Complexity of Wound Healing - Biochemical Changes

In the practice of medicine, most if not all individuals have the basic understanding of rudimentary concepts and principles. The written knowledge shows a somewhat steady upward development, contrasting the personally private knowledge that waxes and wanes depending on specialty, frequency, and involvement. I have often experienced both, the written and practical knowledge.

The following review is of current studies of what goes on in a chronic wound at the molecular level. It has the hindsight intention of taking this understanding to a whole new level, and helping future physicians become empowered in achieving successful results. 

Why is this important? Money. As a whole, chronic cutaneous wounds account for 25 billion dollars spent annually representing approximately 6 million patients per year. By all accounts, this should be enough of a motivator to either self educate or educate others sharing in the wealth of knowledge, benefiting not only patients but fellow practicing specialists. Among disagreements concerting various treatment modalities of chronic wounds, the common practice agrees the intractable ulcers do not follow defined timeframes (i.e. first acute phase, secondly the reparative phase, and thirdly the remodeling phase). 

For an in-depth collaboration, please browse briefly these background definitions:

- serene proteases (endopeptidases) cleave peptide bonds in proteins, where serene serves as nucleophilic amino acid at the enzyme’s active site. Responsible for various physiological functions, digestion, immune response, blood coagulation.

- fibronectin, a high molecular weight glycoprotein of extracellular matrix ECM that binds to integrins (membrane bound receptor proteins). Exist as protein dimers linked by disulfide bonds. There are two fibronectin types known to date: the soluble(plasma, clotting) & insoluble(cellular) fibronectins. Insoluble fibronectins, major components of ECM, are secreted by various cells mainly Fibroblasts. They function as cell adhesion, growth, migration, and differentiation. Fibronectin in wound healing is primarily located in basement membrane of adult tissue, but widely distributed in inflammatory tissues.

- fibroblasts, cells derived from Mesenchyme (undifferentiated loose connective tissue of mesoderm origin), they secrete ECM and collagen, most common cells in connective tissue CT. Inactive fibroblasts are smaller and spindle shape, called fibrocytes with reduced rough endoplasmic reticulum (rough-ER); tissue damage induce their mitosis into fibroblasts. They function to continuously secrete precursors of ECM. Also, they secrete proteases, including matrix metaloproteases MMPs, that digest plasma fibronectin. They also secrete cellular fibronectin that is assembled into insoluble matrix.

Arguably, it is a subjective approach to look at a wound macroscopically. Numerous medical-term algorithmic mnemonics have been devised to help students and practitioners streamline the process of identifying and producing a workable diagnosis and treatment plan. More or less they all refer to overall appearance and shape of the wound, its location, progress (stable, stagnant, healing etc), base (granular, fibrotic, necrotic, eschar, etc), margins/borders (hyperkeratotic, rolling, regular, irregular, etc), undermining (how much in millimeters, which direction, etc), probing (superficial, deep to fascia, tendon, bone, etc), malodor, periwound erythema/edema/calor, lymphangitis (red subcutaneous streaks), drainage (serous fibrous, purulent, bloody, etc), and surrounding area (proximal ascending cellulitis, soft tissue crepitant/gas). The standards of decision making of wound healing progress is based on measuring the area after sequential debridement and comparing it with previous findings, typically length x width x depth in millimeter cubed area. As I look at this information, it reminds me of my academic years: rigid, diagrammatic, and perhaps limiting. When asked practicing physicians if they use these or many other descriptive algorithms I keep getting back the same routine answer: it has to be custom-fit for each patient, otherwise a physician becomes a technician who plugs in a formula and an answer is produced. I am beginning to understand, practiced medicine is one equivalent to an art in the middle of its creation: it takes time but the results are phenomenal. 

Tangentially the microscopic world, however, shows a different picture, that of the molecular and biochemical world typically seen through images of microslides or electron-scan microscopes. Over recent decades, monumental research has been done on both fronts, the macro and microscopic. Today’s scientists have agreed that a vast majority of alterations at the cellular infrastructure is the culprit of wounds that have become stagnant. These microscopic modifications are identified by first looking at normally occurring resident cells that show phenotypic changes, and ultimately protein shape changes. 

As a side note, the “lock-and-key” model may apply here, first identified in 1894 by Emil Fischer who postulated the high specificity of enzymes (proteins). But to be politically correct the “induced fit” model also could apply here, first suggested by Daniel Koshland in 1958, which turns out to be the more accepted of two models for enzyme-substrate complex, because the enzymes are considered flexible structures in which active site continually reshape by interactions with substrate until a final form and shape of enzyme substrate complex is determined. 

But we’re not specifically talking about proteins. Recent findings have suggested unusual shape changes to the normally occurring cells of a damaged area often called “Resident Cells”. These cells make up larger structures, for example fat, blood or lymphatic capillaries, skin layers, tendon and tendon sheath, nerve and nerve sheath, soft tissue, connective tissue, and other structures. 

Additionally remarkable changes briefly explained that should peak your interest are as follows:

- protease regulation

- cytokine pro-inflammatory release

- fibroblast morphology

- keratinocyte & ECM composition

Resident Cells: typical characteristics of resident cells that have undergone phenotypic changes (morphologic or otherwise), and serine proteases (neutrophil elastase) are present in higher amounts in chronic venous leg ulcer fluid for example, resulting in increased degradation of fibronectin, the integral component in extracellular matrix ECM. A quick scroll up to the “background definitions” shows that these otherwise called endopeptidases begin to act unrestrained destroying otherwise healthy structures. 

Altered Protease Regulation: when protease regulation is disrupted in non-healing ulcerations, poor distribution or elevated levels of matrix metalloproteinase MMPs are noted. These MMPs alter fundamental cell processes, apoptosis, angiogenesis, migration, proliferation. Again, too many and perhaps altered in function MMP’s digest important ECM components, destroying the normally occurring scaffold that is at the core of various specialized organs including skin, and underlying structures.

Altered Cytokine Release: inverse relationship exists between levels of pro-inflammatory cytokines and wound healing potential. Decrease of TNF-alpha, IL-1B, and TGF-B1, results in wound healing.

Altered Macrophage Function: in chronic wounds, macrophage function is stalled (suffocated), preventing recruitment of fibroblasts and keratinocytes to area of injury via chemotaxis. 

Altered Fibroblast Morphology: the shape change is due to pro-inflammatory cytokines producing an enlarged polygonal cell contour (shape change) much different than normal spindle-shaped fibroblast. This shape change limits fibroblast’s response to growth factors, compromising its motility and ability to recognize ECM environment.

Altered Keratinocyte Function: keratinocyte adhesion and movement is critical as they allow cutaneous lesions to reach complete closure. Their activity is dependent on ECM and cytokines within, altering their phenotype. Acute wound keratinocytes express a5B1 integrin that permits migration of cell. Chronic wound keratinocytes show markedly reduced expression of a5B1 integrin (recalcitrant wound).

Supplementary Factors affecting wound healing

- molecular chronic wound environment

- peripheral vascular disease

- malnutrition

- infection

- oxygen perfusion

Oxygen perfusion - tissue hypoxia, impairs tissue response to injury and healing. Impaired hydroxylation of lysine and proline, preventing collagen fibril cross-linking. Impaired leukocyte oxidative phosphorylation, thus decreased bacterial destruction.

Malnutrition - lack of minerals and vitamins. Ascorbic acid (vit-c) and Retinoic acid (vit-a) function as cofactors and cellular signals. They function to stabilize and modulate collagen cross-linking and engaging cellular metabolism.

Infection - process where bacteria invade healthy tissue to elicit an immune response. They can form biofilms (drug resistance) and cause protraction (prolongation) of the inflammatory phase, and excess cytokines and proteases are released. Healthy granulation tissue gets degraded, tissue growth factors destroyed, hindered deposition of collagen. Bacterial bio-burden [10^5 -10^6], increase metabolic load placed on wound bed. Endotoxins in cell wall of some gram (-) inhibit migration of fibroblasts / keratinocytes from periphery into ulcer.

Proper Management of healing environment:

- providing adequate perfusion to wound

- management of bioburden

- debridement

- nutritional supplementation

- pressure migration

- management of underlying disease (Diabetes Mellitus, Venous insufficiency)

Debridement - removal of devitalized necrotic tissue / foreign body. Optimum debridement is removal of necrotic tissue and preservation of healthy tissue without affecting healing. Serial debridement reduce wound contamination, controls excessive material load. Dead space that harbors bacteria must be exposed. Removal of necrotic tissue eliminates the physical barrier to growth factor receptor interaction. types of debridement currently employed: surgical, ultrasonic, enzymatic, autolytic, biological, mechanical. 

Besides the large arsenal of wound products wound clinics typically enjoy, there is always those products that show significantly positive results worthy of some mention, for example Debrisoft, DGD, Versaget, and Pulsed Ultrasound. Some are purely chemical, purely mechanical, or combination of both. 

Debrisoft (Active Health Care, UK) a new monofilament fiber product. A polyester product designed to remove and trap exudates, slough, hyperkeratotic tissue, and debris from superficial wounds by physically applying mild pressure in circular motion over affected area. Bahr, et al., found it 93.4% effective in debridement.

Debrase Gel Dressing (DGD) (Mediwound Ltd) a bromelain-based enzymatic mixture derived from stem of pineapple plant. It has been found to have high specificity for necrotic cutaneous tissue, typically taking 4 hours to see proteolytic enzyme results. DGD is rapid and selective, and can be effectively be used in place of surgical debridement in some instances, such as burn wounds and eschar pressure wounds management. 

Versajet - hydrosurgery, of pressurized saline stream, functions like a surgical knife, assists in removing necrotic debris from areas of abnormal contour or locations. 

Pulsed Ultrasound - non-thermal low frequency. It delivers mechanical pressure wave via acoustic vibrations through coupling medium. Pressure wave deforms cell membranes (radiation force), generates microscopic bubbles that expand and contract within tissue (cavitation), and creates eddy currents around these bubbles (micro-streaming). This energy rotates and twists the already destabilized cell membranes, causing increased permeability, changing cell activity. Signal transduction pathways are stimulated promoting angiogenesis, leukocyte adhesion, producing growth factors, nitric oxide and prostaglandins. (Herberger, et al, journal of dermatology).

How much to debride - Debridement is a vital component in chronic wound healing (Steed’s landmark article, basically addressing that more frequent debridement result in positive outcomes). Biopsies from non-healing edges of chronic wounds showed distinct pathogenic morphology and impairment of fibroblast migration similar in gangrenous tissue molecular function. Generally it is recommended a more aggressive removal of non-healing edge to allow for the exposure of cells within the wound to the wound-healing stimuli. Retrospective analysis found 34% reduction in wound mean surface area in serial surgical debridement and 29% wound closure at centers, when compared to 15% non-serial debridement. This clearly emphasizes that it is twice as likely that wounds heal when performing serial debridement, regularly and persistently when compared to singular or irregular wound debridement. 

Current concepts of molecular models have indirectly supported the debridement theory, which stands fundamentally at the center-stage when addressing microscopic biochemical changes that inhibit wound healing. However, it is difficult to control the variability of debridement, techniques, and aggressiveness. The consensus is a multifactorial approach of the wound therapy including quantity and frequency of the primary wound debridement process. Nonetheless, understanding the macro and microscopic biochemical cellular changes play a crucial role in devising workable treatment plans that are both realistic and feasible within adequate time frame. 

REFERENCES:

1. Sen CK, Gordillo GM, et al., Skin Wounds: A Major and Snowballing Threat to Public Health and the Economy. Wound Repair Regen. 2009 Nov-Dec
2. Yager DR, Zhang LY, et al., Wound fluids from human pressure ulcers contain elevated matrix rnetallopro- teinase levels and activity compared to surgical wound fluids. J Invest Dermatol 1996
3. Schultz GS, Mast BA. Molecular analysis of the environment of healing and chronic wounds: cytokines, proteases and growth factors. Wounds 1998
4. Grinnell F, Zhu M. Fibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulin. J Invest Dennatol 1996
5. Wlaschek M, Peus D, Achterberg V, et al., Protease inhibitors protect growth factor activity in chronic wounds. Br J Dermatol 1997
6. Trengove NJ, Bielefeldt-Ohmann H, et al., Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair Regen 2000
7. Mendez MV, Stanley A, Phillips T, et al., Fibroblasts cultured from distal lower extremities in patients with venous reflux display cellular characteristics of senescence. J Vase Swg 1998
8. Stadelmarm WK, Digenis AG, Tobin GR. Physiology and healing dynamics of chronic cutaneous wounds. Am J Swg. 1998 Aug
9. Andersen A, Hill KE, et al., Bacterial profiling using skin grafting, standard culture and molecular bacteriological methods. J Wound Care. 2007 Apr
10. Bahr S, Mustafi N, Hattig P, et al., Clinical efficacy of a new monofilament fibre-containing wound debridement product. Journal of Wound Care. 2011 May
11. Mulder CD, Vande Berg JS. Cellular senescence and matrix metalloproteinase activity in chronic wounds. JAPMA. 2002
12. Sibbald R, et al., Preparing the wound bed-debridement, bacterial balance, and moisture balance. Journal of Wound Management 2000

Japan - Ancient and Modern Technology

What would you as a reader give to be in Japan right now at this very moment? Frankly, I have never had the chance to embark on this trip. But with respect and candor to the untold, I have undergone a bit of work in the archives and local libraries. It is a land of stunning beauty, I've been told. 

I reckon so flows the time beyond the moment, and history sometimes is all that's left. 

Ancient tradition and modern technology have helped Japan achieve so much in the last century. The landscape is dominated by mountains, shaped by highly active earthquakes. The sea, a natural barrier, prevented foreign countries invasion, resulting in an overall physical isolation from the rest of the world. The Japan archipelago combined matches California in size, with 5 times its population. One tenth of worlds active volcanoes are located in the Japan land making this land constantly threatened by sudden and devastating events. People have adapted to such living conditions. They take precautions and include those precautions in their daily lives. They are living with earthquakes, shaping the tradition of Japanese homes. They are built from natural materials, light and easily re-constructible. Despite such unstable landscape, Japan's architecture has flourished over the years.

There are different religions in Japan, primarily the Shinto religion, which traces its roots back thousands of years. Buddhism, the second most important religion in Japan, came from China in the 6th century, which introduced a powerful new idea to Japan. It is concerned with afterlife. On the other hand, Shinto religion is concerned with the living only. Dance rituals are performed as traditional means of expressing their religious traditions. Shinto means the way of the gods, and the Japanese see gods everywhere, in nature in general. In Shinto religion, there is no book, no regular services. It is an accumulation of customs and folklore. It is a religion totally different than the western religion.

There is something to be said about the sharp contrast drawn between religious temples and the robotized factories that help modern economy flourish. Japan also has farmers and farm fields that extend for generations. The family structure is different than in the America: Parents, children and grandparents live under the same roof. Japan youth has inclination towards the western style of living and those allegoric symbols ranging from pop music, fast-foods, and the Magical Kingdom of Walt Disney. However, on the other extreme, the youth continues to be influenced by the deeply rooted traditions that are passed on to the next generation via narrative teachings and followings of what the adults are doing.

Traditions. Western style religion has directly or indirectly infiltrated their customs. Marriage as it turns out can be some sort of fashion. Most of the Japanese would be more inclined to get married in a western fashion way, in church as Christians do it. Expectantly, Christmas indirectly influences the Japanese culture by the ways of advertising and showing reminders of the coming of Christmas as a celebration from the western world. This is an example of indirect influence of western culture onto all Japan regardless if they welcome and dislike the idea of marriage of both cultures under the same roof. However, when it comes to death, they would return to their deeply rooted ways to burry their dead, once again identifying with their true background. Another tradition deeply rooted in Japan is bathing. They bath together as a form of community reinforcement. They have strict rules about bathing, one saying that soap should never mix with the bathed water, unlike what the westerners do. Bowing is another important cultural part in Japan. At the end of the day, family values are more important than the religious ones. But not every custom stays rigid; as anticipated Japan is known to borrow from different cultures and help improve by assimilation. One clear example is the kimono, original introduced from china was altered through time indistinguishable to current standards.

Japan has always been concerned with the growth of rice. This is a year around physical work. Each winter they dig up soil and transport it into the rice fields to replace the depleted soil. In the spring they replant rice once more. Rice growth is a serious business, and a physical work. It also requires the use of everyone from the village. They often have meetings together making sure they all do the work needed and that nobody is left behind. Each of the farm families have a personal shrine where personal and very old documents are kept. The same type of social interaction occurs frequently in factories in the town centers, becoming clearly the key to doing the best at work, and enjoying coming together both socially and spiritually. Japan is famous for quickly adapting to the new western economy and simultaneously keeping its traditions as the source for its overall success.

It is here the traditional samurai villages live, where the samurai leaders were patrons of arts and religious influence. Tea tradition was influenced by the samurai, as they would prepare to face their enemy and/or death. From their perspective, the tea was part of the enhancing the meditation, which was part of the Zen buddhism tradition. Therefore, tea-bowls have an unusual materialistic value, meaning that they could be worth more than a castle. In today’s japanese society, the only direct link to the ancient samurai is the sumo wrestler. These sumo rituals were practiced at Shinto shrines to ensure good and healthy rice crops. Now, they are mainly for tradition and sport.

The legacy of Shoguns is seen in everything that pertains to Japan and its people. This explains why they all obey the rules. Statistically, Japan is the most law abiding society on earth. The first shogun was the one person responsible for the rule obeying phenomenon in Japan. He was the one who unified Japan and gave it 250 years of peace isolation and prosperity. The Tokugawa Shogun created a culture where rules were given and people had to follow them. This quickly became a form of a centralized bureaucracy to control the unification of Japan. The clear example is shown in the distinction between armed me, clerks, priests and bureaucrats. They had their own place in society and the respect that came from their statuses. Therefore, the Tokugawa Shogun has transformed the state of law and obedience into a very strict and rigid society.

This type of structured society based on rules has translated through time into today's society. It is clearly observed in today’s bureaucracy such as in any office work areas in Japan. The design is counter western views. There is no office cubicles, no superficial job divisions. In japan, the rules state that the senior man (always a man) sits at a long line of desk with the senior assistant along the desk with the juniors farthest away from the boss. Also, in conferences, the sitting is done based on importance. The best seat is the one closes to where the boss sits always as far away from the door as possible. The least important seat is the one closest to the door. This type of classification is done differently based on where it occurs, such as in train, in an office, or at home.

Authority is enforced through Police, which keeps records of everything that happens in the cities of Japan or suburbs. There is a police box located every few blocks where citizens can get help and advice. Japanese prisons are powerful instruments to teach and instruct individuals on how to become better citizens. Japan has a reputation for their prisons as being those places where very few inmates ever return to prison. Job placement programs make such reputation true and continuous.

All students are treated equally. Japan schools come in sharp contrast with the western school. Japan government spends less on education than America, and yet Japan students achieve the highest test scores in contrast to the rest of the world. Some important key points to remember in Japan’s education is the importance of doing well in school and abiding to the rules of the society. To reinforce the importance of education, Japan has the longest school years in the world’s education programs. They are two months longer than the rest of the world’s school programs.

Besides length of study time, tasks and various responsibilities play a major role in their success. For example, children are given the primary role of serving food in school. These are all supervised by adults, enriching the interpersonal relationships for later in life. Another example of tasks is that school classrooms are cleaned by students only. In comparison, the higher education enforces more rules and rigidity, adding to the increased pressure in Japan education. Mentally handicapped are treated no different than the regular ones. Nobody is left behind or specially treated based on performance. They are all equally encouraged to do best in school no matter who they are or where they come from.

The universities entrance exams are very strict and claim only the use of memory and no original thinking. The results of exams are uniquely shared with students. Very energetic and in-group sharing of happiness or sorrow. Once students are admitted in any of the state universities such as Tokyo University, student’s studying habits slow down. This is in part due to the belief that once someone gets admitted into such honorary universities, companies would be competing very hard for them, regardless of their academic grades during their university years.

Relaxation and enjoyment in Japanese life is something that westerners rarely see or understand. Similarly to western thinking, Japan has various ways to entertain its public after a hard working day. They have bars, theaters, and sports. The most renown pastime is the Japanese baseball. Karaoke would normally come in second place as far as popularity was concerned. In Japan, there are two types of Theatre entertainment: the Kabuki and the Noh theaters.

Kabuki theatre are known for showing funny and full of wisdom screenplays that have a great effect on the common folk. The aristocracy uses a more sophisticated theatre, which is by far the most traditional of Japan theatre, called the Noh theatre. This was the kind of theatre approved by the Shogun himself.

The land of Shogun was a secluded land, where pilgrims dressed in white, come and symbolize the simplicity and non-mixing of the land with the western civilization. On the other hand, the Shogun world was a world of rice growers with advanced shops, where everyone knew their place in society. However, the time has come for Japan to learn a crash-course in Industrialization, soon catching up with westerners, and nonetheless surpass them in the quality and cost. Then followed the development of army and its military inventory. The only thing that kept surfacing for countries who tried to reach military stability and independence is the responsibility that comes with greater power. In this case, this proved disastrous to the people of Japan, as history has shown.

Post war, the Japan economy crumbled but began to recover soon thereafter. Their lifestyle and economic growth was strictly controlled from their government. Yet, this produced a very aggressive industrial revolution. This introduced innovative products, as part of the new stages of Japan industrial re-growth. The most important economic move done by Japan was from large, big, and strong template, to small, and light, and now to the beauty, feeling, play and creativity. They have done so in direct response to the health of its economy. Its customers are now deciding what is being produced. The quality of service and attention to detail is the norm in the Japan lifestyle.

Social pressure. Japan has successfully blended the western influence with its core group beliefs. However, despite the apparent success, social groups are still pressured by society stereotypes. The rural areas continue to be left behind from the high technologically inclined urban areas. Somehow, the gender inequality is reality. The grim difference is the social pressure that has always been towards male dominated society. Women in japan are paid well less than their equal status men. Comparably, they have the same social distinction as the immigrants in western societies. Despite this apparent discrepancy, Japanese women have a high influence in family lives, working environments, and recently in politics. The rising fashion in clothes design is one of Japan’s most recent move in giving a name for itself in the world’s economy. However, the rest of population in Japan is concerned not with politics, or religion, not even with fashion or industry. The overpopulation continues to remain the main problem of Japan. 

Dear reader, if you have made it this far, it is my personal belief you have learned something new about Japan. If I were you, I would continue next with their language Katakana and/or Hiragana. But that's for another teatime. Perhaps now, if you do end up in Japan as a traveler of sorts, you will stand a bit more versed in the local history and tradition. 

Microsurgery in Podiatry

MICROSURGERY is intricate surgery performed using miniaturized instruments and a magnifying instrument, preferably portable such as a variant of Loupes, or a fixed microscope.
In podiatry, such microsurgery is indicated in repair of nerve entrapment, microvasculature repair, and skin-muscle-tendon grafting or repair.
Typically, deep neurovasculature travels together: comitante vein, artery, and nerve. Proper anatomy identification plays a major role in differentiating artery from vein. A surgeon can use several methods, one being the simplest by blocking vasculature flow to the area in question and slowly releasing the flow observing which structure fills back: first artery fills up, then vein in retrograde fashion. This leaves out the nerve.
In a nerve entrapment, scared tissue extends along its tract sometimes strangulating surrounding tissue.
In my future practice and procedures, I will seek an instant identification of nerve structure from surrounding tissue. A simple chemical marker, yet non-reactive to surrounding tissue is in demand. Its application should vary from being injected or simply applied directly in a sterile wash from a dispensing syringe.
The function of the marker is to perform the following: quickly embed within the epineurium of the questionable nerve structure, and become easily visible either by itself or under a specific visible light spectrum, i.e. UV. It is important to realize this nerve identification is non-reactive to surrounding tissue including epineurium. Once the nerve tissue is identified by the protein marker, it is freed from surrounding tissue using microsurgery, and to prevent further scaring, a layer of regenerated tissue matrix is applied along the nerve sheath.
Typically the scar surrounding the nerve is made primarily of collagen fibers, extracellular proteins with triple helical structures making up the fibrillar and microfibrillar network of extracellular matrix. When nerve ending is damaged, the normal extracellular matrix synthesis is up-regulated. It turns out this hinders the regeneration of new nerve sprouts to reach new interface(s). With microsurgery, new avenues of nerve entrapment repair are possible. Currently there is no one single successful procedure. The use of protein epineurium marker as adjuvant procedure should help the successful identification of healthy nerve tissue from surrounding extracellular matrix allowing successful repair without unnecessary damage to healthy nerve tissue.

Made of Stardust

STAR-gazing, such a privilege to ascend into the past of hundreds of million of years ago as projected into our eyes by long lived photon energy.

stargazer |ˈstärˌgāzər|noun informal an astronomer or astrologer.• a daydreamer.

I feel it is far too seldom we find ourselves looking up into the nakedness of the sky above us. I feel we do ourselves a great disservice ignoring our origins.

Late Carl Sagan used to say "We are all made of stardust", billion year old carbon. I can't explain the peace I feel each stargaze I embrace. But I look around and see so many of us busy with lives and the living, and forgetting of the past we used to admire. Up there hangs our dreams, our pasts, and ultimately our future. Stargazing is to some a place of retreat, but always one of comeback.

From the beginning of time, we have always looked up in to the sky to seek comfort or closure from the unknown. In the end, looking up should produce a feeling of both awe and unmatched realization of our puny little existence, the devout symbol of humanity in the face of infinite infinitesimal.

Nicotine Blows, Literature Review

BACKGROUND
Nicotine has intrigued me to the point where I decided to investigate it. I've come across many articles and references realizing how far we have come to understanding its intricate mechanisms on physiologic and cellular levels. This is only but a notably brief summary of my lengthy research on Nicotine smoking and its deleterious effects to human body.


A quick search leads to basic facts about Nicotine: first ever records point to French-Portugal trade in 1500's, when seeds of Nicotiana tabacum plant became a trading contributor. Since then, it has been used in recreation, medicine, and as insecticide. By 1900's lung cancer was linked to tobacco smoking. Then its side effects started to be taken seriously as they involved every single aspect of the body, including psychiatric, skin health, soft tissue, blood vessels, dentition, hair loss, and not to mention every single major organ of the body. Not soon enough, it was realized that Nicotine smoking was the most efficient drug delivery system.


Because Nicotine has a very short half-life in serum, meaning it lasts in its active form for few minutes while in the blood stream, the smoker continues to dose frequently, which is at the core of the addiction. And with frequency, comes desensitization, thus with time the smoker is seeking increased concentration of Nicotine to reach the same high.


I briefly mentioned Nicotine use as insecticide, which is formulated at very high concentrations. If ingested, however, this causes death within minutes secondary to asphyxiation due to respiratory failure (paralysis).



FACTOIDS
-Nicotine from inhaled tobacco reaches the brain between 5-10 seconds.
-Inhaled smoke gets you 90% of Nicotine in bloodstream.
-Only 20-50% of it gets in your blood from smoke taken into mouth and exhaled.
-Nicotine use remains the leading preventable cause of death in the world.



VASCULATURE EFFECTS
Chronic Nicotine exposure causes long-term homeostatic regulation of endogenous nicotinic acetylcholine receptors (short named nAChRs), which plays a key role in adaptive cellular processes, thus leading to addiction.

In another words, smoking causes a up-regulation of nicotinic acetylcholine receptors, especially of the specific heteromeric receptors non-Alpha7-nAChRs, which by exclusion factor is the Beta2-nAChRs.


You may ask, where are these receptors mainly located? Through tests and imaging studies, these up-regulation of receptors take place in lateral septum, caudate putamen, and nucleus accumbens, or in another words, somewhere inside the brain. Naturally, it is there that our Nicotine seeking takes place, however Nicotine receptors are found throughout our body in every tissue explaining why the effects are so wide spread. [1]


In another study, it was noted that smoking caused a sharp increase in blood pressure and heart rate. Despite this, there was no notable change in stroke and systemic vascular resistance. Interestingly, smoking caused increase in extremities blood flow, primarily in the muscle and a decrease in blood flow to the skin. This study also showed that in habitual smoker, an increase heart rate was observed.


Why is this important to know? Direct effect of smoking causes short term increase in arterial wall stiffness, which is harmful to artery itself, increasing the risk of plaque rupture. Acute cardiovascular events are mainly due to plaque rupture. This shows that smoking (each time you light up that cigarette) might heavily contribute to acute ischemic events. [2]


Yet another study talks about the increased aortic systolic blood pressure and increased arterial stiffness. They call to attention reduced pulse pressure amplification and increased arterial wave reflection, all due to adverse hemodynamic effects. All this means blood flow is adversely decreased in extremities primarily the skin. [3]



WHAT IS COTININE?
You may ask, how can a physician tests a patient if previous smoking occurred? It is done by measuring serum cotinine concentrations. A study reviewed serum cotinine acceptable levels, with low levels between 0.2-1.6ng/mL, and the high of above 1.7ng/mL. This procedure is useful when assessing tobacco exposure in children, known as second hand smoking effects. As explained in this study, children with medium to high levels of serum cotinine showed an increase in aortic Young’s elastic modulus and a decrease in aortic distensibility. This report shows a direct relationship between passive smoking and arterial elasticity in children. [4]


All these previous reviewed studies talk about macrovasculature, i.e. aortic and carotid vessels. Instead, let’s continue by looking at microvasculature, typically those seen in the heart coronary arterial tree, and peripheral microvasculature. The effects of one hour of exposure to tobacco smoke showed a significant decrease in late rise in skin blood flow in response to heating. One way to stimulate the skin’s microvasculature is by directly heating it, which normally should lead to localized vasodilatation and increased localized blood flow. However, this test showed a delayed response of skin to directly warming it, concluding microvasculature was, for lack of better words "in trouble". [5]



KEY POINTS 
Thus far, we can partially conclude that tobacco smoking specifically increase the macrovasculature (aortic wave reflection) through Nicotine-dependent pathway, and impairs microvasculature function, even past the end of the exposure of Nicotine. In another words the afore mentioned nicotinic effects last for at least minutes to hours after you threw away that finished cigarette. Recalling a previously mentioned fact, while the Nicotine half-life is extremely short, its effects last for relatively long time.


But how is the microvasculature impaired? In a study, researchers concluded that Nicotine directly increases the Norepinephrine NE receptors in the skin capillaries, thus producing vasoconstriction. Do you recall the previously mentioned study where heating up the skin produce vasodilatation? Well, another means to produce similar effect is by use of Nitroglycerine NTG, which is a potent vasorelaxant.


In practice, patients requiring skin incisions, skin flap reconstruction, amputations, and other skin procedures, all will experience a tremendous delay in healing time including complications such as rejection of skin grafts secondary to local vascular spasm and subsequent localized ischemia. Poor vascular flow leads to delayed or blocked delivery of nutrients and removal of normal cellular waste, an important attribute to healing. [8]



PREGNANCY EFFECTS
I've always wondered what were the typical effects seen in pregnant women who smoke Nicotine. Several studies investigated such effect. One in particular has shown that smoking caused an acute decrease in intervillous placental blood flow, which had an apparent normalization within 15 minutes. What is expected with decrease blood flow to placenta, even if momentarily? Answer is, direct growth retardation of fetus and other complications of pregnancy including stillborns, premature infants, and low birth weight. [6]





LUNG EFFECTS
Besides lung cancer, what ever happens with those smokers who have the typical chronic nagging cough? It turns out that these individuals have an increase lung tissue concentration of macrophages primarily, increased presence of endothelial adhesion molecules, and cytokines. All these inflammatory cellular conglomerate produce symptoms typically seen in non-smokers who are diagnosed with chronic bronchitis.

The bad news is, smokers who decide to quit are expected to continue experiencing these chronic bronchitis symptoms from weeks to months in a row. However, over time respiratory symptoms will decrease dramatically and so will the nagging bronchitis. The good news is overall lung respiratory capacity will improve with time, as seen in greater than 12 months Nicotine free individuals. [7]



CAUSE & EFFECT
Risk factors are everywhere. Annals of Internal Medicine defines it in a 1961 article as "something that increases the chance of getting a disease or infection." This however does not take into consideration subclinical comorbidities and subclinical symptoms. A disease becomes apparent when it is symptomatic and negatively interferes with individual's daily life activities. [9]


In brief, Nicotine is known by many as a major risk factor for many disorders, including cancer, respiratory disease, heart disease, diabetes, stroke, and peripheral arterial or venous insufficiency. This research has in part shown me that the presence of other comorbidities significantly increase the complication rate and speed by which known diseases become symptomatic in nicotinic abusive population.


What does this mean for the patient and the medical team carrying for such patients? It significantly eliminate treatment options, increases the length of recovery, chance of infection, and life expectancy. This in turn makes living difficult for patient and those who care for them, making them harder to comply to medical regiment imposed by medical team. Expectantly, non-compliance is experienced by many patients caught in this tug war of delayed healing time, the outcome being more complications, more interventions, and the cycle repeats to no avail.



References:
1. Long-term effects of chronic Nicotine exposure on brain nicotinic receptors, Morgane Besson, et al., PNAS 2007
2. Short and long-term effects of smoking on arterial wall properties in habitual smokers, Mirian J.F. Kool et al, JACC 1993
3. Effect of Smoking on Arterial Stiffness and Pulse Pressure Amplification, Azra Mahmud, et al, JAHA 2002
4. Decreased Aortic Elasticity in Healthy 11-Year-Old Children Exposed to Tobacco Smoke, Katariina Kallio, et al, JAAP 2008
5. Acute Effects of Passive Smoking on Peripheral Vascular Function, Jean-François Argacha, et al, JAHA 2007
6. The Acute Effects of Smoking on Intervillous Blood Flow of the Placenta, P. Lehtovirta, et al, BJOG 2005
7. Effect of smoking cessation on airway inflammation in chronic bronchitis, G Turato, et al. JRCCM 1995
8. Effect of Nicotine on vasoconstrictor and vasodilator responses in human skin vasculature, Claire E. Black, et al, JRICP 2001
9. The Framingham Offspring Study, H. J. C. Swan, et al, JACC 1999

The Difficult Tetanus - Case Presentation: A lesson learned.

This blog post is different than my previous. As a medical student on rotations, I am constantly faced with a wide variety of events, some more dramatic than others. In the process, I research current literature and methods of treatment. The following is a recent encounter with a patient infected with tetanus. From history, I soon discover that despite being recently immunized with a booster shot, patient continued to display the classic presentation of tetanus, which unfortunately turned for the worse. In her remembrance and for a better cause, I put together a review on tetanus and what you have to know to prevent its infection. Know what you should do to prevent its manifestations. The story begins with a review.

 

If you thought you were immunized, think again...

Tetanus is an acute often fatal Nervous System (NS) disorder characterized by SUSTAINED muscle spasms and convulsions caused by the toxin-producing anaerobe CLOSTRIDIUM TETANI, which is a obligate anaerobe Gram+ Bacilli (exotoxin), typically found in soil. 

Its clinical features and presentation associated with traumatic injuries have been well-known before the introduction of tetanus toxoid vaccination in 1940’s (among ancient Greeks and Egyptians).

This is the only vaccine preventible disease that is infectious but not contagious between humans.

Keep in mind that the typical bacteria forms a terminal spore that is resistant to heat and antiseptics. However, the organism outside the spore is very sensitive to Oxygen and heat. Another thing to keep in mind is  the very low concentration of toxin needed - minimal lethal dose is 2.5 nanograms/Kg.

Clostridium Tetani usually enters the body through a deep penetrating wound. In presence of anaerobic conditions, typically seen with a local inflammation or early infection, the spores germinate, which later produce the bacteria and the toxin, disseminated via blood and lymphatics.

Toxin acts at certain CNS locations: peripheral motor end-plates, spinal cord, brain, and sympathetic nervous system. Toxin interferes with release of neurotransmitters, blocking inhibitor impulses, which leads to unopposed muscle contraction, and autonomic NS may also be affected.

Once Clinical manifestation occurs after tetanus reached the presynaptic inhibitory nerves, there is little that can be done to slow down disease progression. 
In assessing prognosis, generally the shorter the incubation the worse the outcome.

Incidence and mortality from tetanus by age group in the United States, 1998–2000. (From Pascual FB, et al: Tetanus surveillance—United States, 1998–2000. MMWR Surveill Summ 52[SS-3]:1, 2003.)

Despite the availability of an effective vaccine, tetanus remains endemic worldwide. It is more common in warm, damp climates and relatively rare in cold regions. The global incidence of tetanus is estimated to be between 800,000 and 1 million cases a year, with half occurring in neonates.

Since the introduction of vaccination programs in the United States, the incidence of tetanus has steadily declined from 4 cases per million population in the 1940s to 0.095 cases per million population in 2005.

The highest incidences occurs in people older than 60 years (0.35 cases per million population), Hispanic Americans (0.37 cases per million population), and diabetics (0.70 cases per million population). Fifteen percent of cases occur in injection drug users. The overall case fatality rate is 18% but approaches 50% in patients older than 70 years. Cases have been reported in patients who had been fully vaccinated, but in the eight patients from 1998 to 2000, no deaths occurred.

Clinical Diagnosis: Trismus

trismus |ˈtrizməs|nounMedicinespasm of the jaw muscles, causing the mouth to remain tightly closed, typically as a symptom of tetanus. Also called lockjaw.ORIGIN late 17th cent.: from modern Latin, from Greek trismos ‘a scream, grinding.’

Cultures (anaerobes, time consuming, takes minimum three days to get results back; half the time, the results are false negative because of the difficulty localizing and culturing the bacilli). 

Differentials: 

• Strychnine Poisoning Dystonic reactions to Dopamine Antagonist drugs 
• Oropharyngeal infection (DDX Cephalic Tetanus) 
• Hypocalcemia (DDX Neonatal Tetanus) 
• Meningoencephalitis (DDX Neonatal Tetanus).

The goal of immunization is to provide a continuous serum concentration of 0.01 IU/mL of neutralizing antitoxin. Protection between levels of 0.01 and 1.0 IU/mL is not absolute; some authorities consider an antibody level of 0.15 IU/mL or greater as protective.

Active Immunization is achieved via the Tetanus Toxoid (takes time to build immunity).

Passive Immunization is achieved via the Immune Globulin TIG (passive transfer of active immunoglobulins).

Immunization is given immediately if the patient's tetanus immunization history is not available or is uncertain, or if 60 months or more have elapsed since the last booster dose (5 years or more). TIG is given for other than minor wounds if the number of immunization doses the patient received is fewer than three or is unknown. The antibodies neutralize only free toxins, toxin not bound to nerve.

Table 1. Example of management pre-exposure, typically seen in pediatric patients:

Primary and Secondary Immunization.

 

Table 2. Example of management post-exposure:

 The four treatment strategies for patients with tetanus should be undertaken simultaneously: 
(1) aggressive supportive care, control of muscle spasm with Benzodiazepines - most IV benzos except midazolam have propylene glycol as a coingredient which at high doses causes Lactic Acidosis. But midazolam has a short half life. 
(2) elimination of unbound TS (tetanospasmin), with HTIG or TIG (passive immunization)
(3) active immunization, and 
(4) prevention of further toxin production - treating the C.tetani infection via wound debridement and ABX metronidazole.

Metronidazole - antibacterial, antiprotozoal, microbicidal, against most obligate anaerobics and protozoa, interferes with DNA/ Cytotoxic.

Penicillin - antibacterial, blocks cell wall synthesis, against gram+ bacteria and spirochetes.

Tetracycline - protein synthesis inhibition, bacteriostatic against both Gram+ and Gram -.

 

CASE PRESENTATION:

Chief Complaint (CC): This is the case of an 86yo female status-post (s/p) 1 day inability to open mouth, s/p 6 days rusty metal puncture wound Right Lower Extremity RLE.

NLDOCATS*: Patient (PT) complaints of generalized dull aching pain with a scale of 8-9/10 (0 no pain, 10 worst pain) to leg, neck, and abdomen. Pt relates to a 6 (SIX) days old puncture wound to lower extremity (LE) from a rusty metal soft tissue traumatic encounter. Pt relates to onset of fever and chills several days after her initial injury (day zero) for which she has taken Cipro orally prescribed by her primary care physician (PCP) over the phone. Pt relates, her fever resolved uneventfully. However, pt states few days later after taking Cipro orally, she was awaken to discover her inability to open mouth more than a few millimeters, along with increased stiffness to the neck muscles throughout the morning hours. In patient's defense, a confirmed recent Tetanus booster was completed mid-September 2011, prescribed by her PCP.

(*Nature, Location, Duration, Onset, Course, Aggravating factors, Treatment, Special)

Past medical, surgical, and social histories are non contributory. 

Pt allergies are as follows: Aspirin, Penicillin, Sulfa, Ceclor, Mefoxin, Tetracycline, Nalidixic Acid (Neggram), all producing asthma-like reaction. 

Current Medications: Prednisone 10mg QOD
, Theophylline 100mg daily, 
Beclomethasone spray QID
, Albuterol MDI 2 puffs QID
, Imodium PRN, 
Primidone 50mg at bed time
, Fish Oil
, MVI, 
Vit-C, Ca, Vit-D.

Review of Systems: (ROS) Abdominal pain, Diffuse muscle stiffness, Puncture wound RLE with surrounding erythema, Bruising, ELSE remainder of ROS is non contributory

Physical Exam:
 

Vital Signs: T 96.8, HR 85, RR 16, BP 150/78, PO2 
99% room air
. 

General: Awake Alert and Oriented to person, place, & time (AAOx3), Emaciated, Restless 


HEENT: Atraumatic, Normocephalic Anicteric, External ocular movements intact, pupils equally round reactive to light and accommodation (PERRLA), Unable to open jaw > 0.5cm, mucous membrane moist, teeth worn


Neck: Post cervical neck muscles are spastic, tender
, 

Cardiovascular: regular rate and rhythm (RRR), no murmurs, gallops, rubs, S3, S4, no peripheral edema

Respiratory: clear to auscultation (CTA) bilaterally (BIL), no wheezing, crackles


Abdomen: normative bowel sounds (BS), abdomen firm to palpation, unable to determine hepatoslenomegaly given muscle rigidity


Extremities: UE Strength 5/5 BIL, epicritic sensation intact in all 4 extremities, LE Strength 4/5 BIL, R-Knee Extension 2/5, Dorsal Plantar flexion 5/5 BIL. There is 1-1.5cm circular area of necrosis on Lat LE with fresh tissue in middle that is leaking clear fluid, surrounding erythema cold to palpation, nontender to palpation. 

Neurologic: Cranial nerves II-XII intact, when asked to smile patient exhibited sardonic smile, baseline tremor in BIL hands. Muscle strength as described above. Sensation intact to all 4 extremities


Psychiatric: AAOx3, fluent speech pattern, thoughts are logical, judgement and insight appear to be fair.

Laboratories: CBC & BMP are within normal limits


Podiatry Physical Exam:
 LE exam reveal several scabs and a wound on the L anterior leg. There are bandages, which are dry and intact and remain in place over this area. Left leg shows no erythema, edema, or heat. Pedal Pulses are palpable. Right leg exhibits significant erythema from the level of the mid calf distally. There is +1 pitting edema throughout the lower leg and foot. Pedal pulses palpable, however faint secondary to edema which is present. There is a dry bandage covering the wound located to the R lateral lower leg midtibia level. Examination of wound reveals a black eschar approximately 2cm diameter. Wound borders appear intact with notable erythema, edema, and heat throughout surrounding area. Noted induration palpable proximally and posteriorly to the wound, extending 3cm posteriorly. Upon compression of periwound area there is noted purulent fluid drainage from wound. Patient also responds and is sensitive to this palpation, attempting to retract leg.

Assessment & Plan: 


1. Trismus with generalized spasticity consistent with Tetany. Give a total of 3000 Units IG. Start Metronidazole 500mg Q6H. Cardiac Monitoring. IV Fluids and Valium 2mg every 6h for muscle spasms. Also Magnesium sulfate IV 40mg/kg, or Labetalol IV 0.25-1.0mg per minute for autonomic dysfunction. 

2. Nutrition, emaciated, NG tube or PEG placement for expected 4-6 weeks long tetany course

Podiatry Surgical Debridement: 

Upon Examination, wound appeared erythematous with central eschar. Sharp debridement performed of all devitalized soft tissue, minimal purulence observed for which aerobic / anaerobic cultures were performed. Skin appeared atrophic dissecting easily along the superficial and deep fascial planes proximally. Mechanical Pulse-Lavage performed with 3000 mL Triple Antibiotic in sterile Normal Saline. Wound was packed open and sterile soft dressing applied. Patient transported to Recovery in stable condition, no complications observed. 

Summary of Events:

Day 0: Injury 

Day 4: Fever 100F, Sweats. Tx Cipro PO at home 

Day 5: Symptoms resolve 

Day 6: Locked Jaw, Stiff Neck, RLQ Pain, RLE Pain
➡ ED admission, Intubation, Tetanus IG 3000 IU, Metronidazole 500mg IV Q6H, Valium, IV fluids, Magnesium IV, Labetalol IV. 

Day 7: Sx Wound Debridement w/ Pulse Lavage

Day 10: Severe generalized deterioration, Cardiovascular Instability, not responding to treatment, Autonomic NS failure, possibly Phrenic Nerve involvement. 

Day 12: Immediate family disconnects life support, Pt expires within minutes.

RESOURCE - Tetanus Algorithm:

 

REFERENCES

1. C. Louise Thwaites,  Lam Minh Yen, Harrison's Principles of

Internal Medicine, 18e, Infectious Diseases > Section 5. Diseases Caused by Gram-Positive Bacteria > Chapter 140. Tetanus, McGraw-Hill Companies 2012

 

2. Madonna Fernández-Frackelton, Infectious Diseases - Bacteria, Rosen's Emergency Medicine 7th Ed 2010

 

3. Itzhak Brook, Etiologic Agents of Infectious Diseases - Tetanus, Principles and practice of Pediatric Infections 3rd Ed, Churchill Livingstone, An Imprint of Elsevier, 2009

 

4. Pavani Reddy, Thomas P. Bleck, Clostridium tetani (Tetanus) 244, Bleck, Mandell, Douglas, & Bennett's Principles and Practice of Infectious Diseases, 7th ed - Textbook of Critical Care , Sixth Edition, 2009 - Churchill Livingstone, An Imprint of Elsevier

 

5. C. Louise Thwaites, Lam M. Yen, Tetanus 147, Bleck, Mandell, Douglas, & Bennett's Principles and Practice of Infectious Diseases, 7th ed - Textbook of Critical Care , Sixth Edition, 2009 - Churchill Livingstone, An Imprint of Elsevier

 

6. Gregory J. Moran et al, Antimicrobial Prophylaxis for Wounds and Procedures in the Emergency Department, Journal of Infectious Disease Clinics of North America, 22 (2008) 117–143

 

7. Basic Tetanus Algorithm, AJM PRiSM 2009

 

A LEARNING LESSON:

• if you suspect a dirty tetanus prone infection/deep skin cut
• flush the wound with clean water by placing the wound under running water, removing visible dirt, debris, or foreign materials; I recommend prying open the sound if it's large enough to ensure water flushing is maximized. 
• do not apply sodium peroxide as this strong base will start the local inflammatory process secondary to complete cellular destruction, especially host skin and soft tissue; applying an antibiotic ointment is also not recommended since you need to keep the wound clean and dry for the time being. 
• recall, tetanus spores do not like oxygen & dry environment
• apply a clean gauze / dressing over the affected area and have someone drive you to the nearest Emergency Department. The sterile gauze is the best method to keep the wound as dry as possible absorbing any serous or blood discharge from the wound preventing anaerobic environment. 
• an injection of Immune Globulin is highly indicated despite your history of tetanus booster shots. Tetanus Immune Globulin (TIG) is the only known neutralizer of free unbound tetanus toxin that will soon be released from within the wound. 
• a treatment of oral Metronidazole antibiotic (anti anaerobe gram positive bugs) is highly recommended to treat local soft tissue infection that might reverse the wound to an anaerobic environment.
• recall, the tetanus spore will germinate and release the bacilli into the wound as soon as the wound becomes anaerobic environment seen with early inflammation and infection. Once bacilli is aware of anaerobic environment it will quickly release its toxin which will travel via lymphatics and blood vessels selectively to nerves of muscle, spinal cord, and brain. Once toxin is bound to the nerve it will not be unbound until the nerve end-plate regrows a working duplicate bud that will replace the damaged end-plate - an approximate 4-6 weeks period. 

 

 

American Rag

Traveling, anywhere, an antidote to boredom or the seed for resilience. Sometimes I travel because I feel the need to be away from the epicenter. Other times, I am chased out of my comfort zone. A mode of survival, I guess.

In life's adventure, I will never be too sure who will play the most influence. Not until that formidable influence were gone forever from my embrace, only realize that after the fact. Is that a socio-psychologic effect, one of self fulfilling prophecy?

When I was a young child, I often looked at my elders with interest and distance. There were some questions in my mind that I suppressed for the longest time. But as I too become one of them, I can feel the answer settling in. Every single one of us, will always stay young at heart, despite the aging body, the ship in which we must coexist. It is a sad metaphor, but there is no such thing as aging self.

It is a typical turn of evens that over the years we normally turn to other problems that govern our lives, and as a side effect we will loose the curious child that brought us where we are. Have I lost him yet? When we realize we lost it the question remains, what will we do about that? I know I will try to seek him back every chance i have. But is that feasible? In our progressive process, a new comfortable self has long been established. That core value will not change unless, a direct threat to our existence is imminent. Anything can tip that balance. And we're never ready for it when it happens.

I often pretend to understand the intricate workings of life and death, but pretend is all I do, for I will never truly understand. Medical student or not, the basics are all out there for everyone to grasp. And yet, sometimes there are no answers to seek. Just acceptance. Can you imagine a world with no answers? I can't.