TUMOR RECURRENCE AND TAMOXIFEN RESISTANCE: WHAT MAKES A CELL RESISTANT TO TAMOXIFEN?

Many cellular changes have been associated with the development of tamoxifen resistance, but we still do not fully understand the basis of this clinical problem. After prolonged tamoxifen exposure a selection process may favor cells that have no estrogen receptors 01 cells that produce abnormal or aberrant receptors that fail to recognize tamoxifen. Because tamoxifen is known to have estrogenic effects, scientific studies have shown that estrogenic metabolites of tamoxifen may contribute to the development of cellular resistance to tamoxifen. As in other types of drug resistance, there may be some form of cellular pump that removes tamoxifen from the cell.Other research has focused on the involvement of proteins known as growth factors. Because tamoxifen is understood to increase the release from certain cells of the growth-inhibitory factor known as TGF-b, tamoxifen resistance may also occur when these cells can no longer produce the TGF-b required to continue restraining growth of the breast cancer cells.Much of this new information is speculative, yet it does suggest that several different mechanisms may contribute to the development of tamoxifen resistance. All require further investigation.*43\320\2*

ADVENTURES ON MEMORY LANE: AMNESIA INSIGHTS

Memory impairments, known in technical parlance as “amnesias,” have always occupied a central place in neuropsychology. Not surprisingly, a process as complex as memory can disintegrate in a vast variety of ways. Memory impairment is almost never global. It is almost always partial, producing a number of different forms of amnesia.One of the main distinctions made in neuropsychology is between “anterograde amnesia” and “retrograde amnesia.” Anterograde amnesia is a loss of the ability to learn new information after brain damage had set in. Retrograde amnesia is an inability to recall information acquired before the damage took place. Someone who suffered brain damage in a car accident last year and is now unable to recall what he read in the newspaper yesterday may suffer from anterograde amnesia. And if this person does not remember the name of the company that employed him for five years before the car accident, he is likely to suffer from retrograde amnesia. It is not uncommon to develop the two forms of amnesia together as a result of brain damage, and our poor fellow may be both unable to recall what he learned recently and to access the information acquired before the accident.The distinction between anterograde and retrograde amnesia depends on our knowledge of the exact time when brain damage occurs, which is not always easy to figure out. If a previously healthy individual suffered traumatic brain injury in a car accident, the exact time of the event is usually easy to establish. But in a case of dementia this is not possible, since in dementia the decline is gradual, unfolding over years. By the time a patient is diagnosed with dementia, he or she will have already been ill for a long period of time, often measured in years, not months.Despite these diagnostic quagmires, the distinction between anterograde and retrograde amnesia has been very useful to neuropsychologists and neurologists for years. These two forms of amnesia often appear together; but for reasons idiosyncratic rather than logical, anterograde amnesia has always been given more attention, and it was assumed that it is more common and more severe than retrograde amnesia.My own clinical experience contradicted this widely held assumption. I thought that we had witnessed the effects of a common logical error, the absence of evidence mistaken for the evidence of absence. (Because researchers did not pay nearly as much attention to retrograde amnesia as they did to anterograde amnesia, they did not find it.) In my own work I have always been particularly intrigued by retrograde amnesia, since I felt that it offered a unique window into the way knowledge is organized and stored in the brain.Among other things, retrograde amnesia tells us about the time course of long-term memory formation. When memory of the past suffers following brain damage, not all memories suffer to an equal extent. Virtually without exception, relatively recent memories will be more affected than the memories for a very distant past. This phenomenon is known as the temporal gradient of retrograde amnesia.Someone who suffered head injury in a terrible car accident may have lost his memories for the events of a month or two months, even a year or two years, before the accident, but he is more likely to remember the events of a decade or two decades earlier. The same is true for a patient suffering from dementia. This is why the common sense argument that someone’s memory cannot be all bad, since he remembers the names of his grade school teachers, really proves nothing. A patient suffering from Alzheimer’s disease will have such memories of very distant past preserved well into the advanced disease stages, while the memories for more recent events will be gone relatively early in the course of the disease.The temporal gradient is counterintuitive. Many years ago I conducted a casual survey of a few friends from various walks of life, asking them to venture a guess as to what memories are more likely to suffer in brain disease: relatively recent or very distant. Guided by their common sense but unencumbered by the technical knowledge of brain science or neuropsychology, they all guessed wrongly without exception that the more distant memories would suffer first. This common sense—defying property of retrograde amnesia may serve as a great clinical tool for telling apart the memory loss caused by brain damage from the memory loss caused by psychological factors such as hysteria, or from plain malingering.But the temporal gradient teaches us more than how to confound the unsuspecting public. It tells us volumes about how long-term memories are actually formed. Indeed, if memories remain vulnerable as long as they depend on the reverberating patterns of activation, then the extent of the temporal gradient allows us to estimate the amount of time necessary for long-term memory formation to run its course. And it turns out that retrograde amnesia may affect memories going back years and even decades.It is known, for instance, that hippocampal ablation may result in retrograde amnesia going back as far as fifteen years. This means that it may take that long for a permanent, structural, relatively invulnerable long-term memory to be formed in the brain.The process is gradual and incremental, rather than an abrupt, precipitous emergence of the long-term trace where there had been nothing before a second ago. The gradual nature of the long-term trace formation is illuminated by another peculiar feature of the temporal gradient—its “shrinkage.” As we already know, it is not uncommon for a patient who had just suffered brain damage in an accident to have memory loss extending years and even decades back. But with the passage of time, some of the memories will return, and the recovery of memories will follow an orderly temporal course.The span of the memory loss will “shrink.” (This casual and somewhat inelegant word has in fact been adopted as a technical term in memory research, and scientists write about “shrinking retrograde amnesia,” or “shrinking temporal gradient.”) Like so many other features of retrograde amnesia, this mysterious process defies common sense. The shrinkage unfolds backward, memory for the more distant events returning before memory for the more recent ones. But the shrinkage is usually incomplete and the memories for the most recent events never recover. Just how extensive the permanent memory loss is varies from patient to patient and depends on the severity of brain injury. This permanent memory loss is genuine and intractable. No amount of hypnosis or “truth serum” will help recover the lost memories, and any attempt to do so will simply reflect a lack of neuropsychological sophistication.The orderly and gradual process by which memories recover in “shrinking retrograde amnesia” tells us about the gradual nature of long-term memory formation. The farther along the process is, the more rapidly the memory will recover. But the memories whose formation has been assaulted by brain damage at very early stages are too fragile to rebound. They will be lost forever.So the most critical obstacle on a memory’s path into long-term storage is time itself. It takes years, or possibly even decades, for a long-term memory to form in the brain. Since there is no perpetuum mobile in the physical world, the reverberating loops stand a good chance of being extinguished on their own, and most of them are. Most reverberating loops become extinguished before the structural engram has had a chance to be formed. Nature appears to be very protective of the permanent memory store in the brain and the plank for being admitted into it is very high.*24\302\2*

WHY YOU CAN’T STAY AWAKE: OTHER TYPES OF DOES – PSYCHIATRIC DOES

Sometimes excessive sleepiness can mask the presence of depression, especially if the depression is of the type known as bipolar or manic-depressive illness (where periods of euphoria or mania are followed by depressed periods). As we have seen, however, the more common type of depression, classified as unipolar, usually results in a different sleep problem, that of early-morning insomnia.Besides depression, there are other, far less common, psychiatric conditions that may include excessive daytime sleepiness as a symptom. Generally these are the dissociative disorders in which the victim loses touch with reality through amnesia or some other cause. An example is the fugue state, in which victims suddenly lose all recollection of past or current life, usually wandering off to begin a totally new existence with a new identity in a new location, completely unaware that anything has changed. After a few days or weeks these individuals will suddenly “come to,” returning to their prior identity, unable to remember how they got where they are. Needless to say, such conditions, while fortunately rare, can be extremely distressing. Hypersomnia is also present in many cases of schizophrenia and in borderline personality disorders.*156\226\8*

ALLERGIES, CANDIDA AND ASTHMA

Many asthmatics and other allergy sufferers find that after a few bouts of vaginal, oral or intestinal thrush, they become allergic to more and more foods. This often causes blood sugar fluctuations and hypoglycaemia sets in with its inevitable symptoms. As the immune system is overworked by its fight against the fungi, its ability to cope decreases and a vicious circle begins. The more allergies, the more blood sugar will tend to fluctuate — then less resistance causes more infections, and so on. To break the vicious circle one must do several things:Eradicate the Candida from the gut.Starve the yeast so it will not grow unchecked again.Increase natural resistance to the organism by normalising gut flora.The first step requires special anti-fungal medications; the second consists of special anti-candida diets free of fungi, moulds and ferments. The third step involves the administration of suitable nutrients, the differential diagnosis of coexisting bacterial, fungal, parasitic or viral intestinal infections and their possible effects, such as leaky gut syndrome, as well as the assessment of the liver’s capacity to clear endotoxins and exotoxins.Differential DiagnosisThe differential diagnosis of Candida syndrome uses a combination of several methods, including questionnaires, immunology tests, physical examination, symptomatology, clinical trials with special diets and/or anti fungals and a variety of allergy tests. Most important however, is what we call ‘the clinical picture’, a composite of the patient’s family and personal history, presenting symptoms and clinical evidence which may result from an examination. Far from being simply a matter of reading a questionnaire or asking to name a list of symptoms, the differential diagnosis of the Candida syndrome is a complex procedure requiring considerable diagnostic experience.Kinds of SymptomsThe wide variety of symptoms which Candida can cause fall into the following categories: Loose or irritable bowel, diarrhoea or constipation, alternate constipation and diarrhoea, excessive flatus, malabsorption, abdominal bloating, heartburn and nausea.Although these do occur in patients with other diseases, especially parasitic, viral or helicobacter intestinal infections, they are quite common with intestinal thrush. When they do occur in asthmatics the doctor must suspect that candidiasis is a major contributing factor. Naturally there must be a differential diagnosis to exclude other organisms and the possibility of food allergies or intolerances.Allergic SymptomsAsthma, sinusitis, hay fever, post-nasal drip, throat mucus, headaches, skin rashes, sneezing and chest or bronchial congestion.Again, these could be just signs of allergies to many other factors, including chemicals or foods, rather than Candida; so it is important to make an accurate diagnosis.Mucocutaneous SymptomsThrush; tinea; exzema; skin rashes; ear, nose, throat, mouth, vaginal and rectal infections, inflammation or irritation, discharges and itching; and nail infections, known as ‘paronychia’.Emotional/Mental SymptomsPremenstrual syndrome, anxiety, depression, agoraphobia, nervousness, short temper, poor concentration, poor memory, mood swings.These are common in both candidiasis and many allergies, as well as in hypoglycaemia. In addition, please remember that candidiasis, like viral illness and allergies, is a great masquerader, as we saw earlier, and can provoke a whole range of symptoms which mimic many quite different illnesses.Dermatological SymptomsTinea, skin rashes and skin, rectal, vaginal, ear and throat itchiness.These signs of candidiasis are also experienced by allergic individuals.*58\145\2*

MANAGING YOUR WEIGHT: MEASURES OF BODY FAT

Hydrostatic Weighing TechniquesFrom a clinical perspective, the most accurate method of measuring body fat is through hydrostatic weighing techniques. This method measures the amount of water a person displaces when completely submerged. Because fat tissue has a lower density than muscle or bone tissue, a relatively accurate indication of actual body fat can be computed by comparing a person’s underwater and out-of-water weights. Although this method may be subject to errors, it is one of the most sophisticated techniques currently available.
Pinch and Skinfold MeasuresPerhaps the most commonly used method of determining body fat is the pinch test.Numerous studies have determined that the triceps area (located in the back of the upper arm) is one of the most reliable areas of the body for assessing the amount of fat in the subcutaneous (just under the surface) layer of the skin. In making this assessment, a person pinches a fold of skin just behind the triceps with the thumb and index finger. It is important to pinch only the fat layer and not the triceps muscle. After selecting a spot for measure, the person assesses the distance between the thumb and index finger. If the size of the pinch appears to be thicker than 1 inch, the person is generally considered over-fat.Another technique, the skinfold caliper test, resembles the pinch test but is much more accurate. In this procedure, a person pinches folds of skin at various points on the body with the thumb and index finger. This technique uses a specially calibrated instrument called a skinfold caliper to take a precise measurement of the fat layer. Besides the triceps area, the points most often used in these measurements are the biceps area (front of the arm), the subscapular area (upper back), and the iliac crest (hip). Once these data points are assessed, special formulas are employed to arrive at a combined prediction of total body fat.In the hands of trained technicians, the skinfold caliper test can be fairly accurate. If the person doing the test is inconsistent about the exact locations of the pinch or if there is difficulty in determining the difference between fat and muscle, the results may be inaccurate. In addition, the heavier a person is, the more prone this technique is to error. For obese people, difficulties in assessment are magnified because of problems in distinguishing between flaccid muscles and fat. Also, most currently available calipers do not expand far enough to obtain accurate measurements on the moderately obese (20 to 40 percent overweight) or the morbidly obese (more than 50 percent overweight). Additional errors in skinfold assessments may occur as a result of failure to account for certain age, sex, and ethnic differences in calibrations.
Girth and Circumference MeasuresAnother common method of body fat assessment is the use of girth and circumference measures. Diagnosticians use a measuring tape to take girth, or circumference, measurements at various body sites. These measurements are then converted into constants, and a formula is used to determine relative percentages of body fat. Although this technique is inexpensive, easy to use, and commonly performed, it is not as accurate as many of the other techniques listed here.
Soft-Tissue RoentgenogramA relatively new technique for determining body fat, the soft-tissue roentgenogram, involves injecting a radioactive substance into body and allowing this substance to penetrate muscle (lean) tissue so that distinctions between fat and lean tissue can be made by means of imaging.
Bioelectrical Impedance Analysis Another method of determining body fat levels, bioelectrical impedance analysis (BIA), involves sending a small electric current through the subject’s body. The amount of resistance to the current, along with the person’s age, sex, and other physical characteristics, is then fed into a computer that uses special formulas to determine the total amount of lean and fat tissue.
Total Body Electrical ConductivityOne of the newest (and most expensive) assessment techniques is total body electrical conductivity (TOBEC), which uses an electromagnetic force field to assess relative body fat. Although based on the same principle as impedance, this assessment requires much more elaborate, expensive equipment, and therefore is not practical for most people.Although all of these methods can be t they can also be inaccurate and even harmful unless the testers are skillful and well trained. Before agreeing to undergo any procedure, be sure you are aware of the expense, potential for accuracy, risks, and training of the tester.*7/277/5*

WEIGHT CONTROL: HEALTH RISKS OF OBESITY

- Hypertension (High blood pressure)- Diabetes- Cardiovascular diseases- Cancer- Osteoarthritis- Gout- Depression- Respiratory Problems: Sleep apnea
HypertensionHigh blood pressure can lead to development of heart disease, kidney failure and stroke. Obese people are six times more prone to develop heart disease. Obese people generally have elevated blood lipids thus leading to atherosclerosis and cardiovascular problems.
Diabetes type IIObese people are ten times more likely to develop type II diabetes and obesity is the principal risk factor especially when it is central obesity (higher waist circumference) or (higher waist hip ratio).
Respiratory problemsObesity puts pressure on lungs thus reducing their size, chest wall is heavy and is difficult to lift, thus causing difficulty in breathing, sleep apnea is another disorder where subjects stop breathing in their sleep due to collapse of soft tissues in the throat. On long-term basis sleep apnea can cause hypertension, arrhythmia and sudden death.
Musculoskeletal problemsArthritis and low back pain are common. Joint replacements are also difficult to perform.
Gastroesophageal reflux disease (GERD)Increased stomach pressure results in high rate of reflux where acid from the stomach backs up into the oesophagus. Other problems include decreased or irregular menstrual cycle, infertility, ovarian cyst, etc. Obese women are also more prone to cancer of breast, uterus, cervix, ovaries or gall bladder.Psychological problems include negative image, shame, depression, rejection, etc. Studies have shown that each kg of weight loss is associated with 3- 4 months of prolonged survival; 10 kg weight loss is predicted to restore 35% of life expectancy; 10% of total body weight loss reduces HbAlC by 1.6%, reduces hypertension by 26%, reduces triglycerides, LDL (low density lipoprotein) and increases HDL (high density lipoprotein).
Weight ReductionMost recent WHO recommendation for dietary improvements and increased level of physical exercise provides the basis for the development of strategies to challenge rise in obesity. The more effective obesity therapies should prevent or delay the onset of chronic degenerative diseases like diabetes, hypertension and to maintain the weight loss.*2/356/5*

BACH FLOWER REMEDIES: KEY-NOTE SYMPTOMS

1. AGRIMONY: Conceals his internal mental torture behind the facade of a care-free and cheerful face—weeps inside, laughs outside.2. ASPEN REMEDY: Apprehensions, unfounded fears. Fear without any rhyme or reason at any time of day and night. Mortally afraid of something he knows not what.3. BEECH: Intolerance, criticizes and condemns without making any allowance for even the genuine difficulties of others. Unsympathetic. Lacks humility.4. CENTAURY: Lack of will—a weak willing slave doing other’s job who cannot refuse to be used as door-mat by others. Persons who appear to have no choice except to obey others.5. CERATO: Distrust of ones own judgement. Fails to be guided by his inner voice. Asks other’s opinion about his personal problems, is confused on getting their conflicting views and usually opts for the wrong choice, then laments after discovering that his own judgement was after all correct. Meanwhile he has made a nuisance of himself by asking frivolous questions from others.6. CHERRY PLUM: Desperation. Fear of losing his mind’s control over his actions. Can do anything— even kill some body or kill himself at the spur of the moment, without thinking. Unbearable condition of mind. Apt to act on impulse than on reason.7. CHESTNUT BUD: Inattentive. Repeats the same mistakes again and again; does not learn from past experiences. Absent minded, prone to road accidents.*33\308\8*

MODES OF DETECTION OF DIABETES IN SYMPTOMATIC INDIVIDUALS(Symptoms of Diabetes)MOST COMMON SYMPTOMS

Increase in frequency of urine (polyuria) more at night (Nocturia)Increase in thirst (Polydypsia).Increase in appetite (Polyphagia)Unexplained weight loss & Weakness and Giddiness,COMMON SYMPTOMS OF DIABETESPruritus – Generalized – Itching all over the body. Pruritus Vulva – Itching specially over female genitalias. Balanitis – Scratches, whiteness, reddness, itching at forskin over penis in males.OTHER SYMPTOMSCramps in legs.Impotence (Sexual weakness) in males.Tingling & numbness in lower limbs (feet) & upper limbs (Hands) — (Parasthesia).Repeated infection: Boils / Carbuncles (boil with multiple openings) etc.DIABETES DETECTED DURING THE COURSE OF OTHERILLNESSESFeverHepatitis (Jaundice)Hypertension (High Blood Pressure)DepressionCraniopathies Herpes ZosterMyocardial Infarction (Heart attack)Cerebro Vascular Accident (Paralysis in any part of body)Arthritis (joint pains)Other Endocrinal Disorder (acromegaly, cushing disease etc.)CASES REFERRED FROM OTHER DEPARTMENTSEYE DEPTT. (Ophthomology): Eye complaints leading to detection of diabetes.Frequent changes in spectacles (Refractory Errors)Repeated stye (infection) Repeated Corneal erosionsPremature Cataract Retinopathy etc.GYNAECOLOGICAL COMPLAINTS :Repeated abortionsCongenital Malfoitned BabyBig baby deliverySudden intra-uterine foetal deathSmall for gestational age, HydroamnioasRepeated UTI (Urinary Tract Infection)As a screening procedure during pregnancyPre-operative screeningDelayed wound healingPolycystic ovaries (Insulin resistance syndrome) etc.DENTAL COMPLAINTS :Tooth acheTooth extractionSepsisInfectionBefore dental surgerySURGICAL COMPLAINTS :P re-operative screening Delayed wound healingCarbuncle Diabetic foot — first presentation Infective Ulcer or GangreneAfter Trauma / injury / accident first time diabetes detectsAbscess / Sepsis / anywhere in bodyPost-operative upper abdomen surgery (occasional)ENT COMPLAINTS :VertigoRepeated sorethroatInfection — Nasal, Ear, Tonsilar, ParatonsillarAbscess — Nasal, septum, Ac SOM, Ch SOM (Suppurative Otitis Media)Hearing Loss — May be first presentation in old age. ORTHOPAEDIC COMPLAINTS:Frozen Shoulder (painful movement) Infection: Bone & JointsAbscessTubercular (Potts Spines) Trauma and Fractures, Pre-operative detectionDelayed or non-healing / non union of fractures,Backache Spondylosis etc.SKIN AND SOFT TISSUE : Infection – Fungal, Viral, Bacterial Skin pigmentation over shin (leg area) XanthelasmaNacrobiosis Lipoidica Diabeticorum (NLD) VitiligoAcanthosis Ngricans Pmritus.Conclusion : It is important to realise that Diabetes can be asymptomatic and early diagnosis is mandatory which can prevent or postpone various complications of diabetes.*18\329\8*

EVALUATION OF THE CHILD WITH A FIRST SEIZURE WITHOUT FEVER

Now, let’s talk about the evaluation of a child who has had a first seizure without fever.If your child clearly has had a seizure, your first question, and indeed that of your physician, is “Why? What caused it?” While laboratory tests neither prove nor disprove that your child has had a seizure, they can, at times, be very helpful in searching for a cause and in predicting the likelihood of further seizures.Since a seizure is the result of a disturbance of normal brain function and since there can be many different types of disturbances, there are many different causes of seizures.One type of disturbance is acute, usually only temporary, and while capable of causing a single seizure (a single provoked seizure), rarely causes recurrent seizures. Since some of these—causes such as infection or trauma—could require urgent treatment, your physician will concentrate on them at the time of your child’s first seizure.Most first seizures without fever are of unknown cause.While not knowing a cause for the seizure is frustrating, the diagnosis of an idiopathic seizure (a seizure of unknown cause) is the best possible diagnosis for your child. A diagnosis of idiopathic seizure is an occasion for considerable optimism. It means that your doctor hasn’t found a serious cause. More than half of first seizures are idiopathic. Idiopathic seizures are likely to be completely controlled with medication and are likely to be outgrown. If there is a single such seizure, your child does not have epilepsy.*38\208\8*

ADJUNCTIVE THERAPY FOR ACUTE BACTERIAL MENINGITIS

Steroid UseGiven that many of the damaging sequelae of acute bacterial meninges are due to the host’s inflammatory response, several studies have looked at the role of steroids as an adjunctive measure. Many of the studies have been done in children, and steroids have been shown to decrease the incidence of hearing loss in cases of H. influenzae meningitis in this population. Corroborating retrospective studies, a recent randomized double-blinded study from the Netherlands found significant mortality and morbidity benefit with the use of dexamethasone during the first 4 days of therapy for acute bacterial meningitis, convincingly for pneumococcal meningitis. The authors used doses of 10 mg IV every 6 hours for 4 days, commencing before or concomitant with the first dose of antibiotics. While they did not demonstrate better outcomes with steroids for non-pneumococcal meningitides, the number of non-pneumococcal cases was too small to reach a conclusion. Early steroid use should strongly be considered when the clinical picture with or without CSF data points to bacterial meningitis.
Supportive CareEach patient’s neurologic status should be monitored closely and vigilantly for clinical deterioration, and, if this occurs, the practitioner should consider prompt reimaging, the use of modalities to lower intracranial pressure, and neurosurgical consultation for placement of a ventricular shunt or other neurosurgical intervention. While debate has surrounded intravenous fluid administration and cerebral edema, it is now generally accepted that fluids are often needed to maintain an adequate mean arterial pressure to provide sufficient cerebral perfusion pressure.*7/348/5*