TUMOR RECURRENCE AND TAMOXIFEN RESISTANCE: IF MY BREAST CANCER RECURS, SHOULD I STOP TAKING TAMOXIFEN?
If a breast tumor continues to grow or a new tumor develops either in the breast or elsewhere while you are taking tamoxifen, it is probably best to discontinue the drug. One of the most important questions your doctor may ask before you stop is whether you have taken the drug as prescribed. If you have missed only a few doses, the doctor can reasonably assume that the tumor is no longer responding to the drug and has become resistant to tamoxifen therapy. If, however, you have taken the tamoxifen only sporadically, missing days or even weeks at a time, your doctor may elect to continue tamoxifen for a while to see if daily dosage will slow the growth of the tumor. Noncompliance in the tamoxifen regimen or prolonged absence of drug administration has contributed to tumor recurrence in some patients. It is therefore extremely important that you take tamoxifen exactly as prescribed and that you answer your physician's questions as accurately as possible.
While the intricate details of how memories are formed and retrieved are still being sorted out, an increasingly elaborate insight into these processes comes from computational neuroscience. As with the rest of biology and psychology, brain science has traditionally been an empirical discipline, its general principles established through painstaking observation and experimentation. But ultimately the maturity of any discipline is judged by its ability to develop a theoretical arm.
Enter computational neuroscience. The choice of the adjective is, in my opinion, unfortunately bland, as it fails to convey the breadth and richness of this new discipline. I would have preferred "theoretical neuroscience" by analogy with "theoretical physics" and with similar connotations (even though I realize that the adjective "theoretical" in conjunction with "biology," let alone "psychology," has its baggage). In the past it often carried the connotations of winded verbiage and unprovable, speculative conjectures, an antithesis of the rigor and precision implicit in the term "theoretical physics." It may be for those reasons that people use the term "theoretical neuroscience" with a degree of caution and even reluctance, and feel safer with the austere connotations of "computational."
But today computational neuroscience is probably the most rigorous branch of brain research. At its inception, the methods nurtured in this new field involved mostly mathematical models of somewhat narrow, isolated processes in the brain. The advent of high-power computers has given rise to a peculiar hybrid of theoretical and experimental methods—computer modeling. The theory about the structure of a complex biological system is posited as a computer model, and then the "behavior" of the model is examined empirically, by making it perform various tasks and changing its various parameters. This blend of theory and experiment has yielded results far more powerful and unexpected than either of the two methods by itself. Some of these results bear directly on our understanding of the brain machinery of memory and they were obtained using the so-called formal neural nets.
Formal neural net modeling is among the most powerful and promising tools of computational neuroscience. Assembled from a large number of richly interconnected simple elements ("formal neurons"), they capture the most fundamental properties of the ways in which the actual biological brain works. Like in the real brain, a single element of the network, the neuron is limited in its abilities and cannot do much on its own. Like in the real brain, the problem-solving power of the network arises as a consequence of multiple interactions, both sequential and parallel, among neurons. The informational power of the network is everywhere and nowhere in particular. It is distributed throughout the whole net.
Any even moderately complex cognitive process unfolding in the real biological brain involves too huge a number of neurons and glial cells to permit an experimental analysis of all the important interactions among them. Simply put, the brain is a structure with too many moving parts and its most interesting properties arise from the multiple interactions among the parts, rather than from the parts themselves. But hidden as these multiple interactions may be from the tools of experimental research, many of them reveal themselves in dynamic neural-net models run on computers.
Faced with various tasks, formal neural nets exhibit amazingly brain-like properties. The most interesting among them is the rise of new abilities and skills that had not been explicitly programmed into the model by its designers. We refer to such new, spontaneously arising abilities as emergent properties. By acquiring such abilities on their own, neural networks in a sense truly "invent themselves." The networks exhibit these abilities when they have the benefit of explicit feedback about their prior success or failure (supervised learning), and even when no such feedback is available to them (unsupervised learning).
Among the most intriguing emergent properties are attractors and attractor states. An attractor is a network, a group of closely interconnected neurons with a stable pattern of activity in the absence of direct stimulation from the outside. These self-perpetuating patterns of activity are called "attractor states." The attractor states are possible because the connections between the neurons within the attractor are so strong (the grooves in the sand so deep, to use our earlier analogy) that the activation of any subset of neurons, even a relatively small one, is sufficient to keep the whole pattern going. This means that the same attractor will be activated in its entirety, as a whole, by activating any number of its various components. This property of attractors in the brain is sometimes referred to by the slightly dismissive term degeneracy, first introduced into neuroscience by Gerald Edelman. In fact, "degeneracy" is a fundamental mathematical property, extensively studied in algebra and symbolic logic. Degeneracy is also a very important property of biological attractors.
To better understand how attractors work, it may be helpful to be reminded of the original meaning of this term. The term attractor was borrowed by neuroscientists from mathematics. Originally introduced by the great nineteenth-century mathematician Jules-Henri Poincare, it refers to a situation when an equation yields a single, constant solution for a whole range of numerical inputs. It was then said that such a solution "attracts" a whole range of specific numeric inputs into the equation. Another example of "attractor" can be found in Boolean algebra, where the same logical formula can be realized by a large number of input combinations.
Like a mathematical equation with attractor properties, an attractor neural net in the brain will be activated by a whole range of different inputs from the outside world, all activating the same net. While we recognize a short, black plastic pen as a pen, a long, red metal pen as a pen, and an ostentatiously rich gold pen as a pen, all of them produce very different sensory inputs. Nonetheless, the same neural net will be activated by all three sets of inputs despite their differences, and this is how we recognize a pen as a pen as a pen.
To make matters even more intriguing, every attractor has a so-called basin of attraction, a set of similar activity patterns that tend to transform into attractor state. This means that a whole range of similar, but not identical, activation patterns are "recognized" by the system as being in some sense equivalent. The main attractor properties in the formal neural net, particularly the degeneracy properties, correspond to the propensity of a whole memory to be evoked by encountering any of its component parts. And an attractor with a basin state is like a generic memory, where a whole multitude of similar objects are recognized as members of the same category.
Even though the ideas of attractors and attractor basins come from computational models, the possibility that they capture the essential features of real memory formation in the biological brain is tantalizingly seductive. John Hopfield, one of the pioneers of neural net modeling, was among the first to propose that attractors are in fact memories.
At the very least we know that attractor-like circuits exist in the brain. Their function is not entirely clear, but the evidence in support of the "memories are attractors" hypothesis continues to accumulate. Some of this evidence comes from "morphing" experiments. Most of us have seen Michael Jackson's music video "Black or White," where this technique first appeared, with morphing faces: female faces morphing into male faces, old faces morphing into young faces, Asian faces morphing into Caucasian faces. The same idea has been applied to neuroscience experiments. With the use of computer graphics one can create a continuum of images morphing one animal into another: a dog into a cat or a cow into a camel. Suppose you ask human subjects to classify the computer-generated creatures corresponding to various points on this continuum into two groupings corresponding to the two original animals. You can do the same with computer-synthesized or blended voices uttering sounds of language by morphing vowels: "A" into "0,""0" into "U," and so on.
The classifications of such computer-generated items by human subjects usually produce amazingly discrete boundaries: up to a certain point on the morphing continuum all the items are assigned, unhesitatingly and consistently, to one category; beyond that point they are assigned to the other category, equally unhesitatingly and consistently. The discreteness of these classifications is exactly what one would expect in a brain with distinct attractors and a distinct basin space linked to each attractor.
The real statistic to keep in mind is that suicide is the second leading recorded cause of death in people under 18 or over 65. Sixty percent give some prior indication of their intent, thereby making it preventable. Typical indications might be "I have a friend...," "What would you think if...," stockpiling drugs, or giving away possessions. Take note of new behaviors as cues. People doing things they have never done before may often indicate they have suddenly decided to commit suicide and are now at peace. Examples might be suddenly playing cards, dancing, or taking out the garbage when they have never made a practice of this before.
Certain high-risk factors should be identified if present: recent loss of a loved one; single, widowed, and/or childless people; people living in urban areas; being unemployed, nonreligious, or "oppressed." High-risk emotional factors include anger plus hopelessness, broken or pathological family/friend communications, and marital isolation. Verbal high-risk cues take the form of both direct statements: "I'm going to kill myself," or indirect indications: "I won't be around to give you any more trouble." People entering and leaving a depression are especially vulnerable, as are those with chronic illnesses like arthritis, high blood pressure, ulcers, and malignancies.
Recall that 65% of all suicide attempts are related to alcohol. Several reasons explain this correlation. First, the chemical nature of alcohol tends to release certain brain areas from control. The guarding mechanisms are let down. Hidden thoughts and impulses are released. (You may have witnessed incidents such as the intoxicated guy calling the boss an S.O.B.) Second, because of the chemical action of alcohol, a state is created wherein the integrative capacity of the brain is diminished. It is a condition in which aspects of memory and concentration are lost. Third, when alcohol is used as a medicine, it is unfortunately a good one to initially produce a mood of relaxation and pseudostability. In this state, people may think things are just the way they should be. They feel cool, calm, and collected. Suicide at this point may seem relevant and a good idea: "I'll just jump. It's the rational solution." More alcohol acts as a true depressant with obvious potential consequences. Finally, alcohol may also bring out psychological weakness. It may place people on the edge of reality, tip the scales, lead to loose associations, bring out psychosis, loosen normal fears, produce voices saying: "The thing to do is rid the world of you," or "The world is better off without you." In all these cases, alcohol acts as a catalyst, both physically and psychologically.
The most fertile ground for suicide is in cases of clinical depression. Most people who have the "blues" are not suicidal. They might think, "Gee, I wish I were dead, things are going so badly," or "I don't know how I'll make it. I might just drive off the road if things don't get better." Things usually do get better, however. On the other hand, a clinical depression is characterized by a consistently low mood over a period of weeks, plus weight changes, sleep problems, and other physical symptoms. Pessimism is a part of the illness, just as fever is a part of the flu. Feelings of how bad things are are part of the depression. Depression, therefore, is bad enough alone, but combined with alcohol, it is a potent mix. "There is no way out." "I'm a bad person—the only way out is to kill myself."
A. This question should be divided into two parts—domestic flights and international flights. The former are relatively short distance flights without the distressing immigration and customs formalities, though the security checks have become equally cumbersome now. A patient would, therefore, be fit to undertake a domestic journey by air much earlier than international travel. The loss of atmospheric pressure at the high altitudes at which the aircrafts fly poses no problem because the modern aircraft are fully pressurised. The considerations are the length of the journey, the conditions at the airports of entry and exit, the necessity of carrying heavy luggage, inconvenient timings from country to country and problems of food and rest. While a domestic flight may be undertaken after a month or two of recovery from an uncomplicated heart attack, it may have to be much longer, about a year, before the patient can be considered fit for international flights. It must be admitted that the tolerance to undergo privation and inconvenience as a result of long travel is lowered after a heart attack. This fact has to ue kept in mind when the patient wants to go abroad. If after a test flight the patient does not feel too well, he should avoid such flights in future.
Cancer is actually a group of diseases characterized by uncontrolled growth and spread of abnormal cells. While not all causes are known, most research supports the idea that cancer is caused by both external (chemicals, radiation, and viruses) and internal (hormones, immune conditions, and inherited mutations) factors. Causal factors may act together or in sequence to initiate or promote cancer development. We do not know why some people have malignant cells in their body and never develop cancer, while others may take 10 years or more to develop cancer. Scientists have proposed several theories for the cellular changes that produce cancer.
One theory of cancer development proposes that cancer results from some spontaneous error that occurs during cell reproduction. Perhaps cells that are overworked or aged are more likely to break down, causing genetic errors that result in mutant cells.
Another theory suggests that cancer is caused by some external agent or agents that enter a normal cell and initiate the cancerous process. Numerous environmental factors, such as radiation, chemicals, hormonal drugs, immunosuppressant drugs (drugs that suppress the normal activity of the immune system), and other toxins, are considered possible carcinogens (cancer-causing agents); perhaps the most common carcinogen is the tar in cigarettes. This theory of environmental carcinogens obviously has profound implications for our industrialized society. As in most disease-related situations, the greater the dose or the exposure to environmental hazards, the greater the risk of disease. People, who are forced to work, live, and pass through areas that have high levels of environmental toxins may, in fact, be at greater risk for several types of cancers.
A third theory came out of research on certain viruses that are believed to cause tumors in animals. This research led to the discovery of oncogenes, suspected cancer-causing genes that are present on chromosomes. Although oncogenes are typically dormant, scientists theorize that certain conditions such as age, stress, and exposure to carcinogens, viruses, and radiation may activate these oncogenes. Once activated, they begin to grow and reproduce in an out-of-control manner.
There is still a great deal that remains unanswered about the oncogene theory of cancer development. Scientists are uncertain whether only people who develop cancer have oncogenes or whether we all have proto-oncogenes, genes that can become oncogenes under certain conditions. Many oncologists (physicians who specialize in the treatment of malignancies) believe that the oncogene theory may lead to a greater understanding of how individual cells function and may bring us closer to developing an effective treatment for cancerous cells. Many factors are believed to contribute to cancer development. Experts believe that combining factors can dramatically increase a person's risk for cancer.
Immunity is a condition of being able to resist a particular disease by counteracting the substance that produces the disease. Any substance capable of triggering an immune response is called an antigen. An antigen can be a virus, a bacterium, a fungus, a parasite, or a tissue or cell from another individual. When invaded by an antigen, the body responds by forming substances called antibodies that are matched to the specific antigen much as a key is matched to a lock. Antibodies belong to a mass of large molecules known as immunoglobulins, a group of nine chemically distinct protein substances, each of which plays a role in neutralizing, setting up for destruction, or actually destroying antigens. Once an antigen breaches the body's initial defenses, the body begins a careful process of antigen analysis. It considers the size and shape of the invader, verifies that the antigen is not part of the body itself, and then begins to produce a specific antibody to destroy or weaken the antigen. This process, which is much more complex than described here, is part of a system called humoral immune responses. Humoral immunity is the body's major defense against many bacteria and bacterial toxins.
Cell-mediated immunity is characterized by the formation of a population of lymphocytes that can attack and destroy the foreign invader. These lymphocytes constitute the body's main defense against viruses, fungi, parasites, and some bacteria. Key players in this immune response are specialized groups of white blood cells known as macrophages (a type of phagocytic, or cell-eating, cell) and lymphocytes, other white blood cells in the blood, lymph nodes, bone marrow, and certain glands.
Two forms of lymphocytes in particular, the B-lymphocytes (B-cells) and T-lymphocytes (T-cells), are involved in the immune response. There are different types of B-cells, named according to the area of the body in which they develop. Most are manufactured in the soft tissue of the hollow shafts of the long bones. T-cells, in contrast, develop and multiply in the thymus, a multi-lobed organ that lies behind the breastbone. T-cells assist the immune system in several ways. Regulatory T-cells help direct the activities of the immune system and assist other cells, particularly B-cells, to produce antibodies. Dubbed "helper T's," these cells are essential for activating B-cells, other T-cells, and macrophages. Another form T-cell, known as the "killer T's" or "cytotoxic T's," directly attacks infected or malignant cells. Killer T's enable the body to rid itself of cells that have been infected by viruses or transformed by cancer; they are also responsible for the rejection of tissue and organ grafts. The third type of T-cells, "suppressor T's," turns off or suppresses the activity of B-cells, killer T's, and macrophages. Suppressor T's circulate in the blood-stream and lymphatic system, neutralizing or destroying antigens, enhancing the effects of the immune response, and helping to return the activated immune system to normal levels. After a successful attack on a pathogen, some оf the attacker T- and B-cells are preserved as memory T- and B-cells, enabling the body to quickly recognize and respond to subsequent attacks by the same kind of organism at a later time. Thus macrophages, T- and B-cells, and antibodies are the key factors in mounting an immune response.
Once people have survived certain infectious diseases, they become immune to those diseases, meaning that in all probability they will not develop them again. Upon subsequent attack by the disease-causing microorganism, their memory T- and B-cells are quickly activated to come to their defense. Immunization works on the same principle. Vaccines containing an attenuated (weakened) or killed version of the disease-causing microorganism or containing an antigen that is similar to but not as dangerous as the disease antigen are administered to stimulate the person's immune system to produce antibodies against future attacks - without actually causing the disease.
Autoimmune Diseases Although white blood cells and the antigen-antibody response generally work in our favor by neutralizing or destroying harmful antigens, the body sometimes makes a mistake and targets its own tissue as the enemy, builds up antibodies against that tissue, and attempts to destroy it. This is known as autoimmune disease (auto means "self). Common examples of this type of disease are rheumatoid arthritis, lupus erythematosus, and myasthenia gravis.
In some cases, the antigen-antibody response completely fails to function. The result is a form of immune deficiency syndrome. Perhaps the most dramatic case of this syndrome was the "bubble boy," a youngster who died in 1984 after living his short life inside a sealed-off environment designed to protect him from all antigens. A much more common immune system disorder is acquired immune deficiency syndrome (AIDS).
Almost on a daily basis the question. What's new? comes up in conversations with my patients, and frequently this inquiry is directed towards the latest in filler materials. Innovation is always intriguing to patients, but they are equally interested in learning about new fillers that are long lasting and safe. My reply is that out of all the new injectable fillers that are on the horizon, I am the most excited about the hyaluronic acid family of products.
Hyaluronic acid is a polysaccharide, or natural sugar, that is crucial to the healthy functioning of the human body The skin houses the vast majority of hyaluronic acid, with the remainder found in the muscles and skeleton Its primary function is to provide volume and pliability to the skin and it plays a crucial role in cell growth Interestingly enough, hyaluronic acid is commonly used in moisturisers and other cosmetics, as it is wonderfully efficient at holding onto water. An often quoted characteristic of hyaluronic acid is its capacity to bind water up to a thousand times its volume. This very property makes it ideal as a filler material, for even while a hyaluronic acid filler is being naturally degraded, what remains of the filler attracts water from the body and that function allows it to hold its shape for even longer.
In the 1960s, the first hyaluronic acid product was used for eye surgery. Today there are two families of such fillers currently, available for cosmetic use. The first is created in a lab, while the other is derived from an animal source.
Doctors at the Joslin Diabetes Center are used to dealing with reactions of worry and shock when they deliver the news that tests are positive for diabetes. But the reaction of one patient really surprised them. He was a prominent sportscaster, and he seemed delighted when he heard the news. "Why are you so happy?" his puzzled doctor asked. "Oh," the sportscaster replied, "I felt miserable for so long. I thought I had some hopeless condition for which there would be no help. I am so happy to have something which can be treated!"
How do you know if you have diabetes? A variety of tests are used, for many different purposes. There are quick and easy tests suitable for screening large groups of the population. For example, the doctor may test a urine specimen during a routine medical checkup even if there is no particular reason to suspect diabetes.
One problem with using urine tests to screen for new cases of diabetes is that a person's blood sugar level must be fairly high before any glucose will spill over into the urine. Some people's kidneys will tolerate rather large amounts of sugar in the blood before passing it into the urine. Other people may have sugar in the urine because their kidneys will tolerate only a small amount of sugar in the blood, but turn out to have perfectly normal blood sugar levels. So positive urine sugar tests only indicate the possibility of diabetes. They should be followed up by blood tests.
More complicated tests provide more information: whether diabetes is present, how serious the condition is, and what kind of diabetes it is. Such tests are used when a doctor already suspects that a person has diabetes. They provide information that helps the doctor plan methods of treatment, and they can also be used to check on how well a treatment is working. There are even sophisticated tests that give an idea of whether a person might develop diabetes at some time in the future.
WHY HAVE RESEARCHERS HAD SUCH A DIFFICULT TIME DETERMINING THE PREVALENCE AND EFFECTS OF ADHD (ATTENTION DEFICIT HYPERACTIVITY DISORDER) MONG ADULTS WHO HAD IT IN CHILDHOOD?
It's only in the last decade or so that doctors have come to accept that ADHD is not just a childhood problem. In fact, until recently, most studies and most physicians did not followADHD sufferers beyond adolescence. As a result, there have been very few long-term followup studies. And as with any scientific investigation, the studies that have been done have shown similar but not identical results.
Most studies currently available are what are termed retrospective ("looking back") studies. In one method, researchers check old clinic records and find a population of children previously diagnosed with ADHD perhaps ten to twenty years before. After attempting to contact these subjects, the researchers study those they succeed in finding who agree to participate. Various methods (such as questionnaires, rating scales, interviews, and checking medical, academic, and police records) are used to evaluate current symptoms of ADHD and life achievements, as well as the psychiatric, social, and emotional variables of these grown-up subjects.
Another method of retrospective study is to find a group of adults diagnosed with adult ADHD and to try, through history taking and looking through old school and medical records, to trace the history of their condition and to determine the presence or absence of various symptoms at earlier stages.
For example, a controlled twenty- to twenty-five-year retrospective study conducted by B. L. Borland and H. K. Heck-man analyzed twenty of thirty-seven men who had been diagnosed as hyperactive in childhood. Nineteen brothers were used as a control group. The researchers found that the majority of the men who had earlier been diagnosed as hyperactive were living normal and productive lives, though more than half continued to show symptoms of hyperactivity and a noticeable number demonstrated clear antisocial behavior. They also found that the hyperactive subjects had not done quite as well as their brothers socially or economically.
A similar followup study conducted in Rhode Island analyzed eighty-one adults, averaging twenty-one years of age, who had been diagnosed with ADHD in childhood. Thirty-two older brothers were used as a control group. The researchers found results similar to those of Borland and Heckman, but with a lower percentage of antisocial problems among the ADHD subjects.
Several other studies have strived to analyze the impact and occurrence of ADHD in adults of varying ages and socioeconomic status, with interesting results. Most importantly, nearly all follow-back studies have concluded that symptoms of ADHD continue into adulthood and can predispose individuals to alcoholism and certain psychiatric problems, most notably character disorders.
There are obviously many problems with trying to reconstruct a clinical picture that may be from twenty years before. A more accurate form of study is the prospective study. The researchers begin with a group of children who have been diagnosed as having ADHD and match them with a group of control subjects, i.e., children matched in age, socioeconomic variables, and intelligence, but with no evidence of ADHD or behavioral problems. These two groups are then followed extensively over many years, with intermittent interviews of the child and family, testing, and so on. These studies necessarily take a long time to complete, and since it is only recently that ADHD in adulthood was recognized, there are not yet many groups of studied children with ADHD who have reached adulthood.
Drs. Gabrielle Weiss and Lily Hechtman of the Montreal Children's Hospital have published the fifteen-year followup data of an ongoing study of, originally, 104 hyperactive children. They have studied many aspects of these young adults' lives, including the persistence of ADHD symptoms; psychiatric status; personality pathology, including antisocial behavior; educational and vocational status; socioeconomic status; beliefs and values; as well as general life course and achievements.
They have found that hyperactives had greater difficulties as young adults in several areas when compared with a group of normal controls. Among these are the following.
The hyperactive young adults had more impulsive personality traits.
They were more likely to have been involved in traffic and other accidents.
They were likely to have some persistence of hyperactivity, distractibility, and attentional problems.
They also had a significantly lower level of education and were more prone to leaving school because of poor grades and expulsion.
They were more likely to have a diagnosable psychiatric condition; in particular, a significant number fulfilled the criterion for antisocial personality disorder.
They had much lower self-esteem.
They had less successful social and emotional relationships.
Many questions remain unanswered in the study of adult ADHD, and obviously much more research is needed in this area. The most obvious questions include; Why does ADHD afflict some adults who had it as children, but not others? And to what degree does ADHD in childhood predict personality and psychiatric disorders in adulthood? Which treatment measures can most improve the long-term outcome?
These questions and others are now being addressed. Over 600 children have been enrolled in a six-site NIMH study undertaken with the U.S. Department of Education. This study will compare medication, behavior therapies, psychotherapy, and other clinical treatments available in the child's community. The first data from that study will be available in fall 1997. But the NIMH intends to continue the study over a long period, providing a look at the long-term course of ADHD and the influence of various treatments on its course and outcome.
Intolerance is the key-note of this remedy.
The man likes discipline and orderliness everywhere. He himself observes discipline in his personal life, wants the same in his office amongst his juniors, and likes the same in his family. Liking discipline and orderliness in life is a good thing. We want discipline in Army and Police which are our cherished institutions, and discipline is taught in oW" schools and colleges. It is one thing to like discipline and even insist upon it amongst your juniors.
It is still better if you can impress upon others the goodness of discipline in life by your personal example or guide others to observe discipline by persuation.
Discipline, however, becomes a horror word, if it is stretched too far - if no allowance is made for even genuine difficulties. An office peon starts for his office on cycle, well in time. On the way his cycle gets punctured and he has to walk a few kilometers to reach his office late.
An office assistant goes to his office as usual in a chartered bus. There is an accident in the way. and the chartered bus reaches the office late.
Your child-is ill & you have to get the medicine for the child in the morning. There is long queue of patients in the doctor's clinic. Even with the best of your efforts you reach your office late.