JP5284650B2 - Applications of lasers used to improve and / or treat dysuria - Google Patents

Description

  The present invention relates to a novel use of a laser for use in improving and / or treating dysuria. More specifically, the present invention relates to optimal laser conditions for use in the improvement and / or treatment of dysuria.

  Irradiation with light (especially low response level laser) selectively suppresses nerve transmission of sensory fibers (Aδ, C fibers) that convey pain in the peripheral nervous system, increases pain threshold, suppresses pain substance production, sympathy The effect of suppressing nerve tension and conduction is known. Therefore, the irradiation of light is used for the treatment of neuropathic chronic pain (see: Non-Patent Documents 1 to 5).

In addition, it has been reported that light can be applied to a treatment for removing vascular lesions and pigmented lesions from the skin (Patent Document 1). Furthermore, it has been reported that light can be applied to wrinkle removal and wound healing (Patent Document 2).
However, there is no disclosure or suggestion that light can be used to improve and / or treat dysuria.

  Urination disorder is a general term for abnormalities related to urination. Urinary urgency, increased bladder perception, frequent urination, urinary incontinence (urgency, abdominal pressure, mixed nature, etc.), enuresis, difficulty in urinating, pain in urination, pain in the bladder・ Discomfort, pelvic pain (lower abdomen, sputum, urethra, perineum, testicles, scrotum, etc.) / Discomfort, overactive bladder, detrusor overactivity, low-compliance bladder, interstitial cystitis, neuropathy It means sex bladder and the like.

  Urinary urgency is a sudden, uncontrollable urinary urgency that is difficult to endure. Usually accompanied by frequent urination and urinary incontinence.

  Difficult urination is a general term for the state in which it is difficult to urinate during urination. It takes a long time to start urination even when trying to urinate (delayed urination), the momentum of urine is weak (decrease in urine), and the urinary line is in urination One or more interruptions occur (urinary line disruption), and urine is difficult to produce unless abdominal pressure is applied (abdominal pressure urination).

  Frequent urination is a condition in which the number of urinations is abnormally high. The frequency of urination for normal persons is large between day and individual, but as a guideline, frequent urination is 8 or more times a day and one or more times during sleep. Frequent urination may be accompanied by increased bladder perception (sustained urine from early), bladder / pelvic pain and urination pain.

  Urinary pain is pain that is felt in the urethra during urination, and may be felt only in the early or late urination phase.

  Urinary incontinence is a state of involuntarily leaking urine. There are several types. Incontinence that overflows when the bladder fills the urine and becomes urinary retention (excessive urinary incontinence), incontinence that occurs because urination cannot be suppressed when feeling urine (imminent urinary incontinence), only when abdominal pressure rises Incontinence that occurs (stress urinary incontinence), loss of urethral sphincter function, and incontinence that occurs continuously without urine collecting in the bladder (urethral relaxation incontinence).

In the treatment of urological diseases, it is very important to treat dysuria such as frequent urination, urgency and urinary incontinence. Treatment methods include drug therapy and physical therapy.
The therapeutic agents for dysuria such as frequent urination, urgency, urinary incontinence in pharmacotherapy mainly have anticholinergic action and sympathetic nerve (stimulation) blocking action, and its side effects are difficult to avoid due to the nature of drug administration.
As physical therapy, an electrical stimulation treatment device that can be inserted into the heel or anus is known, but this patient has a strong resistance to use, and it has not been used practically in Japan.
In addition, treatment is basically for each causative disease, but when that is not possible, symptomatic treatment is performed.

  Furthermore, urinary storage disorder treatment methods include pharmacotherapy with anticholinergic drugs as the core and surgical treatment such as bladder dilatation. However, currently no treatment has been reported that does not affect bladder contraction (excretion function).

  In view of the above situation, it has been desired to develop a new method for treating dysuria without causing side effects due to drug administration and pain / invasion caused by treatment.

As a candidate for the above-mentioned new treatment method, a treatment method using a low-frequency current by a low-frequency electrotherapy device has been reported (Patent Document 3).
In this method of treatment, one of the electrodes is placed in the lower abdomen and the other electrode is placed in the buttocks, and a current crossing occurs substantially near the bladder and / or urethra.
That is, it is clearly different from the novel application of the present invention in that no laser is used. Moreover, at the time of this application, there is no report that it is put into practical use as a treatment method for dysuria due to low frequency current.
Pain Clinic Vol.24 No.4 (2003.4) Pain Clinic Vol.16 No.4 (1995.8) Neuroscience Letters 323 (2002) 207-210 Brain Research Bulletin, Vol.34, No.4, pp.369-374 Saitama Medical University magazine Vol.23 No.2 April 1996 Terminology criteria for lower urinary tract function: Report of the International Standards Committee 11-508802 Special table 2006-519047 JP 5-64665

  In order to solve the above-mentioned problems of the prior art, the present invention aims to provide a new material for improving urination disorder and / or a treatment method that is not accompanied by pain / invasion in the treatment and has no side effects of the medicine. It was.

In order to solve the above problems, the present inventor has the effect of selectively suppressing nerve transmission of sensory nerve fibers (Aδ, C fibers) that convey the sensation of the bladder by laser irradiation and raising the threshold of the sensation, Without affecting the function of the motor nerve that regulates the contraction of the bladder (excretion function), urinary urgency due to abnormal sensation of the bladder, urinary abnormalities such as hypersensitivity (hypersensitivity), frequent urination, urinary incontinence, bladder -It was newly found that it can be applied to the improvement and / or treatment of dysuria (especially dysuria) such as pelvic pain and detrusor overactivity. Furthermore, the optimal laser conditions used for improvement and / or treatment of urination disorders have been found.
Based on the above findings, the present inventor has completed the invention of a novel application of a laser used for improvement and / or treatment of urination disorder.

That is, the present invention relates to the following.
“1. Laser wavelength is 700nm to 900nm, laser power is 40mW to 10W, total light dose is 0.9J / cm ^{2 to} 117000J / cm ² and laser irradiation is percutaneous irradiation near the sacral hole on both sides or one side. Use of a laser used to improve and / or treat dysuria characterized by being.
2. 2. The use according to item 1 above, wherein the laser irradiation conditions are any one or more of the following.
(1) The total irradiation amount per time is 0.9 J / cm ^{2 to} 300 J / cm ² .
(2) The irradiation time per time is 10 seconds to 5 minutes.
(3) Irradiation of the same site is 1 to 15 times per day.
(4) The first week is irradiation for 5 to 7 days.
(5) The second week is irradiation for 4 to 6 days.
(6) The third week is irradiation for 3 to 5 days.
(7) The fourth week is irradiation for 2 to 4 days.
(8) The fifth week is irradiation for 1 to 4 days.
3. The use according to item 1 or 2 above, wherein the urination disorder is any one or more selected from the following group;
Urinary urgency, bladder hypersensitivity, frequent urination, urinary incontinence, bladder pain / discomfort, pelvic pain / discomfort, overactive bladder, enuresis, detrusor overactivity, low compliance bladder, interstitial cystitis , And neurogenic bladder.
4). Use of a laser light source for the improvement and / or treatment of urination disorders, characterized in that the laser wavelength is 700 nm to 900 nm, the laser output is 40 mW to 10 W, and the total light amount is 0.9 J / cm ^{2 to} 117000 J / cm ² .
5. Use of a laser irradiation apparatus for improving and / or treating urination disorders, characterized in that the laser wavelength is 700 nm to 900 nm, the laser output is 40 mW to 10 W, and the total light amount is 0.9 J / cm ^{2 to} 117000 J / cm ² . "

By the use of the novel laser of the present invention, it was possible to improve the urination disorder without impairing the discharge function with respect to the urination function.
That is, the use of the novel laser of the present invention is a breakthrough treatment for conditions such as increased bladder sensation (hypersensitivity), urinary dysfunction, detrusor overactivity, urinary urgency, frequent urination, urinary incontinence, and bladder pain. Can provide a method.

  The optimum laser conditions used for the improvement and / or treatment of urination disorder according to the present invention will be described below. However, the laser conditions described below are appropriately selected in consideration of the patient's sex, age, height, weight, symptoms of dysuria, and the like.

(Laser irradiation area)
In the application of the present invention, the laser irradiation site is near the sacral hole on both sides or one side. Preferably, irradiation is performed from the sacral hole of S2, S3 and / or S4 toward the sacral spinal nerve root. The laser irradiation method is basically percutaneous irradiation. The surface area of irradiation at the irradiated site is from about 0.1 cm to about 1.0 cm.
In addition, the present inventor said that percutaneous irradiation to the vicinity of the sacral foramen on both sides is more effective in improving and / or treating urination disorder than that for the vicinity of the sacral foramen on only one side. Have confirmed.

(Laser wavelength)
The wavelength of the laser in the application of the present invention is 700 nm to 900 nm, preferably 750 nm to 850 nm, more preferably 780 nm to 830 nm.

(Laser output)
The output power of the laser in the application of the present invention is 40 mW to 10 W, preferably 60 mW to 500 mW, and more preferably 100 mW to 1.0 W.

(Laser irradiation mode)
Lasers in the application of the present invention use continuous and / or pulsed irradiation.
In addition, when continuously irradiating the peripheral nerve and the sacral spinal nerve root existing behind the sacral hole that is the irradiation site, a high laser output is required. However, there is a problem that increasing the laser power increases the thermal effect (burn) on the body surface.
Therefore, when a high laser output is used, irradiation is preferably performed while suppressing heat generation by pulse irradiation of 1.0 to 10 Hz.

(Total laser light intensity)
The total amount of laser light in the application of the present invention is 0.9 J / cm ^{2 to} 117000 J / cm ² , preferably 13.5 J / cm ^{2 to} 30000 J / cm ² , more preferably 23400 J / cm ^{2 to} 70200 J / cm ² .
In addition, the total light amount (total irradiation amount) of the laser described above is not irradiated at a time, but is divided into 1 to 15 times per day for one day, one week, several weeks, one month or several months. Irradiate.

(Laser irradiation conditions)
The laser irradiation conditions in the application of the present invention are as follows. In addition, it determines suitably from the following condition ranges according to the patient's state of each dysuria.
(1) total dose per irradiation once a ^{0.9J / cm 2 ~300J / cm 2} , preferably ^{60J / cm 2 ~180J / cm 2} .
(2) The irradiation time per time is 10 seconds to 5 minutes, preferably 60 seconds to 3 minutes.
(3) Irradiation of the same site is 1 to 15 times per day.
(4) The number of irradiations is irradiation for 5 to 7 days in the first week, irradiation for 4 to 6 days in the second week, irradiation for 3 to 5 days in the third week, Week 4 is irradiation for 2 days to 4 days, and week 5 is irradiation for 1 day to 4 days.

(Laser light source)
The laser light source in the application of the present invention satisfies the conditions of a laser wavelength of 700 nm to 900 nm, a laser output of 40 mW to 10 W, and a total light amount of 0.9 J / cm ^{2 to} 117000 J / cm ² . Furthermore, the laser light source in the application of the present invention can be incorporated into a laser irradiation apparatus known per se.

(Laser irradiation device)
As the laser irradiation apparatus in the application of the present invention, a known semiconductor laser treatment device used for pain relief can be used.
For example, SOFTLASERY JQ310 manufactured by Minato Medical Co., Ltd., Medilaser Soft 1000, Medilaser Soft Pulse 10 manufactured by Mochida Siemens Medical System, etc. may be mentioned.

(Laser irradiation method)
In the laser irradiation method in the application of the present invention, in order to achieve the above laser irradiation conditions, the probe tip of the laser irradiation apparatus is placed at the irradiation site and irradiated percutaneously. At this time, in order to prevent diffusion in the subcutaneous tissue, the tip of the probe is pressed against the skin as much as possible. The irradiation angle is adjusted according to the angle of the sacral hole. Start with a small output at first, and gradually increase the output. A relatively low output is desirable for elderly people and patients suspected of having a disorder in the peripheral nerve.

(Urination disorder)
The dysuria that can be improved and / or treated in the use of the present invention is any one or more of the following:
Urinary urgency, urinary bladder hypersensitivity, frequent urination, urinary incontinence (immediate, stress, mixed), enuresis, bladder pain / discomfort, pelvis (lower abdomen, vagina, urethra, perineum, testicles, Pain, discomfort, etc.), overactive bladder, detrusor overactivity, interstitial cystitis, and neurogenic bladder.

(Method of treatment)
As an example of a treatment method in the use of the present invention, irradiation is performed for 5 to 7 days in the first week, and is sequentially decreased by one day from the second week, and once it is irradiated for one day per week. During this irradiation period, the presence / absence of the effect and the number of irradiations per week are observed and recorded. If the urination disorder improvement effect does not continue for a while after the treatment period, or if the improvement effect is poor, repeat the above irradiation conditions again, or change the irradiation conditions for the week in which the effect was observed for several weeks. (1-5 weeks). Further, if the effect is poor, the irradiation conditions for the week in which the effect is recognized are continuously performed.
In addition, it is thought that the duration of the urination disorder improving effect is gradually increased by repeatedly performing laser irradiation.

(Judgment method of improvement and treatment effect)
The following determination methods can be used for improvement of urination disorder and / or determination of therapeutic effect in the use of the present invention. However, the determination method is not limited to the following, and a determination method that is used for improving urination disorder and treating effect known per se can be used.
For urgency, frequent urination, urinary incontinence, overactive bladder (OAB), use OAB score (OAB guidelines recommended) and urination diary.
For pelvic pain in the bladder, urethra, perineum, etc. (due to interstitial cystitis, etc.), use a questionnaire regarding the symptoms and problems of interstitial cystitis (interstitial cystitis guidelines recommended) and a urination diary .

(Mechanism of dysuria)
In the mechanism of dysuria, the so-called sensory system is known to involve abnormalities in bladder perception (centripetal system). In addition, abnormalities in bladder perception (centripetal tract system) are considered to be related to detrusor overactivity in urinary storage period (urinary storage disorder) and increased bladder perception (urinary urgency, persistent urinary tract, pain).
In other words, if the centripetal tract of the micturition reflex can be selectively suppressed, the urinary urgency due to abnormal sensation of the bladder, increased bladder sensation, without affecting the function of the motor nerve that regulates bladder contraction (excretion function) It is effective in improving and / or treating urinary abnormalities such as (hypersensitivity), pathological conditions such as detrusor overactivity, urinary urgency, frequent urination, urinary incontinence, and bladder / pelvic pain dysuria (especially dysuria). it is conceivable that.

(Model rat)
The model rats used in the examples are as follows.
(1) Cystitis / Bladder Pain (Due to Bladder / Peripheral Nerve Lesions) Model Rat A rat in which 0.1% acetic acid was injected into the bladder instead of saline. Thereby, the fall (sensitivity) of the stimulation threshold value in the bladder / peripheral nerve can be achieved.
(2) Spinal cord injury (due to spinal cord lesion) model rat This is a rat in which the spinal cord (T8) has been injured (cut) in advance, and the urinary reflex is enhanced 4 weeks after the injury. As a result, enhancement of the micturition reflex (spinal cord-spinal cord) can be achieved by desuppression from the center of the sacrum or higher.
(3) Parkinson's disease (due to changes in brain disease) model rat This is a rat that has been injured by 6-hydroxydopamine in the substantia nigra on both sides and increased urinary reflex 4 weeks after the operation. As a result, enhancement of the micturition reflex (spinal-brain-stem-spinal spine) can be achieved by desuppression from the higher center above the bridge.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated more concretely, this invention is not limited at all by the Example shown below.

(Examination of the effect of laser irradiation on the urination function of each model rat)
Urinary dysfunction (accumulation of urination), which may cause urinary urgency due to abnormal sensation of the bladder, increased urinary bladder sensation (hypersensitivity), detrusor overactivity, urgency, frequent urinary incontinence, bladder / pelvic pain We examined whether each disease state of (disorder) can be improved or treated without affecting the function (excretion function) of the motor nerve that regulates the contraction of the bladder. Details are as follows.

(Model rat and method used)
(1) Model rat used A normal model of SD rat (male: around 250-300 g) and each pathological model (cystitis, bladder pain model rat, spinal cord injury model rat, Parkinson's disease model rat) were used. In each model, as shown below, irradiation was carried out percutaneously and the L6 / S1 intervertebral foramen on both sides (corresponding to human S3) were exposed in advance and irradiated directly.
(2) Method Several days before the examination: A PE 5Fr bladder catheter was placed in the apex of the bladder transperitoneally under pentobarbital intraperitoneal injection anesthesia. On the day of the examination, a catheter may be placed on the bladder apex in a transabdominal wall under urethane anesthesia.
On the day of the examination: Under urethane (subcutaneous + intraperitoneal 1.5 mg / kg) anesthesia, saline was continuously injected from the catheter to the bladder, and the bladder function was continuously observed. After the condition of the bladder has stabilized, each value (urination interval, bladder capacity, single urination volume, residual urine, intravesical pressure during storage / urination (urinary bladder pressure method: one of the indwelling catheters is connected to an external pressure transducer, Pressure sensor, A / D converter, and memory device, and the internal pressure is measured continuously.Then, the L6 / S1 intervertebral holes on both sides are percutaneously or via the probe of the laser irradiation device. Directly (exposed rat) is irradiated with a low-power semiconductor laser or false irradiation (fake irradiation method: place the probe in the same position as during irradiation), and each value of urination function during and after irradiation The probe was brought into contact with the skin of the model rat when irradiated percutaneously, but was not brought into contact with the model rat when irradiated directly.
In the measurement of intravesical pressure, urination interval, bladder capacity, bladder compliance, bladder contraction force at the time of urination can be evaluated.
Irradiation conditions are as follows.
Total light intensity: 60, 100mW × 10, 180mW × 10, 30, 60, 180 seconds (0.6, 1.0, 1.8, 5.4, 10.8, 32.4J)
Laser: Semiconductor laser (GaAlAs)
Wavelength: 810nm
Irradiation equipment used: Minato Medical Science Co., Ltd. SOFTLASERY JQ 310

(Result of urination interval in healthy model when irradiated percutaneously)
FIG. 1 shows the results of the rate of increase / decrease of the urination interval in the healthy model when the skin is irradiated percutaneously.
As is apparent from FIG. 1, the urination interval after irradiation was extended. That is, more urine can be stored in the bladder than before irradiation by laser irradiation.

(Results of a single urination volume in a healthy model when percutaneously irradiated)
FIG. 2 shows the results of the rate of increase / decrease in the amount of urination once in the healthy model when the skin was irradiated percutaneously.
As is clear from FIG. 2, the amount of urination after irradiation increased. That is, more urine can be stored and discharged from the bladder than before irradiation by laser irradiation.

(Results of intravesical pressure during drainage in a healthy model when irradiated percutaneously)
FIG. 3 shows the rate of change in intravesical pressure during drainage in a healthy model when irradiated percutaneously.
As is apparent from FIG. 3, the intravesical pressure during excretion after irradiation did not change. That is, the laser irradiation does not affect the contraction force of the bladder (urine output force). Thus, it was found that the laser irradiation effect does not affect the excretion function (the efferent nerve fiber to the bladder).

(Each result in a healthy model when exposed and irradiated)
In the healthy model when irradiated and exposed, the results were the same as the above results (urination interval, single urination volume, and intravesical pressure during drainage).
That is, it was found that exposure to laser irradiation did not affect the urination interval extension effect, the urination volume increase effect, and the bladder contraction force.

(Each result in each disease state model when irradiated percutaneously)
For each pathological model (cystitis / bladder pain model rat, spinal cord injury model rat, Parkinson's disease model rat) when percutaneously irradiated, the above results (urination interval, single urination volume, and bladder at the time of excretion) (Internal pressure).
That is, laser irradiation improved inflammatory (cystitis) and neuropathic (both brain and spinal cord lesions) dysuria (urine storage disorder) without impairing the drainage function.

(Examination of the mechanism for the effect of laser irradiation on urination function)
We investigated the mechanism of the effect of laser irradiation on urination function. Details are as follows.

(Model rat and method used)
(1) Model rat used A normal model of SD rat (male: around 250-300 g), cystitis / bladder pain model rat was used.
(2) Method Low-power semiconductor lasers were irradiated to both sides of the L6 / S1 intervertebral foramen exposed under urethane (subcutaneous + intraperitoneal 1.5 mg / kg) anesthesia. As a control, one subjected to sham irradiation was used. Refluxed immediately after irradiation or sham irradiation, and the L6 spinal cord was removed. Next, the excised L6 spinal cord was sectioned (40 μm) with a cryostat, and then c-Fos protein was stained by immunostaining (ABC method). The number of cells expressing c-Fos protein in each region of interest in the L6 spinal cord (from the back horn to the middle lateral nucleus) was compared between the irradiation group and the sham irradiation group.
Irradiation conditions are as follows.
Total light intensity: 180mW x 180 seconds (32.4J): 4 times, just before and after 30 minutes of injection into the bladder Laser: Semiconductor laser (GaAlAs)
Wavelength: 810nm
Irradiation equipment used: Minato Medical Science Co., Ltd. SOFTLASERY JQ 310

(Results of examination of the mechanism for the effect of laser irradiation on urination function)
In normal and cystitis / bladder pain model rats, the number of cells expressing c-Fos protein according to the sensory stimulation of the bladder at the L6 spinal cord input site in the afferent tract of the lower urinary tract nervous system was higher than in the non-irradiated group It was confirmed that there was a significant decrease in the irradiation group (see FIG. 4: Cystitis / bladder pain model rat).
That is, it was found that the intensity of input to the spinal cord of the normal bladder sensation and the bladder sensation at the time of urinary storage disorder was suppressed by laser irradiation. The same result was obtained in the normal model.

(Examination of safety by laser irradiation)
We examined safety by laser irradiation. That is, the effect on cells by long-term laser irradiation was examined. Details are as follows.

(Model rat and method used)
(1) Model rat used Normal model of SD rat (male: around 250-300g) (2) Method L6 / S1 intervertebral foramina or sciatic nerve exposed under urethane (subcutaneous + intraperitoneal 1.5mg / kg) anesthesia One side was irradiated with a low-power semiconductor laser, and the other side was irradiated false. Thereafter, the L6 spinal root and sciatic nerve were removed immediately after irradiation or sham irradiation. And after making the thin section of a nerve crossing, it compared in the irradiation group and the pseudo irradiation group.
Irradiation conditions are as follows.
Total light intensity: 180mW x 20 minutes Laser: Semiconductor laser (GaAlAs)
Wavelength: 810nm
Irradiation equipment used: Minato Medical Science Co., Ltd. SOFTLASERY JQ 310

(Results of safety studies with laser irradiation)
Even though the exposed sciatic nerve and L6 nerve root were excessively irradiated (for a long time), there was no change in the morphological (light microscope level) (see FIG. 5).
That is, it is considered that laser irradiation has no safety problem.

From the results of the above examples, laser irradiation can significantly improve the urine storage function without impairing the discharge function with respect to the urination function.
More specifically, laser irradiation affects the excretory function of bladder sensation (hypersensitivity) due to abnormal sensation of the bladder, urinary dysfunction, urgency due to detrusor overactivity, frequent urination / urinary incontinence, and bladder pain. Without any significant improvement.
Furthermore, the mechanism of the improvement of dysuria is considered to be that laser irradiation to the lower urinary tract-dominated peripheral nerve selectively suppressed the afferent reflex centripetal tract.

  That is, the use of the novel laser of the present invention is a breakthrough treatment for conditions such as increased bladder sensation (hypersensitivity), urinary dysfunction, detrusor overactivity, urinary urgency, frequent urination, urinary incontinence, and bladder pain. Can provide a method.

Results of micturition intervals in a healthy model Results of one urination volume in a healthy model Results of intravesical pressure at drainage in a healthy model C-Fos protein staining results in cystitis and bladder pain model rats Section of (sciatic nerve) in healthy model after laser irradiation

Claims (3)

In order to improve and / or treat neurogenic dysuria, the laser wavelength is 700 nm to 900 nm, the laser output is 40 mW to 10 W, and the total light beam is used to percutaneously irradiate the laser beam to both sides or the vicinity of the sacral foramen. A method of operating a laser irradiation apparatus, characterized in that the laser irradiation apparatus operates under a condition of an amount of 0.9 J / cm ^{2 to} 117000 J / cm ² .
The method according to claim 1, wherein the neurogenic dysuria is one or more selected from the following group;
Urinary urgency, bladder hypersensitivity, frequent urination, urinary incontinence, bladder pain / discomfort, pelvic pain / discomfort, overactive bladder, enuresis, detrusor overactivity, low compliance bladder, interstitial cystitis , And neurogenic bladder.
The laser wavelength is set to 700 nm to 900 nm, the laser output is set to 40 mW to 10 W, and the total light amount is set to 0.9 J / cm ^{2 to} 117000 J / cm ^2. A method for setting a laser irradiation apparatus comprising a laser light source for improving and / or treating neuropathic dysuria caused by skin irradiation.