Osteoporosis
 
is characterized by increased porosity of the skeleton resulting from reduced bone mass. The disorder may be localized to a certain bone (s), as in disuse osteoporosis of a limb, or generalized involving the entire skeleton. Generalized osteoporosis may be primary, or secondary

Primary generalized osteoporosis
• Postmenopausal
• Senile
Secondary generalized osteoporosis

A. Endocrine disorders
• Hyperparathyroidism
• Hypo or hyperthyroidism
• Others

B. Neoplasia
• Multiple myeloma
• Carcinomatosis 

C. Gastrointestinal disorders
• Malnutrition & malabsorption
• Vit D & C deficiency
• Hepatic insufficiency 

D. Drugs
• Corticosteroids
• Anticoagulants
• Chemotherapy
• Alcohol 

E. Miscellaneous
• osteogenesis imperfecta
• immobilization
• pulmonary disease 

Senile and postmenopausal osteoporosis are the most common forms. In the fourth decade in both sexes, bone resorption begins to overrun bone deposition. Such losses generally occur in areas containing abundant cancelloues bone such as the vertebrae & femoral neck. The postmenopausal state accelerates the rate of loss; that is why females are more susceptible to osteoporosis and its complications. 

Gross features
• Because of bone loss, the bony trabeculae are thinner and more widely separated than usual. This leads to obvious porosity of otherwise spongy cancellous bones

Microscopic features
• There is thinning of the trabeculae and widening of Haversian canals.
• The mineral content of the thinned bone is normal, and thus there is no alteration in the ratio of minerals to protein matrix

Etiology & Pathogenesis

• Osteoporosis involves an imbalance of bone formation, bone resorption, & regulation of osteoclast activation. It occurs when the balance tilts in favor of resorption.
• Osteoclasts (as macrophages) bear receptors (called RANK receptors) that when stimulated activate the nuclear factor (NFκB) transcriptional pathway. RANK ligand synthesized by bone stromal cells and osteoblasts activates RANK. RANK activation converts macrophages into bone-crunching osteoclasts and is therefore a major stimulus for bone resorption.
• Osteoprotegerin (OPG) is a receptor secreted by osteoblasts and stromal cells, which can bind RANK ligand and by doing so makes the ligand unavailable to activate RANK, thus limiting osteoclast bone-resorbing activity.
• Dysregulation of RANK, RANK ligand, and OPG interactions seems to be a major contributor in the pathogenesis of osteoporosis. Such dysregulation can occur for a variety of reasons, including aging and estrogen deficiency.
• Influence of age: with increasing age, osteoblasts synthetic activity of bone matrix progressively diminished in the face of fully active osteoclasts.
• The hypoestrogenic effects: the decline in estrogen levels associated with menopause correlates with an annual decline of as much as 2% of cortical bone and 9% of cancellous bone. The hypoestrogenic effects are attributable in part to augmented cytokine production (especially interleukin-1 and TNF). These translate into increased RANK-RANK ligand activity and diminished OPG.
• Physical activity: reduced physical activity increases bone loss. This effect is obvious in an immobilized limb, but also occurs diffusely with decreased physical activity in older individuals.
• Genetic factors: these influence vitamin D receptors efficiency, calcium uptake, or PTH synthesis and responses.
• Calcium nutritional insufficiency: the majority of adolescent girls (but not boys) have insufficient dietary intake of calcium. As a result, they do not achieve the maximal peak bone mass, and are therefore likely to develop clinically significant osteoporosis at an earlier age.
• Secondary causes of osteoporosis: these include prolonged glucocorticoid therapy (increases bone resorption and reduce bone synthesis.)
The clinical outcome of osteoporosis depends on which bones are involved. Thoracic and lumbar vertebral fractures are extremely common, and produce loss of height and various deformities, including kyphoscoliosis that can compromise respiratory function. Pulmonary embolism and pneumonia are common complications of fractures of the femoral neck, pelvis, or spine. 

Pulmonary edema

Pulmonary edema is swelling and/or fluid accumulation in the lungs. It leads to impaired gas exchange and may cause respiratory failure.

Signs and symptoms

Symptoms of pulmonary edema include difficulty breathing, coughing up blood, excessive sweating, anxiety and pale skin. If left untreated, it can lead to death, generally due to its main complication of acute respiratory distress syndrome.

Diagnosis

physical examination: end-inspiratory crackles during auscultation (listening to the breathing through a stethoscope) can be due to pulmonary edema. The diagnosis is confirmed on X-ray of the lungs, which shows increased vascular filling and fluid in the alveolar walls.

Low oxygen saturation and disturbed arterial blood gas readings may strengthen the diagnosis

Causes

Cardiogenic causes:

1. Heart failure
2. Tachy- or bradyarrhythmias
3. Severe heart attack
4. Hypertensive crisis
5. Excess body fluids, e.g. from kidney failure
6. Pericardial effusion with tamponade

Non-cardiogenic causes, or ARDS (acute respiratory distress syndrome):

1. Inhalation of toxic gases
2. Multiple blood transfusions
3. Severe infection
4. Pulmonary contusion, i.e. high-energy trauma
5. Multitrauma, i.e. severe car accident
6. Neurogenic, i.e. cerebrovascular accident (CVA)
7. Aspiration, i.e. gastric fluid or in case of drowning
8. Certain types of medication
9. Upper airway obstruction
10. Reexpansion, i.e. postpneumonectomy or large volume thoracentesis
11. Reperfusion injury, i.e. postpulmonary thromboendartectomy or lung transplantation
12. Lack of proper altitude acclimatization.

Treatment

When circulatory causes have led to pulmonary edema, treatment with loop diuretics, such as furosemide or bumetanide, is the mainstay of therapy. Secondly, one can start with noninvasive ventilation. Other useful treatments include glyceryl trinitrate, CPAP and oxygen.

IMMUNITY AND RESISTANCE TO INFECTION

Body's resistance to infection depends upon:

I. Defence mechanisms at surfaces and portals of entry.

II. Nonspecific or innate immunity

Ill. Specific immune response.

I.  Surface Defence Mechanisms

1. Skin:

(i) Mechanical barrier of keratin and desquamation.

(ii) Resident commensal organisms

(iii)Acidity of sweat.

(iv) Unsaturated fatty acids of sebum

2. Oropharyngeal

(i)Resident flora

(ii) Saliva, rich in lysozyme, mucin and Immunoglobulins (lgA).

3. Gastrointestinal tract.-

(i) Gastric HCI

(ii) Commensal organisms in Intestine

(iii) Bile salts

(iv) IgA.

(v) Diarrhoeal expulsion of irritants.

4. Respiratory tract:

(i) Trapping in turbinates

(ii) Mucus trapping

(iii) Expulsion by coughing and sneezing.

(iv) Ciliary propulsion.

(V) Lysozymes and antibodies in secretion.

(vi) Phagocytosis by alveolar macrophages.

5. Urinary tract:

(i) Flushing action.

(ii) Acidity

(iii) Phagocytosis by urothelial cells.

6. Vagina.-

(i) Desquamation.

(ii) Acid barrier.

(iii) Doderlein's bacilli (Lactobacilli)

7. Conjunctiva:

Lysozymes and IgA in tears

II. Nonspecific or Innate Immunity

1. Genetic factors

• Species: Guinea pig is very susceptible to tuberculosis.
• Race: Negroes are more susceptible to tuberculosis than whites
• Sickle cells (HbS-a genetic determined Haemoglobinopathy resistant to Malarial parasite.

2. Age Extremes of age are more susceptible.

3. Hormonal status. Low resistance in:

• Diabetes Mellitus.
• Increased corticosteroid levels.
• Hypothyroidism

4. Phagocytosis. Infections can Occur in :

• Qualitative  or quantitative defects in neutrophils and monocytes.
• Diseases of mononuclear phagocytic system (Reticuloendothelial cells-RES).
• Overload blockade of RES.

5. Humoral factors

• Lysozyme.
• Opsonins.
• Complement
• Interferon (antiviral agent secreted by cells infected by virus) 

III. The Specific Immune Response

Definition

The immune response comprises all the phenomenon resulting from specific interaction

of cells of the immune-system with antigen. As a consequence of this interaction cells

, appear that mediate cellular immune response as well cells that synthesis and secrete

immunoglobulins

Hence the immune response has 2 components.

1. Cell mediated immunity (CMI).

2:. Humoral immunity (antibodies)

(I) Macrophages. Constituent of the M. P. S. These engulf the antigenic material.

(i) Most of the engulfed antigen is destroyed to' prevent a high dose paralysis of the Immune competent cells.

(ii) Some of it persists in the macrophage, retaining immunogenecity for continued stimulus to the immune system.

(iii)The antigenic information is passed on to  effectors cells. There are two proposed mechanisms for this:

(a) As messenger RNA with code for the specific antibody.

(b) As antigen-RNA complexes.

(2) Lymphocytes. There are 2 main classes recognized by surface characteristics.

(A) T-Lymyhocytes (thymus dependant) :- These are responsible for cellular immunity . On exposure to antigen

• They transform to immunoblasts  which divide to form the effectors cells.
• They secrete lymphokines These are
  • Monocyte migration inhibition factor
  • Macrophage activation factor
  • Chemotactic factor
  • Mitogenic factor
  • Transfer factor
  • Lymphotoxin which kills target cell
  • Interferon.
  • Inflammatory factor which increases permeability. .
• Some remain as 1onglived memory cell for a  quicker recognition on re-exposure
• They also modify immune response by other lymphocytes in the form of “T – helper cells “ and “T-suppressor” cells
• They are responsible for graft rejection

(B) B-Lymphocytes (Bursa dependent). In birds the Bursa of Fabricious controls these cells. In man, its role is taken up by," gut associated lymphoid tissue)

(i) They are responsible for antibody synthesis. On stimulation they undergo blastic transformation and then differentiation to plasma cells, the site of immunoglobulin synthesis.

(ii) They also form memory cells. But these are probably short lived.

(C) In addition to T & B lymphocytes, there are some lymphocytes without the surface markers of either of them. These are 'null' cells-the-natural Killer (N,K.) cells and cells responsible for antibody dependent cellular-cytotoxicity.

(3) Plasma cells. These are the effectors cells of humoral immunity. They produce the immunoglobins, which are the effector molecules.

Erythema multiforme is a hypersensitivity reaction to an infection (Mycoplasma), drugs or various autoimmune diseases.
 - probable immunologic disease
 - lesions vary from erythematous macules, papules, or vesicles.
 - papular lesions frequently look like a target with a pale central area.
 - extensive erythema multiforme in children is called Stevens-Johnson syndrome, where there is extensive skin and mucous membrane involvement with fever and respiratory symptoms.

Blastomycosis (North American Blastomycosis; Gilchrist's Disease)

A disease caused by inhalation of mold conidia (spores) of Blastomyces dermatitidis, which convert to yeasts and invade the lungs, occasionally spreading hematogenously to the skin or focal sites in other tissues.

Pulmonary blastomycosis tends to occur as individual cases of progressive infection

Symptoms are nonspecific and may include a productive or dry hacking cough, chest pain, dyspnea, fever, chills, and drenching sweats. Pleural effusion occurs occasionally. Some patients have rapidly progressive infections, and adult respiratory distress syndrome may develop.

Leukaemias
Uncontrolled proliferation of leukocyte precursors (may be with associated red cell and platelet series proliferation).

Factors which may playa causal role are.
- Viral
- Radiation.
- Genetic.

Classification

1. Acule leukaemia:

a. Lymphocytic (lymphoblastic).
b. Myelocytic and promyelocytic (myeloblastic).
c. Monocytic.
d. Myelomonocytic.
e. Undifferentiated (Stem cell).

2. Chronic leukaemia:

a. Lymphocytic
b. Myelocytic

3. Miscellaneous:
a. Erythroleukaemia (De Guglielmo's disease).
b. Eosinophilic leukaemia.
c. Megakaryocytic leukaemia.