FUNGAL INFECTION

Mucormycosis (Zygomycosis; Phycomycosis)

Infection with tissue invasion by broad, nonseptate, irregularly shaped hyphae of diverse fungal species, including Rhizopus, Rhizomucor, Absidia, and Basidiobolus.

Infection is most common in immunosuppressed persons, in patients with poorly controlled diabetes, and in patients receiving the iron-chelating drug desferrioxamine.

Symptoms and Signs

Rhinocerebral mucormycosis is the most common form, but primary cutaneous, pulmonary, or GI lesions sometimes develop, and hematogenous dissemination to other sites can occur. Rhinocerebral infections are usually fulminant and frequently fatal. Necrotic lesions usually appear on the nasal mucosa or sometimes the palate.

Metastatic Tumors 

These are the most common malignant tumor of bone. Certain tumors exhibit a distinct skeletal prediliction. In adults more than 75% of skeletal metastases originate from cancers of the prostate, breast, kidney, and lung. In children, neuroblastoma, Wilms' tumor, osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma are the common sources of bony metastases. Most metastases involve the axial skeleton (vertebral column, pelvis, ribs, skull, sternum), proximal femur, and humerus. The radiologic appearance of metastases can be purely osteolytic, purely osteoblastic, or mixed osteolytic-osteoblastic (majority of cases). In lytic lesions (e.g., kidney& lung), the metastatic cells secrete substances such as prostaglandins, interleukins, etc. that stimulate osteoclastic bone resorption; the tumor cells themselves do not directly resorb bone. Similarly, metastases that elicit a blastic response (e.g., prostate adenocarcinoma) do so by stimulating osteoblastic bone formation.

Hematological examination

This is a method by which abnormalities of the cells of the blood and their precursors in the bone marrow are investigated to diagnose the different kinds of anemia & leukemia.

DYSPLASIA
 It is disturbed growth or  cells in regard to their size, shape arrangement. In its mild degrees it represents a reversible reaction to chronic inflammation whereas the most severe degrees warrant a labelling of intraepithelial neoplasia. Hence it includes a wide spectrum of changes ranging from a reversible disorientation to 'carcinoma-in-situ'.

Histologically it is characterized by:

o    Basal cell hyperplasia.
o    Variation in size and shape of cells.
o    Disorderly maturation.
o    Increased mitotic activity.
o    Disorientation of arrangement of cells (loss of polarity)

Dysplasia is commonly seen in:

o    Squamous epithelium of cervix.
o    Bronchial epithelium in habitual smokers.
o    Gastric and colonic mucosa in long standing inflammation
o    Oral and vulval leucoplakia
 

General chromosome abnormalities
The normal human cell contains 46 chromosomes, including 22 homologous pairs of autosomes and one pair of sex chromosomes (XX for female and XY for male). A somatic cell is diploid, containing 46 chromosomes. Gametes are haploid, containing 23 chromosomes.
Aneuploidy
(a) Any deviation in the number of chromosomes, whether fewer or more, from the normal haploid number of chromosomes.
(b) Nondisjunction—a common cause of aneuploidy. It is the failure of chromosomes to pass to separate cells during meiotic or mitotic cell division.
(c) Often seen in malignant tumors.
 

Deletion: loss of a sequence of DNA from a chromosome.
 

Translocation: the separation of a chromosome and the attachment of the area of separation to another chromosome.

DIABETES MELLITUS 
a group of metabolic disorders sharing the common underlying characteristic of hyperglycemia.  
Diabetes is an important disease because
1. It is common (affects 7% of the population). 
2. It increases the risk of atherosclerotic coronary artery and cerebrovascular diseases.
3. It is a leading cause of 
   a. Chronic renal failure
   b. Adult-onset blindness
   c. Non traumatic lower extremity amputations (due to gangrene) 
     
Classification 
Diabetes is divided into two broad classes:
1. Type1 diabetes (10%): characterized by an absolute deficiency of insulin secretion caused by pancreatic βcell destruction, usually as a result of an autoimmune attack.

2. Type2 diabetes (80%): caused by a combination of peripheral resistance to insulin action and an inadequate secretion of insulin from the pancreatic β cells in response to elevated blood glucose levels. 

The long-term complications in kidneys, eyes, nerves, and blood vessels are the same in both types.

Pathogenesis
Type 1 diabetes is an autoimmune disease and as in all such diseases, genetic susceptibility and environmental influences play important roles in the pathogenesis. The islet destruction is caused primarily by T lymphocytes reacting against immunologic epitopes on the insulin hormone located within β-cell; this results in a reduction of β-cell mass. The reactive T cells include CD4+ T cells of the TH1 subset, which cause tissue injury by activating macrophages, and CD8+ cytotoxic T lymphocytes; these directly kill β cells and also secrete cytokines that activate further macrophages. The islets show cellular necrosis and lymphocytic infiltration (insulitis). Autoantibodies against a variety of β-cell antigens, including insulin are also detected in the blood and may also contribute to islet damage. 

Type 2 Diabetes Mellitus: the pathogenesis remains unsettled. Environmental influences, such as inactive life style and dietary habits that eventuates in obesity, clearly have a role. Nevertheless, genetic factors are even more important than in type 1 diabetes. Among first-degree relatives with type 2 diabetes the risk of developing the disease is 20% to 40%, as compared with 5% in the general population. 
The two metabolic defects that characterize type 2 diabetes are 1.  A decreased ability of peripheral tissues to respond to insulin (insulin resistance) and 2. β-cell dysfunction manifested as inadequate insulin secretion in the face of hyperglycemia. In most cases, insulin resistance is the primary event and is followed by increasing degrees of β-cell dysfunction.

Morphology of Diabetes and Its Late Complications

The important morphologic changes are related to the many late systemic complications of diabetes and thus are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), and nerves (neuropathy). These changes are seen in both type 1 and type 2 diabetes. 

The changes are divided into pancreatic & extrapancreatic 
A. Pancreatic changes are inconstant and are more commonly associated with type 1 than with type 2 diabetes.
One or more of the following alterations may be present.
1. Reduction in the number and size of islets
2. Leukocytic infiltration of the islets (insulitis) principally byT lymphocytes.  

3. Amyloid replacement of islets; which is seen in advanced stages

B. Extrapancreatic changes 

1. Diabetic macrovascular disease is reflected as accelerated atherosclerosis affecting the aorta and other large and medium-sized arteries including the coronaries. Myocardial infarction is the most common cause of death in diabetics. Gangrene of the lower limbs due to advanced vascular disease, is about 100 times more common in diabetics than in the general population. 
2. Hyaline arteriolosclerosis
 is the vascular lesion associated with hypertension. It is both more prevalent and more severe in diabetics than in nondiabetics, but it is not specific for diabetes and may be seen in elderly nondiabetics without hypertension.
3. Diabetic microangiopathy
 is one of the most consistent morphologic features of diabetes, which reflected morphologically as diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the retina, renal glomeruli, and peripheral nerves. The thickened capillary basement membranes are associated with leakiness to plasma proteins. The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
4. Diabetic Nephropathy: renal failure is second only to myocardial infarction as a cause of death from diabetes.

Three lesions encountered are: 
1. Glomerular lesions
2. Renal vascular lesions, principally arteriolosclerosis; and
3. Pyelonephritis, including necrotizing papillitis.  

Glomerular lesions:  these include 
a. diffuse glomerular capillary basement membrane thickening
b. diffuse glomerular sclerosis : diffuse increase in mesangial matrix; always associated with the above.  
c. nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) refers to a rounded deposits of a laminated matrix situated in the periphery of the glomerulus 

Pyelonephritis: both acute and chronic pyelonephritis are more common & more severe 

Ocular Complications of Diabetes: Visual impairment up to total blindness may occur in long-standing diabetes. The ocular involvement may take the form of 
a. retinopathy 
b. cataract formation
c. glaucoma 

In both forms of long-standing diabetes, cardiovascular events such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality. Diabetic nephropathy is a leading cause of end-stage renal disease. By 20 years after diagnosis, more than 75% of type 1 diabetics and about 20% of type 2 diabetics with overt renal disease will develop end-stage renal disease, requiring dialysis or renal transplantation. 
Diabetics are plagued by an enhanced susceptibility to infections of the skin, as well as to tuberculosis, 
pneumonia, and pyelonephritis. Such infections cause the deaths of about 5% of diabetics.