regression were; tumor larger than 4 cm (OR 1.73 P= 0.011), solitary tumor (OR 1.52, P=0.037), and Tg concentration of more than 499 ng/mL (OR 1.85, P=0.003).
Conclusion: The independent predictors of malignancy in follicular or Hurthle cell neoplasms are: tumor size, preoperative Tg concentration and solitary tumor. A total thyroidectomy should be considered in patients with follicular or Hurthle cell neoplasm in the case of solitary tumor larger than 4 cm and preoperative Tg concentration higher than 499 ng/mL, as the possibility of malignancy is significant.
Chapter 12 - Thyroid disorders are known to involve all organ systems in the body and the skin is no exception. Some dermatological skin findings and diseases may be the first symptoms of thyroid disease. Skin manifestations of thyroid dysfunction may be divided into two main categories: (I) direct action of thyroid hormone on skin tissues, and (II) autoimmune skin disease associated with thyroid dysfunction of autoimmune etiology. The nature of the relationship between anti-thyroid autoimmunity and the pathogenesis of autoimmune diseases is presently unknown. Possible explanations include: (1) immunomodulatory effects of anti-thyroid antibodies, (2) molecular mimicry between thyroid and disease-specific epitopes, and (3) genetic link between anti-thyroid autoimmunity and the susceptibility to autoimmune disease. A list of autoimmune conditions apparent when examining the skin includes: vitiligo, alopecia areata, chronic urticaria, bullous disorders and connective tissue diseases.
This chapter is an attempt to update the current knowledge about the relationship between the thyroglobulin antibodies and the skin diseases. Although cutaneous manifestations of autoimmune thyroid diseases are well described, a better understanding of these processes is needed. It is a multidisciplinary problem requiring cooperation of specialists in different fields of medicine. Both dermatologists and endocrinologists have to inquire their patients about the family history of autoimmune diseases and to look for associated autoimmune disorders.
Chapter 13 - Worldwide there are different systems for providing pharmacy services. Most countries have some element of state assistance, either for all patients or selected groups such as children, and some private provisions. Medicines are financed either through cost sharing or full private. The role of the private services is therefore much more significant. Nationally, there is a mismatch between the numbers of pharmacists and where are they worked, and the demand for pharmacy services. The position is exacerbated locally where in some areas of poor; there is a real need for pharmacy services, which is not being met and where pharmacists have little spare capacity. Various changes within the health-care system require serious attention be given to the pharmacy human resources need. In order to stem the brain drain of pharmacists, it is, however, necessary to have accurate information regarding the reasons that make the pharmacists emigrate to the private sector. Such knowledge is an essential in making of informed decisions regarding the retention of qualified, skilled pharmacists in the public sector for long time. There are currently 3000 pharmacists registered with the Sudan Medical Council of whom only 10% are working with the government. The pharmacist: population ratio indicates there is one pharmacist for every 11,433 inhabitants in Sudan, compared to the World Health Organisation (WHO) average for industrialised countries of one pharmacist for 2,300 inhabitants. The situation is particularly problematic in the Southern states where there is no pharmacist at all. The distribution of pharmacists indicates the majority are concentrated in Khartoum state. When population figures are taken into consideration all states except Khartoum and Gezira states are under served compared to the WHO average. This mal-distribution requires serious action as majority of the population is served in the public sector. This study reveals the low incentives, poor working conditions, job dissatisfaction and lack of professional development programmes as main reasons for the immigration to the private-sector. The objective of this communication is to highlight and provide an overview of the reasons that lead to the immigration of the public sector pharmacists to the private-sector in Sudan. The survey has been carried out in September 2004. Data gathered by the questionnaires were analysed using Statistical Package for Social Sciences (SPSS) version 12.0 for windows. The result have been evaluated and tabulated in this study. The data presented in this theme can be considered as nucleus information for executing research and development for pharmacists and pharmacy. More measures must be introduced to attract pharmacists into the public sector. The emerging crisis in pharmacy human resources requires significant additional effort to gather knowledge and dependable data that can inform reasonable, effective, and coordinated responses from government, industry, and professional associations.

Preface vii

Chapter 1 Gastroesophageal Reflux Disease and Sleep Disorders: A Wake-Up Call for Physicians and Their Patients 1

Edward C. Oldfield IV, MD, Parth J. Parekh, MD, Vaishnavi Challapalli Sri, MD and David A. Johnson, MD, MACG, FASGE, FACP

Chapter 2 Soybean-Derived Thyroglobulin As an Analyte Specific Reagent for In Vitro Diagnostic Tests and Devices 23

Kenneth L. Bost, Kevin C. Lambirth, Laura C. Hudson and Kenneth J. Filler

Chapter 3 Optic Neuritis and Sarcoidosis 41

Robert P. Baughman and Karl C. Golnik

Chapter 4 Radiculotherapy: Diagnosis, Treatment Options and Clinical Outcomes 59

Han Chen, MD, Sean W. Kaloostian, MD and Paul E. Kaloostian, MD

Chapter 5 Impact of Betaine HC1 on the Absorption of Orally Administered Drugs 67

Marc R. Yago, Joseph A. Ware and Leslie Z. Benet

Chapter 6 Relationships between Disease Activity, Work-Home Conflict and Burnout among Crohn's Disease Patients 73

Farida Mouda, Marcel Lourel, Pr., Judith Mouchard, Julien Blot, Eric Lerebours, Pr. and Guillaume Savoye, Pr.

Chapter 7 Global Challenges in the Identification and Management of Pre-Eclampsia 89

M. Hall, N. L. Hezelgrave and A. H. Shennan

Chapter 8 Management of Fibromia lgia Symptoms: Effectiveness of Physiotherapy on Balance and Functionality 103

Elisa Maria Garrido Ardila, Luis Espejo Antunez, Juan Rodriguez Mansilla and Maria Victoria Gonzalez Lopez-Arza

Chapter 9 Acid Indigestion: Causes, Symptoms and Treatment Options 115

Renata Carvalho de Miranda Chaves, MD and Tomds Navarro-Rodriguez, MD, PhD

Chapter 10 Environmental Factors Stimulating the Manifestation of Iodine Deficiency Disorders: A Study on Pregnant Women 129

Anelia V. Bivolarska, MD, Penka D. Gatseva, MD, PhD and Tatyana I. Vlaykova, PhD

Chapter 11 Preoperative Serum Thyroglobulin Concentration as a Predictive Factor of Malignancy in Follicular and Hurthle Cell Neoplasms of the Thyroid Gland 145

Nikola Besic and Jerica Skedelj

Chapter 12 Thyroglobulin Antibodies in Patients with Skin Disorders 159

Emina Kasumagic-Halilovic, Nermina Ovcina-Kurtovic and Sladana Samardzic

Chapter 13 Financing Health Care: How to Bridge the Gap in Human Resources for Health 171

Abdeen M. Omer and Gamal K. Ali

Index 201

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