Pemphigus

 Pemphigus vulgaris (PV) is an autoimmune, intraepithelial, blistering disease affecting the skin and mucous membranes. It is mediated by circulating autoantibodies against keratinocyte cell surfaces. Exposure to certain medications like penicillamine and captopril can trigger PV. Such a trigger can happen through the effects on binding to molecules involved in cell adhesion, influence on enzymes that mediate keratinocyte aggregation, and molecules involved in cell and by stimulating neoantigen formation. In addition, NSAID’s, penicillin, cephalosporins have been associated with drug-induced PV.

IgA pemphigus does not present with oral mucosa blisters. Direct and indirect immunofluorescence can both help to differentiate PV from IgA pemphigus.

Pemphigus foliaceus does not affect the oral mucosa and is less common than PV.

Paraneoplastic pemphigus presents with mucocutaneous vesicles and bullae and can be differentiated from PV using indirect immunofluorescence and immunoblot.

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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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