Zephyr Endobronchial Valve

The Zephyr Endobronchial Valve is an endobronchial implant designed to occlude a hyperinflated lobe of the lungs with multiple valves, allowing air to escape while blocking airflow into the treated lobe. This is intended to result in a reduction in lung volume and hyperinflation in the targeted area. This one-way valve therapy leads to an improvement of lung function, exercise tolerance, and quality of life in patients with advanced emphysema.

Key inclusion criteria:

• Severe emphysema: forced expiratory volume in 1 second (FEV1) ≤ 45% of predicted, TLC ≥ 100% of predicted, RV ≥ 150% of predicted
• Resting partial pressure of arterial carbon dioxide (Paco2) ≤ 60 mm Hg
• Resting partial pressure of arterial oxygen (Pao2) on room air ≥ 45 mm Hg
• Body mass index ≤ 31 kg/m2 for men, ≤ 32 kg/m2 for women
• Abstinence from smoking for at least six months
• Completion of pulmonary rehabilitation.

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Diabetic foot infections (DFIs)

Diabetic foot infections (DFIs) is a common complication of longstanding diabetes, and it is associated with considerable morbidity, increased risk of lower extremity amputation, and a high mortality rate. The development of DFI derives from a complex interplay among peripheral neuropathy, peripheral arterial disease (PAD), and the immune system.

Most DFIs are polymicrobial, with aerobic gram-positive cocci, and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently co-pathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be co-pathogens in ischemic or necrotic wounds.

Empiric antibiotic therapy can be narrowly targeted at aerobic gram-positive cocci in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens. Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific.

Osteomyelitis occurs in 15% of ulcers, and 15% of those will go on to require amputation. Approximately 60% of patients undergoing lower extremity amputation have diabetic foot ulcers as the underlying cause. Following a lower extremity amputation, the 5-year mortality jumps to 60%.

Surgical interventions of various types are often needed, and proper wound care is important for the successful cure of the infection and healing of the wound. Patients with a DFI should be evaluated for an ischemic foot, and employing multidisciplinary foot teams improves outcomes.

The prognosis for a diabetic foot infection depends on many factors including vascular blood supply and the presence of neuropathy.

 

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Bleeding manifestation

Petechiae are small, flat, red, discrete areas of skin bleeding that are typically <2 mm in diameter. They are non-blanching, nonpalpable, and occur in dependent areas of the body Purpura results from coalesced petechiae. 

Purpura due to vasculitis is usually palpable and may be pruritic, and the distribution does not follow dependent areas. Wet purpura is the most predictive of serious bleeding in individuals with thrombocytopenia. 

Bruise (also called ecchymosis) is caused by the subcutaneous accumulation of extravasated blood. The skin is flat, and the color evolves over time from purplish blue to reddish brown to greenish-yellow, reflecting the metabolism (breakdown) of hemoglobin to biliverdin and bilirubin. 

Hematoma is a collection of blood in the extravascular space. Hematomas and hemarthroses (joint bleeding) are typical of coagulation factor deficiencies.

Von Willebrand factor

• Glycoprotein
• Synthesized in endothelial cells & megakaryocytes.
• Excessive bruising & prolonged bleeding
• Levels vary with stress; increase with estrogens, vasopressin, GH & adrenergic stimuli.
• Repeat tests at > 2 weeks
• Type O blood normally has the lowest levels
• Platelet levels tend to be normal, PT should be normal.

von Willebrand disease (Diagnosis)

• VWF antigen level VWF:Ag  (Quantity of VWF present in plasma; <50 are considered to be low)
• VWF ristocetin cofactor assay Efficacy of this plasma VWF in its ability to bind platelets in the presence of antibiotic ristocetin.
• Measurement of coagulation factor VIII (FVIII:C)
• Ratio of VWF:RCo/VWF:Ag (differentiate VWD type 1 and 2)

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Digoxin (Cardiac glycoside)

 The chemical formula of Digoxin is C41 H64 O14.

Digoxin (Cardiac glycoside) reversibly inhibits the sodium-potassium-ATPase, causing an increase in intracellular sodium and a decrease in intracellular potassium. The increase in intracellular sodium prevents the sodium-calcium antiporter from expelling calcium from the myocyte, which increases intracellular calcium. The net increase in intracellular calcium augments inotropy. Cardiac glycosides also increase vagal tone, which results in decreased conduction through the sinoatrial and atrioventricular nodes.

Life-threatening digoxin-induced arrhythmias and other toxic manifestations occur at a substantially increasing frequency as the plasma digoxin concentration rises above 2.0 ng/mL. However, toxicity is more likely in the presence of one or more comorbid conditions (eg, hypokalemia, hypomagnesemia, hypercalcemia, myocardial ischemia). Hypokalemia is a particularly important risk factor that can promote digoxin-induced arrhythmias.

PVCs are often the first sign of digoxin toxicity and are the most common arrhythmia due to digoxin toxicity. PVCs can be isolated or occur in a bigeminal pattern. The so-called "digitalis effect" on the ECG consists of T wave changes (flattening or inversion), QT interval shortening, scooped ST segments with ST depression in the lateral leads and increased amplitude of the U waves.

Early recognition of cardiac glycoside toxicity and prompt administration of Fab fragments is essential for the successful treatment of severe poisoning. Fab fragments are highly effective and safe and have transformed the management of cardiac glycoside poisoning.

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Muscle Weakness

 Upper Motor Neuron (UMN) lesions are lesions occurring anywhere in the CNS from the brain up to the spinal cord before the alpha motor neurons arise from the spinal cord. The lesion could arise from the cerebral cortex, internal capsule, midbrain, pons, medulla, and the cortico-spinal tract in the spinal cord.

Lower motor neuron (LMN) lesions may arise from disease processes affecting the anterior horn cell or the motor axon and/or its surrounding myelin. Neuromuscular junction pathology and muscle disorders may mimic an LMN disorder and form part of the differential diagnosis. In an LMN lesion, the muscle becomes hypersensitive to neuro-transmitter as it is denervated. Similarly, the damaged lower motor erratically discharges the neurotransmitter stored within itself as the neuron degrades. So, both increased hypersensitivity and erratic release of neurotransmitter cause fasciculations. However, in UMN lesions, there is regular firing to prevent the atrophy of muscles. LMN syndromes are clinically characterized by muscle atrophy, weakness, and hyporeflexia without sensory involvement.

Neuromuscular Junctions, the junction between a motor neuron and muscle fiber is a specialized synapse. The motor neuron releases a flood of acetylcholine (Ach) neurotransmitters upon stimulation from the axon terminals from synaptic vesicles that bind with the post-synaptic receptors at the plasma membrane. This response is contractile causing muscle contraction and inhibition does not require a neurotransmitter release.

UMC & LMN lesions cause very different clinical findings.

1. UMN lesions are lesions anywhere from the cortex to the descending tracts. This lesion causes hyperreflexia, spasticity, and a positive Babinski reflex, presenting as an upward response of the big toe when the plantar surface of the foot is stroked, with other toes fanning out.
2. LMN lesions are lesions anywhere from the anterior horn of the spinal cord, peripheral nerve, neuromuscular junction, or muscle. This type of lesion causes hyporeflexia, flaccid paralysis, and atrophy.

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Hemoglobin A1c (glycated hemoglobin)

 

Hemoglobin A1c (glycated hemoglobin) reflects the average blood glucose concentration over the course of the RBC lifespan, roughly 120 days in normal individuals. As the average plasma glucose increases, so does the amount of glycated hemoglobin in the plasma. Limitation of hemoglobin A1c is that it does not provide any indication of the changes in glucose concentrations throughout the day, for which frequent glucose measurements are needed.

The equation to calculate eAG (in mg/dL) from hemoglobin A1c (in %) is as follows: 

eAG (mg/dL) = 28.7 x NGSP-A1c (%) – 46.7

The Diabetes Control and Complications Trial (DCCT) reported that a higher mean A1c level was the dominant predictor of diabetic retinopathy progression. Tighter control shown by levels of HbA1c in the 7% range or lower, were correlated with 35-76% decrease in microvascular complications, like retinopathy, nephropathy and neuropathy, in patients with type 1 diabetes. The extension of DCCT into EDIC study showed benefit in the cardiovascular risk and mortality in the long-term for those patients with lower levels of HbA1c.

 A1c exhibited direct correlations with cholesterol, triglycerides, and LDL and inverse correlation with HDL cholesterol. A1c is identified as a significant risk factor for cardiovascular diseases and stroke in subjects who may have diabetes.

Women with HbA1c 5.7%–6.4% have a significantly higher risk of progression to GDM compared with women with normal HgbA1c values and should be considered for closer GDM surveillance and possible intervention.

ADA Recommendations:

Older adults who are otherwise healthy with few coexisting chronic illnesses and intact cognitive function and functional status should have lower glycemic goals (such as A1C <7.0–7.5%), while those with multiple coexisting chronic illnesses, cognitive impairment, or functional dependence should have less stringent glycemic goals (such as A1C <8.0–8.5%).

Since the lifespan of RBCs is about 120 days, glycated hemoglobin (hemoglobin A1c) represents a measurement of the average blood glucose level over the past 2 to 3 months. Serum proteins are present in the blood for a shorter time, about 14 to 21 days, so glycated proteins, and the fructosamine test, reflect average glucose levels over 2 to 3 weeks.

Instances where fructosamine may be considered over A1c include:

1. Rapid changes in diabetes treatment
2. Diabetic pregnancy
3. Shortened RBC life span, such as hemolytic anemia or blood loss. When the lifespan of RBCs in circulation is shortened, the A1c result is falsely low and is an unreliable measurement of a person's average glucose over time.
4. Abnormal forms of hemoglobin – the presence of some hemoglobin variants, such as hemoglobin S in sickle cell anemia, may affect certain methods for measuring A1c.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) recommends against the use of the A1c test in patients with the hemoglobin variants HbSS, HbSC, or HbCC as these patients may suffer from conditions that affect the A1c test, such as anemia, increased RBC turn-over, and frequent blood transfusions.

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Drug-induced gingival enlargement

Drug-induced gingival enlargement is a side-effect of certain drugs where the gingival tissue is not the intended target organ. The key offending drug classes are anticonvulsants, immunosuppressants, and calcium channel blockers. It is estimated that 50% of adults treated with phenytoin experience gingival enlargement, 30% with cyclosporine, and 20% with nifedipine. This overgrowth impedes proper dental hygiene and, apart from the cosmetic damage, causes painful chewing and eating. The common mechanism of action at the cellular level of all these three categories of dissimilar drugs appears to be inhibition of cation influx, particularly sodium and calcium ions. The modalities of treatment are medical and surgical. Medical management is the first line of therapy and includes discontinuing or changing the medication must be placed under consideration. Surgery is reserved for recurrences or cases that persist despite good medical treatment.

 

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Celiac disease

 

Celiac disease (CD) is an immune-mediated, multisystem disorder that affects genetically susceptible individuals who are exposed to gluten-containing grains such as wheat, barley, and rye.

Also known as gluten-sensitive enteropathy, Celiac disease is a condition in which the body responds to gluten with an inappropriate immune response causing small intestinal inflammation and damage.

CD can be associated with different autoimmune and idiopathic diseases, including type 1 diabetes mellitus, Hashimoto’s thyroiditis, selective IgA deficiency, alopecia areata, Addison’s disease, connective tissue diseases (mainly Sjogren’s syndrome), chromosomal diseases (Down, Turner, and William’s syndromes), neurological diseases (cerebellar ataxia, peripheral neuropathy, epilepsy with and without occipital calcifications), hepatic autoimmune diseases (primary biliary cholangitis, autoimmune hepatitis, primary sclerosing cholangitis), and idiopathic dilated cardiomyopathy.

Extraintestinal symptoms are common and may include:

• Anemia due to defective absorption of vitamin B12, folate or iron
• Coagulopathy due to impaired absorption of vitamin K
• Osteoporosis
• Neurological symptoms like muscle weakness, paresthesias, seizures and ataxia

Dermatitis herpetiformis is an extraintestinal manifestation that is pathognomonic for celiac disease. Because the rash is an immunologic response to gluten, it is sometimes referred to as celiac disease of the skin. This papulovesicular rash is extremely pruritic and found on extensor surfaces, such as the elbows, knees, buttocks, and scalp.

The two antibodies measured are anti-tissue transglutaminase antibodies (by enzyme-linked immunosorbent assay or ELISA measured numerically) and anti-endomysial antibodies.

Esophagogastroduodenoscopy with small bowel biopsy is recommended to confirm the diagnosis in most patients, including those with a negative serologic test for whom clinical suspicion of celiac disease persists.

Genetic testing for human leukocyte antigen alleles DQ2 or DQ8 may be performed in select cases.

A gluten-free diet for life is the primary treatment

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Rhabdomyolysis

Creatine kinase (CK) is an intracellular enzyme present in skeletal muscle, myocardium & brain; smaller amounts in visceral tissues. Released after disruption of cell membranes due to hypoxia or other injury.

Sustained increases in these levels can be a sensitive indicator of underlying muscle damage.
CK may increase to as much as 30 times the upper limit within 24 hrs of strenuous physical activity, then slowly decline over next 7 days.
The definitive diagnosis of rhabdomyolysis is reliably made by serologic testing for creatine kinase (CK). Elevated levels of CK are the hallmark of rhabdomyolysis.
CK functions as an energy reservoir for ATP:
Creatine + ATP = creatine kinase + ADP (adenosine diphosphate).
CK has a half-life of 1.5 days; its level elevated in the first 12 hours, peaks during the first 3 days, and normalizes at around 5 days after injury.
CK level five times the upper limit of normal (≈1000 U/L), without apparent cardiac or brain injury, confirms the diagnosis.
Risk of developing AKI is usually low when the CK level is below 10,000 U/L.
AKI at lower levels of CK noted with coexisting conditions, such as sepsis, hypotension, or underlying CKD.
Myoglobin levels rise rapidly (within 3 hours) and peak prior to serum CK levels.
Myoglobin has a short half-life of 2 - 3 hours and is rapidly excreted by the kidneys.
Rapid and unpredictable metabolism makes serum myoglobin a less useful marker of muscle injury than CK, and is rarely used in assessing the risk of AKI.

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Biliary system and physiology

Bile acids are the end products of cholesterol catabolism. Cholic acid and chenodeoxycholic acid are the major primary bile acids synthesized in human livers and are conjugated with taurine or glycine for secretion into bile. Human liver synthesizes about 200 to 600 mg bile acids per day. The net daily turnover of bile acids is about 5% of a total bile acid pool of about 3 g. Conversion of cholesterol to bile acids involves 17 distinct enzymes located in the cytosol, endoplasmic reticulum, mitochondria, and peroxisome. After each meal, cholecystokinin secreted from the intestine stimulates gallbladder contraction to empty bile acids into the intestinal tract. When passing down the intestinal tract, small amounts of unconjugated bile acids are reabsorbed in the upper intestine by passive diffusion. Most bile acids (95%) are reabsorbed in the brush border membrane of the terminal ileum, trans diffused across the enterocyte to the basolateral membrane, and secreted into portal blood circulation to liver sinusoids and are taken up into hepatocytes. Bile acids lost in the feces (~0.5 g/day) are replenished by de novo synthesis in the liver to maintain a constant bile acid pool.

Bile acids stimulate glucagon-like peptide 1 (GLP1) production in the distal small bowel and colon, stimulating insulin secretion, and therefore, are involved in carbohydrate and fat metabolism. Bile acids through their insulin sensitizing effect play a part in insulin resistance and type 2 diabetes. Bile acid metabolism is altered in obesity and diabetes.

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Mercedes Benz sign

Radiological sign, a triradiate radiolucent shadow, characteristic of the automobile maker's trademark. In case of Gallstones, radiolucent lines represent gas accumulation within the body of a calculus. Center of calculus may contract more than its periphery, which would result in the radial fissures. Gas in the fissures typically comprises < 1% O2, 6–8% Co2 & the rest nitrogen.

The inverted Mercedes-Benz sign refers to the shape taken on by a spinal subdural hematoma on axial imaging at the level of the denticulate ligaments, best visualized on MRI. A pair of denticulate ligaments and the dorsal septum constitute the three radiating spikes of the sign, while blood expands and fills the three loculations in-between.

The Mercedes-Benz sign can be seen in aortic dissection on CT. It is seen as three distinct intimal flaps that have a triradiate configuration like the Mercedes-Benz logo. The appearances are postulated to represent secondary dissection in the wall of the dissected false lumen. It is also called a triple-barreled aortic dissection

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Warfarin induced skin necrosis

Warfarin induced skin necrosis is often heralded by paresthesia, or a sensation of pressure, associated with an erythematous flush that is usually poorly demarcated. The lesions are painful, sudden, well localized and initially hemorrhagic or erythematous. In women, the site of the lesion is random and unpredictable, but the breast is the most common site, followed by the buttocks and thighs. Occasionally, the trunk, face and extremities are also involved.

The mechanism is thought to be that, following the initiation of warfarin, both protein C antigen and activity levels drop rapidly, compared with levels of other vitamin K-dependent factors such as factors IX and X, and prothrombin. This observed rapid early fall in protein C level prompted the hypothesis that the administration of warfarin to protein C-deficient individuals causes a temporary exaggeration of the imbalance between pro- coagulant and anticoagulant pathways; that is, the early suppressive action of warfarin on protein C may not be counterbalanced by the anticoagulant effect created by the decline in other vitamin K-dependent factors, thereby leading to a relative hypercoagulable state at the start of treatment. This leads to thrombotic occlusions of the microvasculature with resulting necrosis.

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