N. meningiditis

Major cause of fulminant bacteremia and meningitis.  Has a unique polysaccharide capsule.  It is spread person to person by the respiratory route.  Frequently carried in nasopharynx, and carriage rates increased by close quarters.  Special risk in closed populations (college dorms) and in people lacking complement.  Sub-saharan Africa has a “meningitis belt.”

Pathogenesis is caused by adherence factors that attach to non-ciliated nasopharyngeal epithelium. These factors include pili which promote the intial epithelial (and erythrocyte) attachment, and Opa/Opc surface binding proteins.

Adherence stimulates engulfment of bacteria by epithelial cells.  Transported to basolateral surface.

The polysaccharide capsule is a major virulence factor that prevents phagocytosis and lysis. 

A lipo-oligosaccharide endotoxin also contributes to sepsis.

Aneurysm

An aneurysm is a localized abnormal dilation of a blood vessel or the heart

Types:
1. True aneurysm - it involves all three layers of the arterial wall (intima, media, and adventitia) or the attenuated wall of the heart.
 e.g. Atherosclerotic, syphilitic, and congenital aneurysms, and ventricular aneurysms that follow transmural myocardial infarctions. 

2 False aneurysm 
(also called pseudo-aneurysm) is a breach in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space ("pulsating hematoma"). 
E.g. ventricular ruptures after MI that are contained by a pericardial adhesion
E.g. a leak at the junction of a vascular graft with a natural artery.

Aneurysms are classified by macroscopic shape and size 
Saccular aneurysms 

spherical outpouchings (involving only a portion of the vessel wall, and often contain thrombi. 

Fusiform aneurysms

diffuse, circumferential dilation of a long vascular segment; 

they vary in diameter and length and can involve extensive portions of the aortic arch, abdominal aorta, or even the iliacs.

Aortic Aneurysm 

The two most important causes are: 

1- atherosclerosis : the most common cause 
It causes thinning and weakening of the media. The intimal plaques compress the underlying media and also compromise nutrient and waste diffusion from the vascular lumen into the arterial wall. The media consequently undergoes degeneration and necrosis, thus allowing the dilation of the vessel 

2- cystic medial degeneration of the arterial media. E.g. Marfan syndrome.

3- Other causes include: trauma, congenital defects (e.g., berry aneurysms), infections (mycotic aneurysms), systemic diseases, such as vasculitis.

Mycotic  Aneurysm :  
Infection of a major artery that weakens its wall is called a mycotic aneurysm

possible complications: thrombosis and rupture. 

It can originate from: 
(1) embolization of a septic thrombus, usually as a complication of infective endocarditis 
(2) extension of an adjacent suppurative process; 
(3) circulating organisms directly infecting the arterial wall 

Mycotic AAAs are atherosclerotic lesions infected by lodging of circulating microorganisms in the wall 

- e.g.  bacteremia from a primary Salmonella gastroenteritis. 

Abdominal Aortic  Aneurysm

Atherosclerotic aneurysms occur most frequently in the abdominal aorta ,the common iliac arteries, the arch, and descending parts of the thoracic aorta can also be involved 

Pathogenesis 

AAA occurs more frequently in men and rarely develops before age 50. 

Atherosclerosis is a major cause of AAA 

 hereditary defects in structural components of the aorta (e.g., defective fibrillin production in Marfan disease affects elastic tissue synthesis) 
 
 Morphology :
  Usually positioned below the renal arteries and above the bifurcation of the aorta 
  
  AAA can be saccular or fusiform 
  
  as large as 15 cm in diameter, and as long as 25 cm. 
  
  Microscopically: atherosclerosis with destruction and thinning of the underlying aortic media 
  
  the aneurysm frequently contains a laminated mural thrombus
  
  Syphilitic Aneurysm 
  
  Caused by The spirochetes T. pallidum 
  
  Tertiary stage of syphilis can cause obliterative endarteritis of the involve small vessels in any part of the body, including the vasa vasorum of the aorta 
  
  This results in ischemic medial injury, leading to aneurysmal dilation of the aorta and aortic annulus, and eventually valvular insufficiency. 
  
  valvular insufficiency and massive volume overload lead to hypertrophy of the left ventricle. The greatly enlarged hearts are sometimes called "cor bovinum" (cow's heart).
  
  CLINICAL CONSEQUENCES
  
  1.  Rupture → massive potentially fatal hemorrhage 
  2. Obstruction of downstream vessel → tissue ischemic injury
  3. Embolism → from atheroma or mural thrombus 
  4. Impingement and compression on an adjacent structure 
  5. Presentation as an abdominal mass 

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. 

Iron deficiency anaemia.

Absorption of iron is affected by :
- Iron stores.
- Rate of erythropoiesis
- Acid pH aids absorption.
- Phosphates and phytates in diet impair absorption.

Causes  of deficiency:

- Increased demand:
o    Growth (in children)
o    Menstruation, Pregnancy, lactation.
- Inadequate intake and absorption.
o    Dietary deficiency.
o    Achlorhydria or gastrectomy.
o    Malabsorption states.

- Chronic blood loss
o    Peptic ulcer, bleeding piles
o    Menorrhagia.
o    Hook worm infestation

Features:
- Anaemia.
- Koilonychia.
- Atrophic glossitis and angular stomatitis.
- Dysphagia-Plummer Vinson syndrome.

Blood findings:

- Microcytjc_hypochromic cells, ring cells and pessary cells.
- Anisocytosis and poikilocytosis.
- Low MCV. MCH and MCHC.
- Serum iron is low but iron binding capacity is increased

Bone marrow

Erythroid hyperplasia with imcronormoblasts. Iron stains reveal depleted stores

Differential  diagnosis .-

- Sideroblastic anaemia which is also microcytic hypochromic  but there is excess iron in the erythroid cells .Some are pyridoxine responsive.
- (ii) Thalassaemia
 

Ichthyosis vulgaris is a genetic disease characterized by increased cohesiveness of the cells in the stratum corneum, resulting up in a piling up stratum corneum (scales like a fish).

Miscellaneous Bone Tumors 

1. Ewing Sarcoma & Primitive Neuroectodermal Tumor (PNET) are primary malignant small round-cell tumors of bone and soft tissue. They are viewed as the same tumor because they share an identical chromosome translocation; they differ only in degree of differentiation. PNETs demonstrate neural differentiation whereas Ewing sarcomas are undifferentiated. After osteosarcomas, they are the second most common pediatric bone sarcomas. Most patients are 10 to 15 years old. The common chromosomal abnormality is a translocation that causes fusion of the EWS gene with a member of the ETS family of transcription factors. The resulting hybrid protein functions as an active transcription factor to stimulate cell proliferation. These translocations are of diagnostic importance since almost all patients with Ewing tumor have t(11;22).

Pathological features

• Ewing sarcoma and PNETs arise in the medullary cavity but eventually invade the cortex and periosteum to produce a soft tissue mass.
• The tumor is tan-white, frequently with foci of hemorrhage and necrosis.

Microscopic features

• There are sheets of uniform small, round cells that are slightly larger than lymphocytes with few mitoses and little intervening stroma.
• The cells have scant glycogen-rich cytoplasm.
• The presence of Homer-Wright rosettes (tumor cells circled about a central fibrillary space) indicates neural differentiation, and hence indicates by definition PNET. 

Ewing sarcoma and PNETs typically present as painful enlarging masses in the diaphyses of long tubular bones (especially the femur) and the pelvic flat bones. The tumor may be confused with osteomyelitis because of its association with systemic signs & symptoms of infection. X-rays show a destructive lytic tumor with infiltrative margins and extension into surrounding soft tissues. There is a characteristic periosteal reaction depositing bone in an onionskin fashion. 

2. Giant-Cell Tumor of Bone (GCT) is dominated by multinucleated osteoclast-type giant cells, hence the synonym osteoclastoma. GCT is benign but locally aggressive, usually arising in individuals in their 20s to 40s. Current opinion suggests that the giant cell component is likely a reactive macrophage population and the mononuclear cells are neoplastic. Tumors are large and red-brown with frequent cystic degeneration. They are composed of uniform oval mononuclear cells with frequent mitoses, with scattered osteoclast-type giant cells that may contain 30 or more nuclei.

The majority of GCTs arise in the epiphysis of long bones around the knee (distal femur and proximal tibia).
Radiographically, GCTs are large, purely lytic, and eccentric; the overlying cortex is frequently destroyed, producing a bulging soft tissue mass with a thin shell of reactive bone. Although GCTs are benign, roughly 50% recur after simple curettage; some malignant examples (5%) metastasize to the lungs