Photoreceptors in human retina. Three types of cones and a rod.

The retina contains two types of photoreceptors, rods and cones.

During evolution human ancestors first had four different types of cones, then lost two of them and then got back to three by duplicating one and changing it slightly. “Green” and “red” cone were derived from duplication of one original cone and help us see differentiate colors better than most mammals (see Color vision in vertebrates).

The rods are more numerous, some 120 million, and are more sensitive than the cones. However, they are not sensitive to color. The 6 to 7 million cones provide the eye’s color sensitivity and they are much more concentrated in the central yellow spot known as the macula. In the center of that region is the “fovea centralis”, a 0.3 mm diameter rod-free area with very thin, densely packed cones.

Current understanding is that the 6 to 7 million cones can be divided into “red” cones (64%), “green” cones (32%), and “blue” cones (2%) based on measured response curves. They provide the eye’s color sensitivity. The green and red cones are concentrated in the fovea centralis. The “blue” cones have the highest sensitivity and are mostly found outside the fovea.

References: Hyperphysics

Ishihara Table used for Color Vision testing

Although not universal, a capacity for colour vision is sufficiently widespread across the animal kingdom.

The consensus is that all vertebrate visual photopigments are specified by opsin genes belonging to five gene families, one linked to rod photopigments while the other four underlie cone pigments (Yokoyama 2000; Hisatomi & Tokunaga 2002).

Of the major contemporary vertebrate groups, representatives of all four cone opsin gene families have been found in various birds, fishes and reptiles, while only three of these have so far been detected in contemporary amphibians (Bowmaker 2008). Mammals depart from these standards.

There is evidence that at least three of the four cone opsin gene families characteristic of the vertebrates were represented in early mammals. Of these, an SWS2 gene persists in the monotremes, but this gene family was subsequently lost at some point prior to the divergence of marsupials and eutherians. Whether the pigment products of Rh2 genes, common in many other vertebrates, were present in early mammals remains uncertain (Jacobs 2009).

The cone pigment complements of a variety of contemporary mammals are linked to two families of cone opsin genes, SWS1 and LWS. Each pigment has in turn been placed into one of four groups according to the inferred or measured spectral location of peak sensitivity: ultraviolet (UV), short wavelength (S), middle wavelength (M), long wavelength (L). Some primates are polymorphic for the M and L pigments, or they have both types (Jacobs 2009).

A number of mammalian species have lost their S-cone photopigments as a result of opsin gene mutation (Peichl 2005). Humans diagnosed as having tritanopia, one of the congenital colour vision defects (estimated to be no more frequent than 1 in 10 000), similarly lack a population of functional S cones. With the advent of molecular genetic techniques it was learnt that many tritanopes have mutational changes in their S-cone opsin genes that render them non-functional (Weitz et al. 1992), and a similar explanation was shortly thereafter found to account for the absence of viable S cones in two species of non-human primates, the owl monkey (Aotus) and the bushbaby (Galago) (Jacobs et al. 1996b).

The retinas of most eutherian mammals feature two classes of cones—one containing an SWS1 pigment, the other an LWS pigment, a pairing that in all cases so far studied provides the pigment basis for a single dimension of colour vision. At present there seems to be no general adaptive explanations for the diversity of spectral positions of the LWS cones in dichromatic mammals.

UV signals are known to play important roles in the visual behaviours of some vertebrates, particularly in birds, and that linkage suggests that this may also be the case for these rodents that have UV pigments (mouse, rat, gopher).

The retinas of all mammals contain both rods and cones, but there are impressive species variations in the relative representation of the two receptor types. For instance, even though it has a smaller retina, the nocturnal rat has eight times more rods than does the highly diurnal ground squirrel—in rat about 1 per cent of all receptors are cones, while the comparable figure for the ground squirrel is approximately 86 per cent.

Comparative studies usually focus on the number of cone types and on their spectral sensitivity, but for predictions about the utility of colour vision an understanding of the rod/cone weighting is also apt to be highly relevant.

Rods can also influence mammalian colour vision in more direct ways. In all duplex visual systems, rods and cones operate in common over a considerable range of retinal illuminances: for example, in the case of human vision across some four log units of light intensity. Rod and cone signals have multiple locations of potential interaction in the retina and they course along shared output pathways into the central visual system. In humans, rod signals can be shown to influence colour perception in complex ways (Buck 2004); in fact, under the right conditions of viewing rod and cone signals can be contrasted to yield an additional dimension of colour vision (Smith & Pokorny 1977). Rod influences on colour vision remain virtually unstudied in other mammals, but given that many of these species are normally most active under lighting conditions that should support joint rod and cone function, rod contributions to mammalian colour vision may well turn out to be of great importance.

As a result of events that occurred during the early history of mammals, eutherian mammals retain only two of the four cone opsin gene families found in many other vertebrates. Very likely during this same time frame, the elaborate system of coloured oil droplets characteristic of photoreceptors in many vertebrates were also abandoned, as was a portion of the specific retinal circuitry dedicated to processing colour information (Jacobs & Rowe 2004). These changes left most eutherian mammals with a single dimension of colour vision. Primates subsequently escaped this restriction by evolving a series of visual system alterations that provided opportunities for expanded colour vision. These changes, that are quite variable across different primate lineages, include a greatly enhanced population of cones densely organized around a centralized fovea, the addition of a third type of cone photopigment, and the appearance of retinal circuitry that facilitates the comparison of signals from different cone classes.

The first primates are generally believed to have been nocturnal (Martin & Ross 2005), and probably featured single representative pigments from the SWS1 and LWS gene families, supporting dichromatic colour vision. Subsequently, many primate lineages became diurnal, fostering an enhanced dependence on vision. LWS opsin genes in mammals are on the X-chromosome. All contemporary catarrhine primates (Old World monkeys, apes, humans) have two LWS genes that are positioned in a head-to-tail tandem array. These genes specify spectrally discrete cone pigments (?_max values of approx. 530 and 560 nm, usually termed M and L). In conjunction with an SWS-derived pigment, this provides three cone pigments that support a capacity for trichromatic colour vision. The M and L photopigments were apparently derived from duplication of the original X-chromosome opsin gene (Nathans et al. 1986).

Multiple cherry hemangiomas on the upper trunk.

Cherry hemangiomas are cherry red papules on the skin containing an abnormal proliferation of blood vessels. They are also called senile angiomas or Campbell de Morgan spots, after the nineteenth-century British surgeon Campbell De Morgan who first noted and described them. Cherry hemangioma is an extremely frequent dermatosis involving more than 75% of the population over 70 years of age. Normally they are multiplex spots and focus predominantly on the upper trunk, arms and scalp. Frequency increases with age in both sexes and all races.

Causes

Little is known about the factors that contribute to the formation of cherry hemangiomas. Most cases are idiopathic associated with aging. The gradual appearance of multiple cherry angiomas over many years is common and often is expected. Other causes include chemical exposure (mustard gas, 2-Butoxyethanol) and hormomal changes (pregnancy, increased prolactin). For multiple cherry hemangiomas that have appeared over a short period, an internal malignancy should be excluded.

History and Physical

Cherry angiomas typically present in the third or fourth decades of life, and early lesions may appear as small red macules. Lesions may be found on all body sites, but usually, the mucous membranes are spared. Most patients report an increase in number and size of individual lesions with advancing age. On physical examination, lesions may have a variable appearance, ranging from a small red macule to a larger dome-topped or polypoid papule. The color of the lesions typically is described as bright cherry red, but the lesions may appear more violaceous at times. Rarely, a lesion demonstrates a dark brown to an almost black color when a hemorrhagic plug occupies the vascular lumen, often raising concern about the possibility of a malignant melanoma.

Image 2: Various colors and shapes of cherry hemangiomas

Diagnosis

The diagnosis is usually made clinically; however, biopsy allows histopathologic confirmation in doubtful situations. A skin biopsy (shave or punch) allows histologic confirmation of the diagnosis. On scanning magnification, a sharply circumscribed vascular proliferation usually is noted, often embraced in part by a collarette of epithelium and adnexal structures. Higher magnification demonstrates numerous venules in a thickened papillary dermis. Older lesions often display prominent collagen bundles, which is an appearance suggesting septa. Rarely, some confusion may arise in determining whether a deeply violaceous or a darkly pigmented papule represents a traumatized and thrombosed cherry angioma or malignant melanoma. In any situation in which doubt exists regarding the diagnosis of a cutaneous neoplasm, a skin biopsy needs to be performed for the histopathologic analysis.

Image 3: histologic appearance of cherry hemangioma.

Treatment

Treatment for cherry hemangioma lesions is recommended in situations of irritation or hemorrhage or in instances in which the lesions are deemed by the patient to be cosmetically undesirable.

• Shave excision: This procedure allows delicate removal of the lesion by blade and histologic confirmation of the diagnosis. Hemostasis following removal may be obtained by chemical means (aluminum chloride) or by performing electrocautery.
• Curettage and electrodesiccation: These techniques permit reliable elimination of the lesion through tissue destruction. The risk of scarring usually is minimal when the technique is performed by a skilled operator.
• Pulsed dye laser – using an intense beam of light to remove the angioma. The use of a pulsed dye laser with a green light source allows selective absorption of the laser energy by the hemoglobin contained within the red blood cells and subsequent obliteration of the vascular lumen.This technique involves minimal harm to surrounding skin tissue. Unless the lesion is particularly large (1/4 inch across or more), you can expect excellent cosmetic results.

More Cherry Hemangioma Images

References

1. Pembroke AC, Grice K, Levantine AV, Warin AP. Eruptive angiomata in malignant disease. Clin Exp Dermatol. Jun 1978;3(2):147-56.
2. Dawn G, Gupta G. Comparison of potassium titanyl phosphate vascular laser and hyfrecator in the treatment of vascular spiders and cherry angiomas. Clin Exp Dermatol. Nov 2003;28(6):581-3.
3. Gupta G, Bilsland D. A prospective study of the impact of laser treatment on vascular lesions. Br J Dermatol. Aug 2000;143(2):356-9.
4. Calonje E, Wilson-Jones E. Vascular tumors: tumors and tumor-like conditions of blood vessels and lymphatics. In: Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, eds. Lever’s Histopathology of the Skin. 8th ed. Philadelphia, Pa: Lippincott-Raven; 1997:902.
5. Hagiwara K, Khaskhely NM, Uezato H, Nonaka S. Mast cell “densities” in vascular proliferations: a preliminary study of pyogenic granuloma, portwine stain, cavernous hemangioma, cherry angioma, Kaposi’s sarcoma, and malignant hemangioendothelioma. J Dermatol. Sep 1999;26(9):577-86.
6. Mazereeuw-Hautier J, Cambon L, Bonafé JL. [Eruptive pseudoangiomatosis in an adult renal transplant recipient]. Ann Dermatol Venereol. Jan 2001;128(1):55-6.
7. Odom RB, James WD, Berger TB. Dermal and subcutaneous tumors: cherry angiomas. In: Andrew’s Diseases of the Skin: Clinical Dermatology. 2000. 9th ed. Philadelphia, Pa: WB Saunders; 2000:751.
8. Sanchez JL, Ackerman AB. Vascular proliferations of skin and subcutaneous tissue. In: Fitzpatrick’s Dermatology in General Medicine. Vol 1. New York, NY: McGraw-Hill; 1993:1219-20.

Foxglove

Digoxin, also known as Digitalis, is a purified cardiac glycoside extracted from the foxglove plant, Digitalis lanata. Digoxin is widely used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication.

Common adverse effects include: loss of appetite, nausea, vomiting, diarrhea, blurred vision, visual disturbances (yellow-green halos), confusion, drowsiness, dizziness, nightmares, agitation, and/or depression, as well as a higher acute sense of sensual activities. 

Mechanism of Action

Digoxin binds to a site on the extracellular aspect of the ?-subunit of the Na⁺/K⁺ ATPase pump in the membranes of heart cells (myocytes) and decreases its function. This causes an increase in the level of sodium ions in the myocytes and corresponding decreased extracellular Na⁺ levels, which in turn slows down the extrusion of Ca²⁺ by the Sodium-calcium exchanger that relies on the high Na⁺ gradient.

This effect causes an increase in the length of Phase 4 and Phase 0 of the cardiac action potential, which when combined with the effects of Digoxin on the parasympathetic nervous system, lead to a decrease in heart rate.

Increased amounts of Ca²⁺ are then stored in the sarcoplasmic reticulum and released by each action potential, which is unchanged by digoxin. This leads to increased contractility of the heart.

Digoxin also increases vagal activity via its action on the central nervous system, thus decreasing the conduction of electrical impulses through the AV node. This is important for its clinical use in different arrhythmias

Adverse Effects

The occurrence of adverse drug reactions is common, owing to its narrow therapeutic index (the margin between effectiveness and toxicity). Adverse effects are concentration-dependent, and are rare when plasma digoxin concentration is <0.8 ?g/L. They are also more common in patients with low potassium levels (hypokalemia), since digoxin normally competes with K⁺ ions for the same binding site on the Na⁺/K⁺ ATPase pump.

Common adverse effects include: loss of appetite, nausea, vomiting, diarrhea, blurred vision, visual disturbances (yellow-green halos), confusion, drowsiness, dizziness, nightmares, agitation, and/or depression, as well as a higher acute sense of sensual activities. Less frequent adverse effects include: acute psychosis, delirium, amnesia, shortened QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with AV block, ventricular tachycardia or fibrillation, heart block but when systematically sought, the evidence for this is equivocal. The pharmacological actions of digoxin usually results in electrocardiogram (ECG) changes, including ST depression or T wave inversion, which do not indicate toxicity. PR interval prolongation, however, may be a sign of digoxin toxicity. Additionally, increased intracellular Ca²⁺ may cause a type of arrhythmia called bigeminy (coupled beats), eventually ventricular tachycardia or fibrillation. The combination of increased (atrial) arrhythmogenesis and inhibited atrio-ventricular conduction (for example paroxysmal atrial tachycardia with A-V block – so-called “PAT with block”) is said to be pathognomonic (i.e. diagnostic) of digoxin toxicity.

An often described but rarely seen adverse effect of digoxin is a disturbance of colour vision (mostly yellow and green colour) called xanthopsia. It has been proposed that the painter Vincent Van Gogh’s “Yellow Period” may have somehow been influenced by concurrent digitalis therapy.