Fanconi’s syndrome

Characterized by the failure of the proximal renal tubules to resorb amino acids, glucose, and phosphates.
May be inherited or acquired.

Clinical manifestations include 

glycosuria, hyperphosphaturia, hypophosphatemia, aminoaciduria, and systemic acidosis.

SPIROCHETAL DISEASE

Syphilis

A contagious systemic disease caused by the spirochete Treponema pallidum, characterized by sequential clinical stages and by years of latency.

ACQUIRED SYPHILIS

T. pallidum is a delicate spiral organism about 0.25 µm wide and from 5 to 20 µm long, identified by characteristic morphology and motility with a darkfield microscope or fluorescent techniques

In acquired syphilis, T. pallidum enters through the mucous membranes or skin, reaches the regional lymph nodes within hours, and rapidly disseminates throughout the body. In all stages of disease, perivascular infiltration of lymphocytes, plasma cells, and, later, fibroblasts causes swelling and proliferation of the endothelium of the smaller blood vessels, leading to endarteritis obliterans.

In late syphilis, T. pallidum elicits a granulomatous-like (gummatous) reaction causing masses, ulcerations, and necrosis. Inflammation may subside despite progressive damage, especially in the cardiovascular and central nervous systems.

The CNS is invaded early in the infection. During the secondary stage of the disease, > 30% of patients have abnormal CSF and may have symptoms of meningitis

Symptoms, Signs, and Course

The incubation period of primary syphilis can vary from 1 to 13 wk but is usually from 3 to 4 wk. The disease may present at any stage and long after the initial infection

Primary stage: The primary lesion, or chancre generally evolves and heals within 4 to 8 wk in untreated patients. After inoculation, a red papule quickly erodes to form a painless ulcer with an indurated base that, when abraded, exudes a clear serum containing numerous spirochetes

The regional lymph nodes usually enlarge painlessly and are firm, discrete, and nontender. Chancres occur on the penis, anus, and rectum in men and on the vulva, cervix, and perineum in women. Chancres may also occur on the lips or the oropharyngeal or anogenital mucous membranes.

Secondary stage: Cutaneous rashes usually appear within 6 to 12 wk after infection and are most florid after 3 to 4 mo.

Frequently, generalized, nontender, firm, discrete lymphadenopathy and hepatosplenomegaly are palpable. Over 80% of patients have mucocutaneous lesions, 50% have generalized lymphadenopathy, and about 10% have lesions of the eyes (uveitis), bones (periostitis), joints, meninges, kidneys (glomerulitis), liver, and spleen.

Acute syphilitic meningitis may develop, with headache, neck stiffness, cranial nerve lesions, deafness, and, occasionally, papilledema.

Condyloma lata--hypertrophic, flattened, dull pink or gray papules at the mucocutaneous junctions and in moist areas of the skin--are extremely infectious. Hair often falls out in patches, leaving a moth-eaten appearance (alopecia areata).

Latent stage

In the early latent period (< 2 yr after infection), infectious mucocutaneous relapses may occur, but after 2 yr contagious lesions rarely develop, and the patient appears normal. About 1/3 of untreated persons develop late syphilis

Late or tertiary stage: Lesions may be clinically described as (1) benign tertiary syphilis of the skin, bone, and viscera, (2) cardiovascular syphilis, or (3) neurosyphilis.

The typical lesion is a gumma, an inflammatory mass that evolves to necrosis and fibrosis and that is frequently localized but may diffusely infiltrate an organ or tissue

Benign tertiary syphilis of the bones results in either periostitis with bone formation or osteitis with destructive lesions causing a deep, boring pain, characteristically worse at night. A lump or swelling may be palpable.

Cardiovascular syphilis: A dilated, usually fusiform aneurysm of the ascending or transverse aorta, narrowing of the coronary ostia, or aortic valvular insufficiency usually appears 10 to 25 yr after the initial infection

Neurosyphilis

In meningovascular neurosyphilis, brain involvement is signaled by headache, dizziness, poor concentration, lassitude, insomnia, neck stiffness, and blurred vision. Mental confusion, epileptiform attacks, papilledema, aphasia, and mono- or hemiplegia may also occur

Diagnosis:

Two classes of serologic tests for syphilis (STS) aid in diagnosing syphilis and other related treponemal diseases: screening, nontreponemal tests using lipoid antigens detect syphilitic reagin and include the Venereal Disease Research Laboratory (VDRL) and the rapid plasma reagin (RPR) tests. Specific treponemal tests detect antitreponemal antibodies and include fluorescent treponemal antibody absorption (FTA-ABS) test, microhemagglutination assay for antibodies to T. pallidum (MHA-TP), and Treponema pallidum hemagglutination assay (TPHA).

In darkfield microscopy, light is directed obliquely through the slide so that rays striking the spirochetes cause them to appear as bright, motile, narrow coils against a dark background

Osteomyelitis
This refers to inflammation of the bone and related marrow cavity almost always due to infection. Osteomyelitis can be acute or a chronic. The most common etiologic agents are pyogenic bacteria and Mycobacterium tuberculosis.

Pyogenic Osteomyelitis

The offending organisms reach the bone by one of three routes:
1. Hematogenous dissemination (most common)
2. Extension from a nearby infection (in adjacent joint or soft tissue)
3. Traumatic implantation of bacteria (as after compound fractures or orthopedic procedures). Staphylococcus aureus is the most frequent cause. Mixed bacterial infections, including anaerobes, are responsible for osteomyelitis complicating bone trauma. In as many as 50% of cases, no organisms can be isolated. 

Pathologic features 

• The offending bacteria proliferate & induce an acute inflammatory reaction.
• Entrapped bone undergoes early necrosis; the dead bone is called sequestrum.
• The inflammation with its bacteria can permeate the Haversian systems to reach the periosteum. In children, the periosteum is loosely attached to the cortex; therefore, sizable subperiosteal abscesses can form and extend for long distances along the bone surface.
• Lifting of the periosteum further impairs the blood supply to the affected region, and both suppurative and ischemic injury can cause segmental bone necrosis.
• Rupture of the periosteum can lead to an abscess in the surrounding soft tissue and eventually the formation of cutaneous draining sinus. Sometimes the sequestrum crumbles and passes through the sinus tract.
• In infants (uncommonly in adults), epiphyseal infection can spread into the adjoining joint to produce suppurative arthritis, sometimes with extensive destruction of the articular cartilage and permanent disability.
• After the first week of infection chronic inflammatory cells become more numerous. Leukocyte cytokine release stimulates osteoclastic bone resorption, fibrous tissue ingrowth, and bone formation in the periphery, this occurs as a shell of living tissue (involucrum) around a segment of dead bone. Viable organisms can persist in the sequestrum for years after the original infection.
Chronicity may develop when there is delay in diagnosis, extensive bone necrosis, and improper management. 

Complications of chronic osteomyelitis include
1. A source of acute exacerbations
2. Pathologic fracture
3. Secondary amyloidosis
4. Endocarditis
5. Development of squamous cell carcinoma in the sinus tract (rarely osteosarcoma).

Tuberculous Osteomyelitis

Bone infection complicates up to 3% of those with pulmonary tuberculosis. Young adults or children are usually affected. The organisms usually reach the bone hematogenously. The long bones and vertebrae are favored sites. The lesions are often solitary (multifocal in AIDS patients). The infection often spreads from the initial site of bacterial deposition (the synovium of the vertebrae, hip, knee, ankle, elbow, wrist, etc) into the adjacent epiphysis, where it causes typical granulomatous inflammation with caseous necrosis and extensive
bone destruction. Tuberculosis of the vertebral bodies (Pott disease), is an important form of osteomyelitis.

Infection at this site causes vertebral deformity and collapse, with secondary neurologic deficits. Extension of the infection to the adjacent soft tissues with the development of psoas muscle abscesses is fairly common in Pott disease. Advanced cases are associated with cutaneous sinuses, which cause secondary bacterial infections. Diagnosis is established by synovial fluid direct examination, culture or PCR

HEALING

Definition. Replacement of damages tissue by healthy tissue. It is an attempt to restore the tissue to structural and functional normalcy.

Healing may be of 2 types

A. Regeneration.

B. Repair by granulation tissue.

A. Regeneration

Where the replacement is by proliferation of parenchymatous cells of type destroyed. This depends upon:

(1) Regenerative capacity of cells. Cells may be :

(a) Labile cells which are constantly proliferating to replace cells continuously shed off or destroyed

Epithelial cells of skin and lining surfaces.

Lymphoid and haemopoietic tissue.

(b) Stable cell. Cells mostly in resting-phase, but capable of dividing when necessary e.g.

• Liver and other parenchymatous and glandular cells.
• Connective tissue cells.
• Muscle cells have a limited capacity to divide.

(c) Permanent cell. These cells, once differentiated are not capable. of  dividing e.g.-nerve

(2) The extent of tissue loss. If  there is extensive destruction including disruption of the framework, complete.regeneration is not possible. even with labile an stable cell

B. Repair by granulation tissue

Granulation tissue is formed by proliferation of surrounding connective tissue elements. which migrate into the site to be repaired.

Granulation tissue formation  seen in :

• Wound healing.
• Organisation of exudates.
• Thrombi.
• Infarcts.
• Haematomas.

The process of repair can be best studied in clean incised wounds, where there is .no or minimal tjssue loss or the_edges or the  edges of the wound are approximated closely as in a surgical wound. This is called Primary union (healing by first intention).

1. The blood in the incised area clots and the fibrin binds the edges together.

2. During the first 24 hours, an acute  inflammation sets in to .bring protein and phagocyte rich exudates to the site.

3. The superficial part of the clot get dry and dehydrated{scab). The surface epithelium proliferates just beyond the cut edges and the cells migrate-deep to dry scab. Epithelialisation is usually complete by 24- 48 hours.

4 Granulation tissue, with actively growing fibroblasts and capillary buds invades the clot (stage of vascularisation). These fibroblasts 'posses contractile myofibrils & hence are termed as myofibroblasts'.

5. Simultaneously, demolition of the debris and clot components takes place.

6 The granulation tissue initially lays down a mucopolysacharide rich ground substance

7.Reticulin and later collagen fibrils are formed by the fibroblasts (with 5 days)

8 with progressive maturation of collagen, some of the capiliary buds develop into arterioles and venules and majority of them are obliterated (stage of devascularisation).

9. With time (weeks to months) the tensile strength of the scar increases and it shrinks.

Secondary union (excised wound-healing by secondary intention).

1. Coagulum forms and fills the gap.

2. Inflammatory reaction is seen as in primary union but is more intense, as a lot more debris has to be removed. .

3. Epithelial proliferation starts covering the surface from the periphery by proliferation beyond the edges and migration under scab.

4.Debridement starts and simultaneously granulation tissue grows into the coagulum from the sides and base of the wound. This is much more exuberant than in primary union. The surface now looks red and granular.

5. Wound contraction. This is early contraction (starts after 3 days and is complete in 2 weeks) and  must be differentiated from contraction after scar formation Wounds can contract by up to 80% of original size of that the gap to be filled is much reduced, resulting in faster healing with a smaller scar.

Wound contraction is probably caused by:

• Dehydration
• Collagen contraction.
• Granulation tissue contraction .(myofibroblasts).

The exact mechanism is not known.

6. Laying down of collagen.

7 Maturation to form a scar which later shrinks and devascularises.

Factors affecting wound healing

Wound healing is delayed by :

A. Local  factors

1. Poor blood supply.

2. Adhesion to bony surfaces (e.g. over the tibia).

3. Persistent injurious agents (infective or particulate) results in chronicity of  inflammation and ineffective healing. .

4. Constant movement (especially in fracture healing).

5. ionizing radiation (in contrast, ultraviolet rays hasten healing).

6. Neoplasia.

B. General factors

I. Nutritional deficiency, especially of.

(i) Protein

(ii) Ascorbic acid (Vitamin C).

(iii) Zinc

2. Corticoids adversely affect wound contraction and granulation tissue formation

(anabolic steroids have a favorable effect).

3. Low temperature.

4. Defects (qualitative or quantitative) in polymorphs and macrophages

.Complication of wound healing

1. Wound dehiscence

2.  Infection

3. Epidermal inclusion (implantation) cysts.

4. Keloid formation

5. Cicatrisation resulting in contract Ires and obstruction(in hollow viscera).

6. Calcification and ossification.

7. Weak scar which could be a site for incisional hernia

8. Painful scar if it involves a nerve twig.

9. Rarely neoplasia (especially in burn scars).

Microbiological examination

 This is a method by which body fluids, excised tissue, etc. are examined by microscopical, cultural and serological techniques to identify micro-organisms Microbiological examination responsible for many diseases.

Cholelithiasis (Biliary calculi)
- These are insoluble material found within the biliary tract and are formed of bile constituents (cholesterol, bile pigments and calcium salts). 

Sites: - -Gall bladder, extra hepatic biliary tract.  Rarely, intrahepatic biliary tract. 

Predisposing factors:- 
- Change in the composition of bile. - It is the disturbance of the ratio between cholesterol and lecithin or bile salts which may be due to Hypercholesterolaemia which may be hereditary or the 4 F (Female, Forty, Fatty, Fertile). Drugs as clofibrate and exogenous estrogen. High intake of calories (obesity).
Increased concentration of bilirubin in bile- pigment stones
Hypercalcaemia:- Calcium carbonate stones.

2- Staisis.
3- Infection. 

Pathogenesis   i- Nucleation or initiation of stone formation:- The nidus may be cholesterol “due to supersaturation” Bacteria, parasite
RBCs or mucous.  
ii- Acceleration:- When the stone remains in the gall bladder, other constituents are added to the
nidus to form the stone. 

Complications of gall stones:- 
- Predispose to infection.- Chronic irritation leading to 
a. Ulceration       b. Squamous metaplasia & carcinoma.