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.

Clinical & biologic death

Clinical death

Clinical death is the reversible transmission between life and biologic death. Clinical death is defined as the period of respiratory, circulatory and brain arrest during which initiation of resuscitation can lead to recovery.

Signs indicating clinical death are

• The patient is without pulse or blood pressure and is completely unresponsive to the most painful stimulus.

• The pupils are widely dilated

• Some reflex reactions to external stimulation are preserved. For example, during intubations, respiration may be restored in response to stimulation of the receptors of the superior laryngeal nerve, the nucleus of which is located in the medulla oblongata near the respiratory center.

• Recovery can occur with resuscitation. 

Biological Death

Biological death (sure sign of death), which sets in after clinical death, is an irreversible state

of cellular destruction. It manifests with irreversible cessation of circulatory and respiratory

functions, or irreversible cessation of all functions of the entire brain, including brain stem.

Monocytosis:
Causes

-Infections causing lymphocytosis, especialy tuberculosis and typhoid. 
-Monocytic leukaemia.
-Some auto immune diseases.

Nevus

A nevus refers to any congenital lesion of the skin, while a nevocellular nevus specifically refers to a benign tumor of neural crest-derived cells that include modified melanocytes of various shapes (nevus cells).
 - nevocellular nevi are generally tan to deep brown, uniformly pigmented, small papules with well-defined, rounded borders.
 - most nevocellular nevi are subdivided into junctional, intradermal, or compound types.
 - most nevocellular nevi begin as junctional nevi with nevus cells located along the basal cell layer producing small, flat lesions, which are only slightly raised. 
- junctional nevi usually develop into compound nevi as nevus cells extend into the underlying superficial dermis forming cords and columns of cells (compound: nevi at junction and in the dermis).
 - eventually, the junctional component of a nevocellular nevus is lost, leaving only nevus cells within the dermis, thus the term intradermal nevus.
 - junctional → compound → intradermal nevus.
 - although uncommon, certain nevi may evolve into a malignant melanoma, particularly those which are congenital and those which are referred to as dysplastic nevi.
 - a dysplastic nevus is commonly associated with patients who have multiple scattered nevi over the entire body (dysplastic nevus syndrome) with individual lesions that have a diameter greater than 1 cm.

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. 

Thrombosis

Definition-The formation from constituents of the blood, of a mass within the venous or arterial vasculature of a living animal. Natural defense of the body to acute vascular injury.

Pathologic thrombosis includes deep venous thrombosis (DVT), pulmonary embolism (PE), coronary artery thrombosis leading to myocardial infarct and cerebrovascular thrombosis leading to stroke.

Coagulated blood- clots formed 

Clot – formation of solid mass of blood components formed outside the vascular tree
Thrombosis with resulting embolic phenomena is important cause of morbidity and mortality.

Haemostatic system allows blood to remain in fluid form under normal conditions and causes the development of temporary thrombus at site of vascular injury.

Components of haemostatic system:
1.    Platelets
2.    Vascular endothelium
3.    Procoagulant plasma protein clotting factors
4.    Natural anticoagulants
5.    Fibrinolytic proteins
6.    Antifibrinolytic proteins

Normal haemostasis:
1.    Primary haemostasis-platelet plug formation
2.    Secondary haemostasis-stable plug or thrombus
3.    Natural anticoagulants-confines thrombus site and size to maintain blood flow
4.    Fibrinolysis-degrades fibrin , limits thrombus size and dissolves thrombus once vessel injury is repaired

Changes in any of these factors may result in pathologic thrombosis.

Pathophysiology of thrombosis:
Virchow’s Triad-Thrombosis results from a) decreased blood flow b) vascular endothelial injury and c) alterations in the components of blood.

Vessel wall:
EC (intima), smooth muscle cells (media) and the connective tissue (adventitia).Vascular endothelium is thromboresistant. EC injury leads to TF expression and thrombosis.
Vessel wall has antiplatelet, anticoagulant and fibrinolytic activities which make it thromboresistant.
Antiplatelet activities:
1.    Prostacyclin synthesized by EC in response to thrombin. Inhibits platelet adhesion as well as causes vasodilation
2.    NO regulates vascular tone as well as functioning as inhibitor of platelet adhesion. Constitutive expression as well as induced expression by EC in response to cytokines
3.    Ectozymes which metabolize ADP and ATP to AMP and adenosine. Adenosine inhibits platelet function, ADP is platelet agonist

Anticoagulant activities:
1.    Synthesis of heparin like GAG which inactivate activated clotting factors
2.    Protein C and S and thrombomodulin-Thrombin generated binds to thrombomodulin which activates protein C which then binds to Protein S and this inhibits coagulation by its proteolytic effect on Factors Va and VIIIa
3.    TFPI is synthesized by EC and  regulates TF-VIIa activation of Factor X. Also inhibits vascular cell proliferation

Fibrinolytic activities:
1.    Secretion and synthesis of plasminogen activators TPA in response to thrombin and vasoactive stimulants such as vasopressin and histamine
2.    Synthesis of urokinase in response to inflammatory cytokines
3.    FDP’s generated have antiplatelet and antithrombin activity
4.    Secretion of PAI

Prothrombotic properties of vascular endothelium promote coagulation with appropriates stimuli.

EC exposure to stimuli such as trauma, cytokines, atherogenic stimuli, endotoxins and immune complexes result in increased TF expression, reduced Protein C activation and reduced fibrinolysis so converting an antithrombotic surface to a prothrombotic surface.
Inherited conditions which result in abnormalities of EC derived or regulated proteins will cause thrombosis.

Arterial thrombosis:
1.    Abnormal vessel wall due to atherosclerotic plaque rupture, arterial outflow obstruction, vessel dissection EC injury promote platelet adhesion and activation
2.    Release of contents of platelet granules cause recruitment  and activation of additional platelets
3.    Thromboxane synthesis induces platelet aggregation
4.    Thrombin generation due to presence of PL

Platelets are pathogenetically more important in arterial thrombi thus antiplatelet agents are very important in arterial thrombosis management.

Venous thrombosis:
1.    Vessel wall is usually normal except if there is direct vessel trauma, extrinsic venous compression or damage due to drugs like chemotherapy
2.    Reduction in venous tone is important in pathophysiology

Venous thrombi can be of two types.

A. Phlebo thrombosis 
This is thrombus formation in an uninflammed vein usually due to stasis or changes in coagulability of blood. This occurs mostly in deep calf veins and varicose veins in the legs originating near valve pockets. They may propagate to extend to popliteal ,femoral and iliac-veins. These are a common source of massive emboli ‘Phlegmasia alba dolens’  (painful white leg) is a condition seen in late pregnancy and puerperium.  In this condition, in addition to iliofemoral thrombosis , there is arterial spasm

B Thrombophlebitis:
In this condition venous wall is inflamed and initiates thrombosis. This is more firmly attached to the vessel wall and also there is much less tendency for propagation Hence there is little chance or embolism.

Cardiac Thrombosis
Intra cardiac thrombus formation can be at 3 sites 

•    Valvular: as in endocarditis
•    Atrial : as in atrial fibrilation ('ball valve thrombus") over MacCallum’s patch is Rheumatic Fever.
•    Ventricular mural thrombus  over site of MI

Fate of Thrombus

- Resolution : if small, the thrombus is rapidly covered by endothelial cells. Then it can Resolved by a combination of retraction, phgocytosis , platelet autolysis, and fibrinolysis 
-  Organisation: there is in growth of vascular granulation tissue. This can result in
 a. recanalisation
 b. collagenisation and-scarring
-    Detachment resulting in thromboembolism