Gastro-esophageal reflux disease (GERD) is among the most common chronic diseases in the Western world, affecting up to 30% of the general population in Europe and the US. It is a condition which develops when the acidic contents of the stomach flow backwards into the esophagus and cause what’s known as heartburn. While most patients respond well to the standard therapy of proton pump inhibitors which block acid-secreting cells in the stomach, we are still trying to understand the molecular reasons why 30-40% of reflux patients do not respond adequately to acid-suppressant therapy. Not only does GERD have a significant negative impact on health-related quality of life, but the over-subscription of ineffective drugs causes a significant economic burden on healthcare.

Heartburn is the most noticeable and troublesome symptom of GERD. From what we currently understand about the pathophysiology of the disease, we know that the reflux of acid evokes different types of pain, but the basic mechanisms and pathways by which this pain is generated is incompletely understood. The junction between the esophagus and stomach is structurally and functionally designed in a way to ensure that any acid secreted in the gastrointestinal tract flows towards the stomach, and not up onto the lining of the esophagus. This function is served by the muscle structure sitting at this junction, called the lower esophageal sphincter (LES), which ensures that the ingested food following a meal does not reflux. However, there are several factors which can make the LES’s job more difficult. One of the most obvious factors includes the excessive consumption of food, particularly during the later hours of the day. There is convincing evidence that 90% of reflux episodes occur post-prandially, due to minor elevations of intragastric pressure which causes the LES to relax and therefore allow the reflux of acid. In more advanced cases of reflux disease, acid pockets form at the gastroesophageal junction where unbuffered acid collects into a reservoir. When the LES fails in this setting, there is reflux of a higher volume of acid.

Focusing on the microscopic structure of the esophagus and stomach, we can see a minute yet essential difference between the linings of these two gastrointestinal organs. The esophagus has a stratified squamous epithelial lining, which acts as a tight protective barrier against food but is readily damaged when exposed to a chemical environment. On the other hand, the stomach is lined by tall columnar epithelium, which is designed to withstand very low pH and high levels of proteolytic activity. Our gastrointestinal tract (and the human body in its entirety) is perfectly designed to carry out the specific role of transporting food from the oral cavity from the esophagus to the stomach, where it is digested for our nourishment. It is oftentimes our greediness and overindulgence which disrupt the perfect order of our anatomy at a molecular level, resulting in the macroscopic changes we see at endoscopy and the symptomatic discomfort we feel from the painful circumstances of reflux. 

The stomach is our center of nourishment. Given that every food particle has the purpose of nourishing the cells of our body, why do we so commonly make the mistake of eating excessively, nocturnally, and quickly? Fatty foods influence the relaxation of the lower esophageal sphincter, along with alcohol, coffee, and acidic drinks. Large meals and rapid food intake distend the stomach, increase intragastric pressure and facilitating the reflux of acid from the stomach. Given these, it is plain to see that, in most cases, simple lifestyle changes can prevent the development of such chronic and discomforting diseases. The following verse in the Holy Qur’an offers a short but very effective prescription: “Eat and drink, but do not be wasteful” (7:31).

The philosopher and physician Ibn Sina (Avicenna) summarized the science of medicine as follows: “Eat little when you eat, and after eating do not eat again for a certain period of time; health lies in digestion. There is nothing heavier for the body to tolerate than putting food after food in the stomach.” Frugality in eating is also echoed in the teachings of Prophet Muhammad, peace be upon him, who famously said “There is no vessel which the son of Adam can fill more evil than his stomach, for it is sufficient for him to take a few mouthfuls in order to straighten his back; but if he must, then fill one-third with food, one-third with drink, and one-third with air” (Tirmidhi).

The lifestyle factors that are strongly associated with GERD are obesity and smoking. In the 30-40% of GERD patients who do not respond to acid-suppressant therapy, simple lifestyle changes such as cutting out acidic drinks and eating more slowly, and not after 7 pm have been effective alternative treatments. While our understanding of molecular pain mechanisms of the esophagus need further improvement, the simple act of making minor changes in our eating habits can ensure that the anatomy and function of our gastrointestinal tract remains optimal.

The family is the smallest unit of society and it should be a source of happiness for the individual. This is why a sound dialogue between parents and their children is so important. When we bring up our children, we should regard them as being entrusted to us by the Almighty. Treating them affectionately and inspiring confidence in them plays an important role in terms of preparing them for their future life as physically and psychologically healthy individuals.

In spite of the cozy atmosphere of the home, we might come across some problems that are difficult to solve. Some problems are apparent to our friends and neighbors, while others are known only by family members and are kept secret. In such cases, we may not know how to deal with a problem, and therefore need to seek help from an expert. Wetting the bed is a typical example of such problems. When such a problem persistently occurs it is only compounded if we hurt the child and cause them to feel bad or inferior because of this problem; what many people do not realize is that this is a problem that is easily solved.

Families with children who wet the bed while between the ages of 5 and 15, sometimes even up to the age of 20 have a serious problem. Every morning, these families wake up to find another problem. The nasty smell, changing the sheets and cleaning the pajamas are not things that people enjoy first thing in the morning.

Along with the burden of dealing with dirty clothes and sheets, the family members become worried, as they do not know when the problem will end. But it is the child who worries most. The problem is only compounded as the child realizes that they cannot have friends to stay, nor stay at someone else’s house, as this may lead to others finding about the problem; such worries only cause further problems such as losing self-confidence, inferiority complexes, shyness and poor performance at school.

Some families do not try to search for solutions, saying illogical things like, “His uncle used to wet the bed too. That didn’t go on for too long. The same will happen with our child as well,” or “It’s nothing unusual. Most children do it. It will be alright,” or “It will just stop without treatment. They say that there is no treatment anyway.”

Bedwetting is actually a common problem. What then, are the underlying reasons? How common is it in reality? Is there an effective treatment for it? Does it just stop on its own? If so, when and how does it stop? Or is it possible for someone to remain a bed-wetter all of their lives? Does the treatment have any side effects? What is the success rate of the treatment? We will try to answer all these questions.

Occasional cases of bedwetting until the age of five are considered as nothing unusual. If bedwetting continues after the age of five, then this indicates an illness known as “enuresis.” Research carried out on primary school aged children found that between 20-30% of children wet the bed in general. It is usually more common among boys. The percentage increases with children from families of a lower socio-economic background, mostly due to malnutrition.

The main causes for bedwetting

Genetic factors are accepted as playing a role, based on the fact that 70% of the children who wet the bed have close relatives with the same problem, and that there is a high incidence rate among identical twins. It is thought to be caused mostly by a lack of an anti-diuretic hormone that reduces urine production at night. There are other reasons as well.

If a person with diabetes has too great an intake of fluids before bedtime they may wet the bed. Moreover, urinary tract infections, kidney stones, parasites, anemia, a lack of calcium, magnesium, zinc, or vitamins (A, B, D, E), problems with adenoids, and enlarged tonsils may all cause bedwetting.

Anemia and adenoids cause hypoxia (a deficiency of the amount of oxygen available in the blood) and hypercapnia (the presence of an abnormally high level of carbon dioxide in the blood). If these conditions are present, then the patient sleeps too soundly and the control of the central nervous system over the other systems is weakened. As a result, the patient wets the bed as they have lost some control over their muscles.

At least half of people who suffer from bedwetting are considered to do so because of psychological reasons. If a child begins to wet the bed in spite of having had no such problem before, this indicates that the child subconsciously wants to return to their infancy when they were the center of attention. By wetting the bed, the child might be wishing to receive more care from the parents.

Wetting the bed might be a reaction to family problems or the birth of a sibling. Various types of anxiety may cause the child to suffer from depression, which is another reason that causes very sound sleep.

Bedwetting is thought to result from psychological problems if it is accompanied by problems like suffering from a tic, stuttering, nail-biting, over-jealousy, or failure at school. A child with a urinary tract or bladder infection or kidney stones may not be able to control their need to urinate during the day either. If no physical illness can be detected, then there may be a serious psychological disorder.

Diagnosis and treatment

Starting from the principle “every disease has a cause,” we should first of all search for any possible causes. We can begin with simple ways, such as urine and blood tests. If these do not provide a satisfactory answer, then the other possible causes that were mentioned above should be investigated. The kidneys and the bladder should be checked with an ultrasound, while the adenoids and chronic bronchitis, as well as the tonsils, should be examined. If no viral or organic cause can be found, then psychological problems should be investigated. When the reason has been found, then it is time to start the treatment.

After a diagnosis has been made, the parents should be informed about the cause of the problem. It should also be noted that enuresis may result from incorrect forms of toilet training.

In the treatment of psychologically-caused cases of bedwetting, taking the child to a doctor, carrying out blood and urinary tests, and the family’s efforts to treat the child (i.e. paying for the treatment, waiting at the doctor’s, etc) are all considered to be part of the treatment. The child sees that importance has been given to them, that efforts are being made and that money is being spent on them alone. Having seen that the parents and the doctor have played their part, it is the child’s turn to do what is expected of them. Prescribing the correct medicine, or if there is no physical problem, merely saying, “nothing is wrong” is the start of the treatment.

If the bladder turns out to be smaller than normal, the child is advised to hold their urine longer than normal in order to expand the bladder. The period of waiting is lengthened gradually. The child is asked to keep a record of “wet” and “dry” days and they are rewarded for the “dry” days. Drinking less in the evening may facilitate treatment.

Medication and treatment

The medication changes according to the diagnosis. For instance, if there is a urinary tract or bladder infection, then antibiotics are used. If there are psychological reasons, special pediatric anti-depressants will be prescribed. Anti-depressants cause the patient to sleep lighter. When the child does not sleep so soundly, they are able to control their urination, and wake up and go to the toilet.

There are drugs that help to expand the bladder capacity of people whose bladders are smaller than normal; these drugs can be very useful indeed. Some problems with the urinary tract or bladder can also be eliminated by surgery.

If the patient has trouble breathing due to adenoids or enlarged tonsils, these should be removed by surgery as well. For anemia, the patient is given substances such as vitamins, iron and zinc along with a prescribed diet. In cases of calcium deficiency, a calcium-rich diet and calcium tablets are recommended.

If a child shows more than one of the symptoms, then a combined treatment is followed. Laser acupuncture treatment can also be useful. Bedwetting can be prevented by using anti-diuretic hormone tablets or sprays as well. With the correct diagnosis and treatment, the success rate of such treatments is between 95-98%.

The most common occurrence is that children will stop wetting the bed after puberty without any need for treatment. However, it is not a good idea to wait for this to happen, because treatment that will help bedwetting stop occurring is available. Only 2-5% of patients continue to wet the bed after the age of twenty. Most often, such patients wet the bed due to some organic problem.

The medicines prescribed against bedwetting have been in use for about 30-35 years; they have been proven to be safe and to have no side effects.

A related study

In a study carried out in Bursa, Turkey, the records of 164 patients who suffered from bedwetting were examined. According to this study, the following data was obtained: 52 patients (32%) were girls and 112 patients (68%) were boys. 36 of the boys were aged 6-8, 48 of them were aged 9-12 and the remaining 28 were 13 years of age or older. 20 girls were aged 6-8, 16 girls were aged 9-12 and 16 girls were 13 or older.

When the causes were investigated, it turned out that 18 of the 112 boys (16%) had urinary tract or bladder infections and kidney stones, while 18 boys were suffering from cystitis, which can be diagnosed with an ultrasound, 12 boys (11%) had problems with their adenoids, chronic bronchitis, and tonsils, which made breathing difficult for them. No organic causes were found in 64 patients (57%); in these cases it was found that the cause was purely psychological. 24 out of 52 girls (46%) had urinary tract or bladder infections, while the other 54% had psychological reasons for wetting the bed.

Half of the patients stopped wetting the bed at the end of the first month, and almost all the patients were treated successfully by the end of the second month. The success rate was 98%.

After having examined this data, it is clear that the problem of bedwetting is not difficult to solve without blaming and hurting our children. When we confront such problems in life, we should not despair or panic. We should keep in mind that God Almighty has created a cure for every problem, and that finding the cure requires patience and determination.

Mucus is a viscoelastic gel-like material. It has been used to describe the coating and/or lining layers of vertebrates (e.g. fish, mammals) and invertebrates (e.g. coelomates, molluscs) (Rose, 1992). As noted earlier, in mammals the term mucus is restricted to the material covering the epithelial surfaces and providing an interface between the external environment and the epithelial layers. In vertebrates, this interface provides lubrication, maintenance of tissue hydration, and cytoprotection against proteases – a group of enzymes that break down the bonds amoung aminoacids – pH extremes, chemical irritants, and biological agents. Whereas invertebrate mucus has additional biological functions, like navigation, locomotion, and structural support (Denny, 1989). In the human both, the importance of these biological functions may vary depending on the location of the mucus: for example, in the respiratory tract, to clear the airways of inhaled particles: in the eyes, to prevent corneal surfaces from drying: in the reproductive tract, to protect the uterine cavity and control the survival and penetrability of the spermatozoa. However, there is one important function common to all systems, namely the maintenance of the mucosal water balance.

The composition of mucus

It is important to know something about the biological composition of mucus. In humans, this viscoelastic gel usually contains more than 90% water, 0.5-5% high molecular weight glycoproteins, termed mucins, and also a large number of other components such as electrolytes, lipids, plasma proteins and nucleic acids. Mucins are extremely large and heavily glycosylated molecules that consist primarily of a non-globular, thread-like polypeptide backbone and 0-linked oligosaccharide side chains. Within the mucin producing cells the molecules are found, without water, within large membrane-bound granules that fill the upper part of the cell. It appears likely that the mucins are the major determinants of mucus behaviour, and non-mucin constituents such as DNA, lipids and proteins are, when present, likely to influence the properties of the gel (Carlstedt, 1988). However, acidic mucopolisaccharides and glycoproteins are the major macro- molecular components of mucus in other animals, such as marine snail mucus (Rose, 1992).

In general, the gel forming mucin macromolecules have an oligomeric structure and are assembled from subunits via disulphide bonds. They can be fragmented into subunits by reduction of these disulphide bonds (Thornton. 1995). On the basis of their sensitivity to proteases it is believed that mucins typically contain two different types of domains that are highly glycosylated regions (rich in serine and threonin) and ‘naked’ hydrophobic regions that have lower substitution with carbohydrates. Where when and how does such a complex substance get synthesized, assembled and secreted? And what can happen if the process goes wrong or gets out of balance?

In the gastrointestinal tract

One of the common places where mucus has many vital functions is the gastrointestinal tract. The main site of production of intestinal mucin is the goblet (mucous) cell. However; there is a small amount of mucus production in columnar cells (intestinal epithelial cell). Mucus secretion is probably under both neural and hormonal control. However, little is known about exocytosis in which the membrane of the granules fuses with the apical plasma membrane, thereby releasing its contents.

In this tract, mucus forms a protective layer between the epithelial surface and the luminal compartment, and has been indicated in the mechanical protection of the gastrointestinal epithelial cells from bile acids, pH extremes, digestive enzymes, biological agents such as bacteria, virus and parasites, and mechanical damage. Also, in the stomach, mucus provides a mixing and diffusion harrier which protects the stomach wall from the damaging effects of the secreted hydrochloric acid which plays a big part in the digestion of our food. Bicarbonate ions are secreted into the unstirred mucus layer to help neutralize the acid and limit its harmful effects (Flemstrom, 1987). We are unaware of this function of mucus generally; however, when someone has a stomach or duodenal ulcer, or any types of gastritis, they have to take some anti- acidic drugs and so become aware of their neutralizing mucus blanket.

We know little about the involvement of gastrointestinal mucus in disease. It is suggested that there is a selective loss of a ‘specific’ mucin subpopulation in ulcerative colitis which is an inflammatory intestinal disease (Podoisky & Isselbacher, 1984). Many recent studies indicate that mucins secreted by colorectal carcinoma are immunologically and biochemically different from those in normal colon and adenomatous colon in which there is epithelial benign tumour and/or tumours in the colorectum (Gendler eta1., 1990; lass et al., 1994). Moreover, it has been shown that some components of mucus can be employed as a marker for colonic carcinoma and pre-cancerous conditions (Guang & Abdulkalam. 1995).

In the respiratory tract

Another common place for mucus is the respiratory tract, where mucus is produced by submucosal glands and by goblet cells interspersed among the ciliated respiratory epithelial cells. The cilia are like tiny hairs and are very numerous on epithelial cells of the upper respiratory tract. There maybe 250 or more cilia on the surface of a ciliated epithelial cell, arranged in regular rows. The ciliated epithelial cells, together with a thin mucus layer, constitute the mucociliary transport system designed to clear the airways from foreign particles such as dust, pollen, bacteria or other harmful particles. When we inhale these harmful particles into the lungs, a local stimulation of mucus secretion is evoked. The mucus blanket surrounds the particle and is moved by the cilia which beat in a rhythmical, wave-like manner into the trachea and from there it is swallowed to the gastrointestinal tract. In this propelling the gel towards the pharynx (the upper part of the trachea), the tips of the cilia interact with the mucus layer so that the energy can be passed from the cilia to the mucus blanket. If something goes wrong with the ciliated epithelium or the epithelium is depleted of mucus, this transport may not necessarily occur.

Although in healthy individuals goblet (mucous) cells represent on average 1/10 of ciliated cells, in a chronically obstructed airway (when diseases such as bronchitis, asthma, bronchorrhea and cystic fibrosis are present) the number of the goblet cells and of the submucosal glands increases markedly. In these particular diseases, hyperplasia of goblet cells, hypertrophy of submucosal glands and the hypersecretion of mucus are the prominent features of the pathological process. The most common inherited disease where mucus is very important is cystic fibrosis. This disease appears in about 1 in 2000 people born in Europe and America, although 1 in 20 people carry the defective gene. In this case mucus is stickier than normal and so the abnormally sticky mucus cannot be easily removed from the lungs. Instead of acting as the means for removing bacteria, the mucus becomes a breeding medium for them and the complications of the resulting infection ultimately lead to early death. 

In the reproductive tract

Besides the gastrointestinal and respiratory tracts, mucus is very important also in the reproductive tract. The cervical canal, the entrance to the upper reproductive tract, is filled with mucus whose biological functions are to protect the genital tract from infection and to control the survival and penetrability of the spermatozoa (male germ cell). The amount and physical properties of mucus vary during the ovulatory cycle. At ovulation, when the woman produces ova from her ovary, there is an increased hydration of mucus which results in a watery secretion with high spermatozoal penetrability and low viscoelasticity (Wolf et al., 1978). In contrast, during the luteal phase, the second part of the menstrual cycle, the mucus is scant, contains less water and provides an effective barrier to the spermatozoa (Carlstedt et al., 1988). During pregnancy a large mucus plug blocks the cervical canal in order to protect the uterine cavity including the baby from any external effects. If the composition of the mucus changes during the early stages of the pregnancy, this mucus plug may become defective and the pregnancy may result in abortion or premature birth. It has been shown that high levels of cell-surface MUC1 (a mucin gene product) inhibit both cell-cell and cell-matrix adhesion that is important in human embryo implantation and this occurs in the mid-secretory phase of the menstrual cycle (Aplin & Hey, 1995). Moreover, the changing of mucus composition may be an important factor in infertility, because it controls the survival and penetrability of the spermatozoa. Also, there is the same significant alteration in the biochemical characteristics of the mucus in endometrial carcinoma.

Alterations in mucus composition

As mentioned earlier, there are some notable alterations in the biochemical characteristics of mucins in many diseases. For example, in chronic obstructive respiratory disease excess mucus is present in airways. In cancer, one frequently finds abnormal carbohydrate structures on mucins that can serve as surrogate markers for tumour progression. Also, mucin peptide epitopes that are normally covered with carbohydrates become uncovered and can serve as markers. Since membrane mucins can function as anti-cell adhesion molecules, and their over expression in cancer may facilitate tumour dissemination and therefore metastases. However, there is still a lot of work to be done to understand biosynthesis, secretion and functions of the mucus, especially mucins, in healthy people or in diseased conditions. How is it that mucus can change in response to environmental influences, bacterial attack, or hormonal balance? What is the relationship between mucus and the progression of cancer or such kind of life-threatening diseases? It is clear that mucus is susceptible to almost infinite and rapid modification. When we understand how this capability is employed and controlled, we may be one step nearer to controlling sonic life-threatening diseases, such as cystic fibrosis, cancer, or some abnormal conditions, like infertility and miscarriage.

As a conclusion we can say that mucus may appear a sticky, tiresome, messy nuisance hut it is obvious that a life without mucus would he extremely uncomfortable. It is a gift of the Creator to all living beings, and a miracle, many of whose wonderful mysteries remain to he discovered. 

References

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• Carlstedt I. (1988) Mucus Gylcoproteins: Structure and Macromolecular Properties, Lund University Press, Lund,
• Denny M.W, (1989) ‘Intervertebrate mucus secretions: functional alternatives to vertebrate paradigms’. Symp. Soc. Exp. hal. 43, p. 337.
• Flemstrom (3. (1987) Physiology of Gastrointestinal Tract, Raven Press, New York, pp. 1011-29.
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• cloning and expression of human tumour-associated polymorphic epithelial mucin’. .J Biol. Chem. 265, pp. 15286-93.
• Guang Y.Y. & Abdulkalam MS. (1995) ‘A new monoclonal antibody, CMU1O, as a marker for colonic carcinoma and precancerous conditions’. Arch, Pathol. Lab. Med., 114, Mayc pp. 454-60.
• Jass JR., Robertson A.M. (1994) ‘Colorectal mucin histochemistry in health and disease: a critical review’, Pathol. Int,. 44, pp.487-504.
• Podolsky D. & Isselbacher K.J. (1984) Gastroenterology, 87, pp.99 1-8. Rose MC. (1992) ‘Mucins: structure, function, and role in pulmonary diseases’. The Am. Physiol. Soc., pp. L413-L429.
• ThorntonD.J., Howard M., Devine P.L.,. Sheehan J.K. (1995) ‘Methods for separation and deglycosylation of mucin subunits’. Analytic Biochemistry. 227, pp.162-7.
• Wolf DR Blasco L., Khan M.A., Litt M. (1978) , Fertil. Steril. 30, pp.163-9