The mechanisms of atherogenesis remain uncertain. The "response-to-injury" theory is most widely accepted. Endothelial injury causes vascular inflammation and a fibroproliferative response ensues. Probable causes of endothelial injury include oxidized low-density lipoprotein (LDL) cholesterol; infectious agents; toxins, including the byproducts of cigarette smoking; hyperglycemia; and hyperhomocystinemia. Circulating monocytes infiltrate the intima of the vessel wall, and these tissue macrophages act as scavenger cells, taking up LDL cholesterol and forming the characteristic foam cell of early atherosclerosis. These activated macrophages produce numerous factors that are injurious to the endothelium.
Elevated serum levels of LDL cholesterol overwhelm the antioxidant properties of the healthy endothelium and result in abnormal endothelial metabolism of this lipid moiety. Oxidized LDL is capable of a wide range of toxic effects and cell/vessel wall dysfunctions that are characteristically and consistently associated with the development of atherosclerosis.The response-to-endothelial injury theory
Ross proposed this more unifying theory. Termed the response-to-injury hypothesis, it postulates that atherosclerosis begins with endothelial injury, making the endothelium susceptible to the accumulation of lipids and the deposition of thrombus.
The currently accepted response-to-vascular injury theory
Over the past decade, Fuster and colleagues have proposed that vascular injury starts the atherosclerotic process.1 The effect of such vascular injury can be classified as follows:
- Type I - Vascular injury involving functional changes in the endothelium with minimal structural changes, (ie, increased lipoprotein permeability and white blood cell adhesion)
- Type II - Vascular injury involving endothelial disruption with minimal thrombosis
- Type III - Vascular injury involving damage to media, which may stimulate severe thrombosis, resulting in unstable coronary syndromes
An 84-year-old woman presents with a blistering rash. The rash began 1 week ago on her right hand, but it has progressed to her arm, upper chest, and abdomen. The rash is painless but intensely itchy, and it limits her ability to complete routine tasks. She has had no fever, no history of trauma, and no recent travel. She lives alone and uses an electric scooter to assist her with mobility. The patient relies on help from family and caretakers for the activities of daily living. She has a medical history of 100% estrogen-receptor-positive nonmetastatic breast cancer, ischemic heart disease, osteoporosis, and chronic renal insufficiency. The patient takes aspirin, isosorbide mononitrate, ramipril, simvastatin alendronate, and a calcium supplement. Her breast cancer is treated with an aromatase inhibitor. She has had no recent changes in her medication regimen and does not take any over-the-counter or herbal medications.
On physical examination, the patient appears frail but nontoxic. Her temperature is 98.4°F (36.9°C). Her heart has a regular rhythm with a rate of 88 bpm. Her blood pressure is 146/88 mm Hg and her respiratory rate is timed at 16 breaths/min. She has clear, equal bilateral breath sounds. There are no heart murmurs, but a loud S2 heart sound is heard. Her apical impulse is not displaced. The patient's abdomen is soft and nontender, and no appreciable organomegaly is detected. She has a deep, fixed 3-cm mass underlying the nipple of her right breast, with overlying skin puckering. She does not have any axillary lymphadenopathy. Her current breast examination is unchanged from her last documented examination. Examination of the skin reveals several tense bullae, excoriated papules, and vesicles ranging in size from a few millimeters to 3 centimeters over her right arm, anterior chest, and abdomen (see Figures 1 and 2). These bullae and vesicles rest on an erythematous base, and they contain clear fluid. There is no involvement of the mucous membranes and the Nikolsky sign (blistering of healthy-appearing skin when it is rubbed) is not elicited.
Laboratory tests are performed, which demonstrate normal erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and C-reactive protein (CRP) findings. She has a hemoglobin level of 12.7 g/dL (127 g/L), with a mild eosinophilia measured at 0.48 × 109/L. Her blood urea nitrogen is 28 mg/dL (10 mmol/L) and her creatinine level is 2.1 mg/dL (185.64 µmol/L). Her liver function tests are unremarkable.
Questions answered incorrectly will be highlighted.
Hint: Pay attention to the patient's age.
The patient in this case exhibited many factors suggestive of a diagnosis of bullous pemphigoid. Her advanced age, the clinical appearance of the skin lesions, and the subacute onset of an intensely pruritic, nonpainful rash were consistent with the diagnosis of bullous pemphigoid, and a skin biopsy sent for routine histology, direct immunofluorescence, and indirect immunofluorescence studies confirmed it. Histopathology of a subepidermal blister demonstrated an eosinophil-rich inflammatory infiltrate in the dermis. Viral and bacterial culture swabs from the blister fluid had a negative result, which excluded an infectious process (such as herpes zoster).
Bullous pemphigoid is the most common blistering autoimmune disorder in the Western world, with an estimated incidence of 6-7 cases per million in France and Germany, and an unknown incidence in the United States. It is a relatively benign condition that tends to run a waxing and waning course, with recurrent episodes of remission and relapse. It most commonly affects the elderly but can also rarely occur in younger patients and infants.[1,2,4] In cases of bullous pemphigoid, immunoglobulin G (IgG) autoantibodies attack the skin basement membrane zone, which induces an inflammatory response and activates the complement system. The 2 main antigenic targets that have been identified are known as bullous pemphigoid antigen 1 (BPAg1; a 230-kd protein) and bullous pemphigoid antigen 2 (BPAg2; a 180-kd protein). They are both components of the hemidesmosome and allow linkage of intermediate filaments to the basement membrane. Of these antigens, BPAg2 is thought to be the major contributor to the pathophysiology of bullous pemphigoid. Animal studies have shown failure of blistering to occur with antibodies induced solely against BPAg1.[2] In these cases, eosinophils are characteristically found on skin histopathology. They migrate to the area of injury by the activity of an eosinophil-specific chemokine called eotaxin.[2] Interleukin-16 (IL-16) is another cytokine that has been found in high concentrations in the serum of patients with bullous pemphigoid. IL-16 stimulates CD-4 helper cells and up-regulates interleukin-2 receptors.
Bullous pemphigoid can present acutely or subacutely with tense round or oval-shaped blisters and vesicles. Intensely itchy urticarial lesions can precede the bullae by days, weeks, or even months. The lesions of bullous pemphigoid may either be localized or generalized throughout the body, and they often affect the flexor areas of the limbs, as well as affecting the abdomen, chest, and medial thighs. Mucous membrane involvement may occur, but it is not common. The lesions heal without any scarring.[1,2] Although more commonly seen in pemphigus, the Nikolsky sign can also be occasionally seen in cases of pemphigoid. The Nikolsky sign is described as the separation of superficial skin from the deeper dermis with the application of gentle pressure.
A full history and physical examination is essential for recognizing the diagnosis and determining the etiology. Drug-induced bullous pemphigoid is well recognized and has many causes, including diuretics, antibiotics, and angiotensin-converting enzyme (ACE) inhibitors. Cessation of the drug normally prevents recurrence.[3] There is evidence of an association between bullous pemphigoid and malignancy; however, bullous pemphigoid itself has not been shown to increase the incidence of malignancy in age- and sex-matched controls.[1] Interestingly, Gül et al described a case of breast cancer with bone metastases presenting with bullous pemphigoid in a 62-year old-woman.[6] Bullous pemphigoid is a disease of the elderly and, of course, this population is much more prone to developing malignancy as well; therefore, a thorough examination for a possible associated malignancy is prudent.
The clinical differential diagnosis for bullous pemphigoid is broad and could include pemphigus vulgaris, linear immunoglobulin A (IgA) disease, epidermolysis bullosa acquisita, bullous lupus erythematosus, and dermatitis herpetiformis. Blistering rashes can also be seen with impetigo, acute viral infections, drug eruptions, and herpes zoster. The patient's history and physical examination will help narrow down this differential. The patient's age, vital signs, the distribution of the blisters, and the nature of the blister (ie, tense or flaccid) all provide clues; however, testing is ultimately necessary, including immunofluorescence studies, histopathology, and viral and bacterial swabs.[1,4] In bullous pemphigoid, indirect immunofluorescence using serum will demonstrate circulating antibodies to the basement membrane zone of human skin or monkey esophagus substrate in a linear pattern in 70% of patients.[2] Skin biopsy of a blister will often reveal an eosinophilic inflammatory infiltrate, whilst direct immunofluorescence of normal skin adjacent to the lesion will show linear deposits of IgG and C3 at the basement membrane zone.
Other variants of bullous pemphigoid include gestational pemphigoid and cicatricial pemphigoid. Gestational pemphigoid occurs during pregnancy and leads to bullae or urticarial lesions on the abdomen, trunk and extremities, with mucous membrane sparing. The fetus is not affected and the disease regresses after pregnancy, although it may reappear with future pregnancies. Cicatricial pemphigoid rarely involves the skin and tends to affect mucous membranes, with ocular and oropharyngeal involvement, and it can lead to scarring and significant morbidity from blindness and airway obstruction.[4]
The treatment options available for bullous pemphigoid include oral steroids or topical steroid creams, antibiotics, steroid-sparing immunosuppressants (such as azathioprine, mycophenolate mofetil, and methotrexate), plasmapheresis, and immunoglobulin infusions. Steroidal options include the use of high-potency topical steroids, and oral steroid therapy with prednisone 0.5-1mg/kg/day can be used as well. In patients with a high risk of osteoporosis, calcium and vitamin D supplements with a bisphosphonate should be considered.[2] For acutely ill patients or those with extensive skin involvement, fluid replacement, thermoregulation, and infection management may be necessary. Most patients with bullous pemphigoid are elderly; they may have multiple comorbidities and may be taking multiple medications. Treatment should be carefully tailored to minimize side effects yet allow for adequate disease control.
A systematic review by Khumalo et al found potent topical steroids were safe and effective in patients with bullous pemphigoid, with less systemic side effects than oral steroid treatment.[5] The side effects of steroid treatment can include diabetes mellitus, peptic ulcer disease, glaucoma, cataract formation, and agranulocytosis. The prognosis of patients with bullous pemphigoid is generally very good. Disease remission can vary from 1-5 years with treatment.
The patient in this case was treated with high-potency topical steroids and experienced a good result. The patient tapered the medication over a period of several weeks, and she regularly followed up with her health care provider.
You are examining a patient and suspect that she is suffering from bullous pemphigoid. Which of the following findings is MOST likely to be found in this patient?
| Your Colleagues Responded: | |||
| Mucosal involvement |  5% | ||
| Tense blisters | Correct Answer | 86% | |
| Healing scar-like lesions | 3% | ||
| Pyrexia | 1% | ||
| Dermatomal distribution | 4% |
You are examining a 76-year-old patient who presented with a vesiculobullous rash on his elbows and knees that began 2 months ago. The rash is painful and limits his activities. His history reveals that he has experienced similar episodes in the past. You diagnose this patient with bullous pemphigoid, which is confirmed by histopathologic analysis and direct immunofluorescence testing. Which of the following choices would be the mainstay of treatment for this patient?
| Your Colleagues Responded: | |||
| Steroid therapy | Correct Answer | 89% | |
| Methotrexate | 3% | ||
| Plasmapheresis | 0% | ||
| Intravenous immunoglobulin | 2% | ||
| Azathioprine | 3% |
Chronic bronchitis is defined clinically as the presence of a chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded)
Emphysema, on the other hand, is defined pathologically as an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis
*Airflow limitation in emphysema is due to loss of elastic recoil and decrease in airway tethering, whereas chronic bronchitis leads to narrowing of airway caliber and increase in airway resistance
Pathophysiology
The pathophysiology of IPAH is poorly understood. An insult (eg, hormonal, mechanical, other) to the endothelium may occur, possibly in the setting of increased susceptibility to pulmonary vascular injury (ie, multiple hit theory), resulting in a cascade of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle) proliferation.Early in PAH, as the pulmonary artery pressure increases because of increasing right ventricle work, thrombotic pulmonary arteriopathy occurs. Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis of small muscular arteries of the pulmonary vasculature
In later stages, as the pulmonary pressure continues to rise, plexogenic pulmonary arteriopathy develops. This is characterized by a remodeling of the pulmonary vasculature with intimal fibrosis and replacement of normal endothelial structure.
Associated conditions
IPAH can be associated with portal hypertension (sometimes called portopulmonary hypertension), suggesting that patients with shunting of splanchnic blood, with or without liver disease, have a higher risk of developing PPH. Additionally, exposure of the pulmonary circulation to substances in the splanchnic circulation that normally are detoxified via the liver may contribute to the development of pulmonary hypertension. More research is necessary to better understand this relationship.
Patients with connective-tissue diseases, namely the CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) variant of scleroderma, systemic lupus erythematosus, and mixed connective-tissue disease, are also predisposed to developing IPAH-like disease..((This is now termed associated PAH, or APAH. However, the pathophysiologic nature of this predisposition is unclear. In the past, most experts used the term secondary pulmonary arterial hypertension for these diseases, indicating that, similar to IPAH, the process involves the precapillary circulation but is somehow caused by the underlying disease.))
Physical
Physical findings in persons with PAH can be quite variable.
- Physical examination of the cardiovascular system often reveals the following findings:
- The pulmonic component of the second heart sound is usually increased, which may demonstrate fixed or paradoxic splitting in the presence of severe right ventricular dysfunction. Occasionally, the second heart sound may be palpable.
- Pulmonic regurgitation (Graham Steell murmur) may also be apparent.
- A murmur of tricuspid regurgitation can be present, and a right ventricular lift (heave) may be noted.
- Jugular venous pulsations may be elevated in the presence of volume overload, right ventricular failure, or both. Large V waves are often present because of the commonly present severe tricuspid regurgitation.
- Other findings may include (1) hepatomegaly with palpable pulsations of the liver and (2) an abnormal abdominal-jugular reflex. Ascites is not uncommonly present in untreated patients or in patients with worsening decompensated right heart failure.
- Lung examination findings are usually normal.
- Extremity examination may reveal pitting edema of varying degrees. Patients who are bedridden may have presacral edema.
Causes
The strict definition of IPAH is pulmonary hypertension with no known cause. However, associations have been recognized (eg, connective-tissue diseases, liver cirrhosis, stimulant abuse,2 HIV infection; see Associated conditions in Pathophysiology).Mortality/Morbidity
IPAH has no cure. Untreated, IPAH leads to right-sided heart failure and death. The overall survival rate in one study was approximately 30% at 3 years. Prior to the 1990s, therapeutic options were limited. The recent emergence of prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and other novel drug therapies has greatly improved the outlook for patients with IPAH and IPAH-like diseases. In one study, the use of long-term prostacyclin agents resulted in a 5-year mortality rate greater than 65%. With newer therapies, perhaps in combination, these figures are expected to further improve.
Rachel is a 42-year-old married mother of 2 children. She presents to her primary care provider (PCP) with fatigue, trouble sleeping, and feelings of being overwhelmed and easily frustrated. She reports that she has been experiencing problems at work, as her new manager is more stringent than her previous supervisor. She is unable to handle her current workload as a bookkeeper at a local law office, and has been handing in her assignments late or not fully complete. The supervisor has also added new duties to Rachel's workload, tasks that she doesn't really enjoy or feel prepared to accomplish. She's been putting in a lot of overtime, bringing work home to complete, and is often preoccupied with worry about her job. In addition, she has been late picking up her kids from soccer practice and has forgotten about pre-arranged playdates, which has caused more bickering with her husband. She attributes her trouble sleeping to worry over these, and other, concerns. The PCP diagnoses Rachel with depression and anxiety, prescribes a selective serotonin reuptake inhibitor (SSRI), and schedules a follow-up visit for 6-8 weeks to evaluate the benefits of the antidepressant medication.
At the follow-up visit, Rachel complains that the SSRI doesn't appear to be helping enough -- even after 2 months. She is still feeling overwhelmed and fatigued at home; the house is a mess, she doesn't feel like cooking dinner except on weekends, and she's rarely interested in having sex with her husband. She doesn't perceive much benefit of the SSRI at work, either, noting that she is still not able to focus on the task at hand, except when she's conducting audits, which she enjoys. She is finding it more difficult to get motivated at work. The PCP mentions that sometimes it takes months to realize benefits from the SSRIs; he increases the dosage and schedules a follow-up visit for 6 weeks later.
-->According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV), ADHD is a "persistent pattern of inattention and/or hyperactivity-impulsivity," some symptoms of which must have been present prior to the age of 7 years.[5] Patients can be diagnosed with 1 of 3 ADHD types: hyperactive/impulsive; inattentive; or, most commonly, combined type, which includes both hyperactive/impulsive and inattentive symptoms. Diagnosis requires positive identification of at least 6 of 9 DSM-IV characteristics of hyperactivity/impulsivity or inattention in 2 or more settings.
**what is DSM IV??
( Diagnostic and Statistical Manual of Mental Disorderss DSM)
Whereas childhood ADHD is typically characterized by hyperactivity and inattention, adults with ADHD are less likely to be hyperactive and more likely to have symptoms of inattention, distractibility, and impulsivity.[2] Adult ADHD is a disorder of underperformance and inattention. Adults with ADHD manifest with poor concentration, disorganization, problems with time management, and an "internal restlessness"[6]; they report making careless errors, having difficulty staying organized, and being forgetful and easily distracted.
We know life's hard, truth is hurt but lies are the worst, they are all hard to accept when they have been
found out, history homework failed . I think i tend to hold a class for history instead of telling you about me, i'm basically a super hardworking guy messy (^_^) but when it comes to life,
I am more analytical and critical about things, and likes to take the past experience and try to avoid doing mistake .haha.
it's amazing. amzing how people change the way of things, like how I used to hate outdoors in Band
felt it was a complete waste of time, i've acquired to like it more, i guess people change, their thereotical means and applications in life just goes on into a new direction, and see things in another perspective, i guess- it's
all in the mind. It really amazes me how these comes into action, from someone so pessimistic has changed his own view of things, and thus my friend is scoring much better, being more optimisitc and not think of his old way of suicidal
thoughts, which are pretty daunting. and thus we need to see things, in another light, another perspective and another new way, to enable us to open up our minds, and make more new things, the new way it is. 