Cipro.

By V. Lars. University of Central Arkansas.

It is thought that continence is achieved by the support given by the tape order cipro 250 mg mastercard antibiotics for acne and the pill, which is focused at the point where the closure transmission forces occur in the midurethra purchase genuine cipro on line antibiotic jock itch. Since the anterior urethral wall is fixed anteriorly by the pubourethral ligaments and the posterior urethral wall lacks support trusted cipro 250mg virus envelope, real-time imaging has shown that the urethral segment proximal to where the tape is located presents no motion of the posterior urethral wall. Surprisingly, the benefit that bladder neck mobility is reduced makes no improvement in continence control [45]. Recent randomized controlled trials have demonstrated equivalence among retropubic and transobturator tension-free slings [46]. The abundance of surgical procedures to correct incontinence, and modifications, thereof, reflects deficiencies in understanding of the pathophysiology of this condition. Currently, urinary continence is considered to be the result of a complex process with contributions from bladder neck, urethral, 1060 vascular, neural, and myofascial components. Unfortunately, a comprehensive understanding of the contributions of all of these elements has yet to have evolved. Optimized urethral function (coaptation and vascular flow) with integrity of urethral support and bladder neck smooth muscular function all summate to the continent condition. As of yet, no single procedure addresses all of these components comprehensively, hence the lack of any single procedure providing universal continence to all women undergoing that intervention. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Dynamic urethral pressure profilometry pressure transmission ratio determinations after continence surgery: Understanding the mechanism of success, failure, and complications. Development of a plan for the diagnosis and treatment of urinary stress incontinence. A proposal for a new classification for operative procedures for stress urinary incontinence. An ambulatory surgical procedure under local anaesthesia for treatment of female urinary incontinence. Structural support of the urethra as it relates to stress urinary incontinence: The hammock hypothesis. Advancing the understanding of pathophysiological rationale for the treatment of stress urinary incontinence in women: The trampoline theory. Periurethral collagen injection for the treatment of female stress urinary incontinence: 4-year follow-up results. Urodynamics: Prediction, outcome and analysis of mechanism for cure of stress incontinence by periurethral collagen. Stress urinary incontinence: Long term results of laparoscopic Burch colposuspension. Prospective comparison of laparoscopic and traditional colposuspension in the treatment of genuine stress incontinence. Effectors of Burch colposuspension on the relative positions of the bladder neck to the levator ani muscle: An observational study that used magnetic resonance imaging. A simplified surgical procedure for the correction of stress incontinence in women. Female stress urinary incontinence clinical guidelines panel summary report on surgical management of female stress urinary incontinence. The tension free vaginal tape procedure for the treatment of stress urinary incontinence in the female patient. La bandelette transoburatrice: Un procede mini-invasifpourtraiterl’incontinenceurinairie de la femme. Although surgical technique is a major factor influencing outcome, other factors such as appropriate patient selection, preoperative investigation and preparation, and postoperative care are also important considerations. Urinary incontinence and urogenital prolapse are distressing conditions with a significant deleterious impact on quality of life [1,2], but are rarely, if ever, life threatening. Therefore, surgery for these conditions is elective and allows sufficient time for adequate preparation and case selection, which in turn should improve surgical outcome. Although urogynecological procedures are very rarely associated with surgical mortality, every attempt must be made to minimize intra- and postoperative morbidity. Generally, while measures of objective “cure” tend to be favored in the research setting and in the reporting of clinical trials, in everyday clinical practice, more subjective measures of outcome are preferred [4]. The use of patient-reported goals has been described as the fourth dimension in assessing pelvic floor dysfunction [5]. There is also an evidence to suggest that the use of a more individualized qualitative approach may help to tailor patient care and enable clinicians to focus on those specific and often very personal symptoms, which bother patients most. More recently, global indices that ask a patient to rate the response of her condition to intervention (such as surgery in pelvic organ prolapse) have been used in clinical and research settings. These are much more simple and easy to use, interpret, and ultimately compare across units offering interventions in the management of urogenital dysfunction [7,8]. It is vital that before proceeding to a surgical procedure, a woman should feel that she has had the opportunity to take part in the decision process as this may have a profound influence on her emotional, psychological, and sexual well-being. The information on the possible effects of surgery on physical (with particular regard to bowel and bladder function), hormonal, reproductive, and sexual function should be provided. The full range of therapeutic measures available, expectant, medical, and surgical, should be discussed to allow an informed choice. It is also important to give a realistic view of success rates of individual procedures as well as any possible complications and their likelihood and possible sequelae. This ensures that the woman has realistic expectations regarding her surgery and a clear idea of potential complications, which goes a long way to reducing medicolegal problems. Use of Alternative Therapies Surgical intervention should not be undertaken without a comprehensive discussion on available alternative forms of therapy. These options may be particularly relevant for those women unsuitable or unwilling to undergo surgery. As physiotherapy is associated with good success rates and is not associated with significant adverse outcomes, it is recommended that surgical intervention is undertaken only after adequate course of physiotherapy. Duloxetine, a balanced serotonin and noradrenaline reuptake inhibitors, is the only medical treatment available for stress incontinence. A number of mechanical devices may also be considered in the conservative management of pelvic floor dysfunction. These may be useful in the short term, while women undergo physiotherapy or are on the waiting list for surgery, in those who are unwilling or unfit for surgery and during pregnancy. Information Leaflets Research has shown that at any given time, only 10% of verbal information during a consultation is remembered by the patient afterward. This can be substantially increased by the use of written information given to patients during a consultation [17]. Patient information leaflets can be particularly useful if they have been written locally to reflect practice in a particular unit. Written information leaflets can also be reread at leisure by women, allowing them time to consider treatment options and think of any questions that may be addressed at subsequent consultations. In addition, documentation of the use of such leaflets may be particularly useful in medicolegal disputes.

As alkalosis discount 750 mg cipro otc antibiotic resistance is caused by, hypokalemia and hyponatremia—and tetanic pyloric obstruction is partial order online cipro antibiotics for uti erythromycin, most infants will be able to spasms may complicate the picture purchase cipro pills in toronto antibiotic guideline malaysia. T e use of a pacifer or a small feed, covering the hospitalization, incomplete response and risk of atropine- infant and examining while in mother’s lap are all helpful related cardiac side efects coupled with uniformly maneuvers. Failure to palpate pylorus necessitates further good results of surgery, medical management of pyloric work-up to rule out severe gastroesophageal refux hypertrophy is not in vogue. Hiatal Hernia Diagnosis (Partial T oracic Stomach) Clinical impression is confrmed by ultrasound and, if still In the most common type of hiatal hernia in infants, in doubt, by a barium meal study. A note should be made of Frequent aspiration associated pneumonitis, any cardiac anomaly, skeletal Impending stricture. An echocardiogram and a renal ultrasonography is a part of the work-up of Esophageal Atresia and Tracheoesophageal such a child. Associated Early diagnosis, adequate preoperative preparation and common anomalies are congenital heart disease 20– surgical repair may prove life saving. Te repair of the esophageal pouch is done hydronephrosis) and gastrointestinal (20%, anorectal when the baby is clinically stable. Te incidence of polyhydramnios in the gastrostomy or transanastomotic tube is started. Te fndings include excessive salivation (blowing Babies with H-type fstula require division of fstula bubbles), coughing, gagging and even choking, respiratory by cervical approach with repair of both trachea and distress and cyanosis on the very frst feed. Either a delayed thorough examination of such baby to rule out associated primary repair or esophageal replacement is required anomalies. During follow-up an eye is kept, as these Diagnosis babies are prone to develop anastomotic strictures. Evaluation is done by barium studies and then esophageal Choking, cyanosis and regurgitation after the frst feed, dilatations may be required. Congenital Diaphragmatic Hernia On suspecting the condition, oral suction should be Etiopathogenesis done to clear the pooled oral secretions before an attempt to pass a catheter is done. Ten a stif radio-opaque Tis condition is characterized by herniation of abdominal catheter 8–10 French size (like a commonly available red contents into thoracic cavity as a result of a developmental rubber catheter) is passed into the upper esophagus till a defect in the diaphragm (usually through the posterolateral hitch is felt and is secured. Chest and abdominal X-rays foramen of Bochdalek on left side), pulmonary hypoplasia are taken in anteroposterior and lateral views. Clinical Features In the present era, a reliable diagnosis can often be made by an antenatal ultrasonogram performed at any time beyond 14 weeks as routine or later for evaluation of polyhydramnios. All such mothers should be referred to higher tertiary care centers for immediate neonatal care and surgery. Clinically, these neonates have asymmetric funnel chest 820 in duodenum (especially in Down’s syndrome) followed by ileum, jejunum and colon. Tese children present with bilious vomiting and abdominal distension, which starts on day 1 of life. In general, lower the site of atresia more the abdominal distension and later the onset of vomiting (distension is not seen in duodenal obstruction due to proximal obstruction). In jejunal atresias, three bubbles may be seen—triple bubble sign while in lower more air-fuid levels are seen. Note the multiple loops of bowel and a nasogastric tube coursing into the chest cavity with In the intrauterine life, the embryologic midgut undergoes pushing of the heart to the opposite side. As a result of this with shift of the mediastinum, absent breath sounds and duodenojejunal fexure crosses over and lies to the left of presence of peristaltic sounds on the afected side. Heart spine and colon crosses over the small bowel mesentery sounds are displaced and abdomen is scaphoid. It is appropriate to do blood gas analysis to extreme surgical emergency as practically the whole of the assess the extent of hypoxia and acidosis. Te other cause of obstruction in this scenario is due to Ladd’s bands which course from Treatment abnormally located cecum across the second and third After confrmation of diagnosis, all eforts are made to part of duodenum and cause external compression on stabilize the cardiorespiratory system. A nasogastric tube is placed and a rectal syringing given Chronic midgut volvulus: Recurrent abdominal pain to defate the stomach and colon respectively. Te infant is sedated and Ladd’s bands leading to acute upper gastrointestinal metabolic acidosis and hypoxia is corrected. More common in neonates and Congenital diaphragmatic hernia is no longer infants, the clinical picture includes recurrent forceful considered a surgical emergency; instead it is a bilious vomitings without abdominal distension. Once stable the child is taken up for laparotomy and reduction of viscera with large stomach bubble with few distal gas shadows. Good results can be expected if meal studies show that the duodenojejunal junction lies the pulmonary hypoplasia is not very severe. Te small bowel loops are predominantly on the left side of the Duodenal and Other Intestinal Atresias abdominal cavity. Partial or complete occlusion of the intestinal lumen may Ultrasound may show abnormal orientation of the occur congenitally in any part of the intestine commonly superior mesenteric artery and veins establishing the diagnosis. Treatment is exploratory laparotomy followed Ultrasound will show a target sign in upper abdomen 821 by lysis of the Ladd’s bands and widening of the base of or in left iliac fossa due to presence of intussusceptum the mesentery. Barium enema may show the intussusception as an inverted cap or a claw sign may be seen. Tere Intussusception is an obstruction to the retrograde progression of Te disorder is characterized by telescoping of one of the barium into ascending colon and cecum. In the area portions of the intestine into a more distal portion, leading of intussusception, there may be a ceiling-spring to impairment of the blood supply and necrosis of the appearance to the column of barium. Of the three forms (ileocolic, ileoileal Treatment and colocolic), ileocolic is the most common. It is the most Conservative hydrostatic reduction gives good results frequent cause of intestinal obstruction during the frst 2 years of life. It is performed by insertion of an unlubricated Te most common form is idiopathic and occurs classically balloon catheter into the rectum. Te predisposing factors include of 90 cm, barium is allowed to fow into the rectum. Under Henoch-Schönlein purpura, Meckel’s diverticulum, fuoroscopy, the progress of barium is noticed. Total parasites, constipation, inspissated fecal matter in cystic reduction is judged from: fbrosis, foreign body, lymphoma and infection with Free fow of barium into the cecum and refux into the rotavirus or adenovirus. Fever and prostration are Passage of charcoal, placed in child’s stomach by the usually appear 24 hours after the onset of intussusception nasogastric tube, per rectum. Surgical reduction is indicated in patients who are A sausage-shaped lump may be palpable in the upper unft for hydrostatic reduction or who fail to respond to abdomen in early stages. Spontaneous reduction with recurrent episodes is known Plain X-ray abdomen may reveal absence of bowel in older children. Hirschsprung’s Disease (Congenital Megacolon) Tis disorder results from absence of parasympathetic ganglion cells in both Meissner and Auerbach’s plexuses at rectosigmoid segment with or without involvement of some additional part of the distal large bowel. Clinical Features Constipation (persistent, not responding to various measures), abdominal distention, vomiting and growth failure may begin soon after birth. Te patient is generally grossly malnourished with multiple nutritional defciencies.

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One should be careful not to drop any fragments in the abdomen purchase cipro overnight epstein-barr virus, which can lead to splenosis and recurrent disease discount 500 mg cipro overnight delivery bacteria 4 billion years ago. This depends on the surgeon’s experience and in particular on the degree of trauma to the tail of the pancreas during the dissection purchase 250mg cipro with visa antibiotic lecture. If a drain is used, it should be taken out through a separate incision to avoid herniation of the small bowel while removing the drain through a large port site. The beneft of this approach is improved exposure of the hilar vessels compared to the anterior approach; however, in the anterior approach, the hilar vessels are controlled earlier in the procedure, which reduces the risk of uncontrollable bleeding later in the procedure. The surgeon begins the procedure by taking down the inferior pole vessels, as described for the anterior approach. After division of these vessels, the spleen is gently retracted medially and the splenophrenic ligament is divided using the harmonic shears (Fig. This dis- section continues superiorly until the short gastric vessels are encountered. Careful dissec- tion of the splenorenal ligament is done at this point, with extreme attention given to avoid injury to the left adrenal gland. Next, the short gastric vessels are divided using the har- monic shears and clips as needed. The hilar vessels will now be in view, and can be dis- sected with a right angle dissector before being divided separately or together with a vascular endo cutter (Fig. Amylase and lipase levels should be checked on the frst postoperative day to ensure there has been no pancreatic injury during the operation. A clear liquid diet is initiated if the levels are normal, and the patient can be discharged home once the diet has been tolerated. Two etiologies are possible: Bleeding from an unnamed vessel, such as a short gastric vessel or a branch of the inferior or superior pole vessels. Irrigation and aspiration of the surgical site should follow to evaluate the rate of bleed- ing. Sometimes, elec- trocautery will control the situation and allow safe placement of the clips. Compression using a laparoscopic 2 × 2 cm gauze can control the bleeding, allowing the operative site to be cleaned in preparation for hemostasis. Control of a Major Vessel The situation is different when a major vessel is injured. Examples are the splenic vein or artery, or the direct terminal branches of the main trunk. Flow is usually very high in these vessels, and blood reaching the left upper quadrant of the abdomen will obscure the view. In these circumstances, one can try to control the bleeding using the steps described previously, using a larger atraumatic instrument such as a bowel clamp to grasp the whole hilum. If this is not successful, it is usually wise to convert the patient rapidly through an open left subcostal incision. Splenic Injury Another possibility is an injury to the spleen itself during the dissection. Although resultant bleeding may obscure the dissection, simple compression with a 2 × 2-cm surgical gauze together with appropriate electrocautery should control bleeding. If a combination of bleeding from the spleen and a minor vessel occurs, it is not possible to control both at the same time. It is recommended to either grab the bleeding vessel with a grasper while cauterizing the capsule, or control the capsular bleeding with a 2 × 2 gauze and compression while the bleeding vessel is clipped. Maneuver of Last Resort During Bleeding of the Hilar Vessels In the event of a splenic injury in traditional open surgery, the surgeon rapidly mobilizes the splenic attachments after inserting a large piece of gauze to compress the hilum. The surgeon’s left hand retracts the splenic handle and the right hand clamps the vessels “en bloc” using large and long Kelly clamps. The same maneuvers can be realized laparo- scopically if the surgeon and assistant have very good laparoscopic skills. As the short gastric vessels and the inferior attachments are already divided, the surgeon should promptly divide the phrenic attachments to mobilize the spleen. Once the spleen is mobilized, the assistant can retract the whole spleen superiorly with an open fan retractor, and the surgeon fres one or two shots of a linear cutter with vascular staples. If this maneuver is not successful, conversion to an open procedure should be initiated. In order to accomplish Partial this, it is important to identify the inferior pole vessels, or any vessel per se, that is sup- Splenectomy plying the territory that has to be removed. Once the vessel is isolated using a right angle dissector, clips are placed and the vessel is divided, immediately producing a zone of ischemia in the spleen (Fig. Once this has been achieved, harmonic shears are used to perform a partial splenectomy. It is important to leave 2 or 3 mm of zonal ischemia tissue on the remaining healthy spleen, and divide the spleen in the ischemic territory to avoid massive bleeding (Fig. Once the partial splenectomy is performed, fbrin sealant is sprayed on the remaining tissue to further enhance homeostasis. Ligation of the inferior polar vessels in this example that delineates a segmental zone of ischemia Fig. An incision is made for the nondominant hand the Splenectomy same size as the surgeon’s glove size (7. It is important to place this incision rather away from the camera on the right side of the patient to avoid interaction between the hand and the scope. The nondominant hand of the surgeon is introduced here Distal Splenopan createctomy 199 This procedure is illustrated in Fig. The frst step of the splenectomy is the mobili- Distal zation of the inferior aspect of the spleen, dividing the phrenic attachments of the colon. Splenopan­ The next step is the mobilization of the phrenic attachment of the spleen. The superior createctomy aspect of the spleen is then separated from the diaphragm. Once this is done, the short gastric vessels are taken down, exposing the pale tissue of the pancreatic tail. Alternatively, this mobilization of the spleen can be performed after the control of the splenic vessels and the division of the pancreatic tail. Alternatively, 1, 2, 3 can be performed after 4 and 5 200 Chapter 12  Splenectomy (Total and Partial) and Splenopancreatectomy Slowly and carefully, the splenic artery and vein are identifed. Sometimes it is pos- sible to dissect both en bloc, but in most cases the splenic artery and the splenic vein are divided separately. Using the right angle dissector, the vessels are identifed, dissected out, and divided using clips; it is indeed safer to place large clips than use a vascular lin- ear stapler. Hemeostasis is rechecked and any bleeding site is sutured to minimize the risk of pancreatic leak. J Am Coil Surg 179(6):668–672 Danno K, Ikeda M, Sekimoto M, Sugimoto T, Takemasa I, Yamamoto H, Doki Y, Monden M, Mori M (2009) Diameter of splenic vein is a risk factor for portal or splenic vein thrombosis after laparoscopic splenectomy.

In contrast cipro 750 mg low cost antibiotic resistant bv, in advanced stages of the disease buy generic cipro online antibiotic jock itch, the drug improved bladder storage function [109] discount cipro 250 mg without prescription antibiotic blue capsule. Peripheral Targets Possible peripheral targets for pharmacological intervention may be (1) the efferent neurotransmission, (2) the smooth muscle itself, including ion channels and intracellular second messenger systems, and (3) the afferent neurotransmission. The five gene products correspond to pharmacologically defined receptors, and M –M is used to describe both the1 5 molecular and pharmacological subtypes. These receptors are also functionally coupled to G-proteins, but the signal transduction systems vary [114–119]. Detrusor smooth muscle contains muscarinic receptors of mainly the M and M subtypes [2 3 114–119]. The M receptors in the human bladder are believed to be the most important for detrusor contraction. Supporting a role of Rho-kinase in the regulation of rat detrusor contraction and tone, Wibberley et al. Thus, the main pathway for muscarinic receptor activation of the detrusor via M receptors may be calcium influx via L-type calcium channels and increased sensitivity3 to calcium of the contractile machinery produced via inhibition of myosin light chain phosphatase through activation of Rho-kinase [122]. In certain disease states, M2 receptors may contribute to contraction of the bladder. Thus, in the denervated rat bladder, M receptors2 or a combination of M - and M -mediated contractile responses and the two types of receptor seemed to2 3 act in a facilitatory manner to mediate contraction [127–129]. In obstructed, hypertrophied rat bladders, there was an increase in total and M receptor density, whereas there was a reduction in M receptor2 3 density [130]. The functional significance of this change for voiding function has not been established. They concluded that2 whereas normal detrusor contractions are mediated by the M receptor subtype, in patients with3 neurogenic bladder dysfunction, contractions can be mediated by the M receptors. The inhibitory prejunctional muscarinic receptors have been classified as M in the human bladder [4 132]. The muscarinic facilitatory mechanism seems to be upregulated in hyperactive bladders from chronic spinal cord–transected rats. The facilitation in these preparations is primarily mediated by M3 muscarinic receptors [133,134]. The urothelium, as mentioned previously, has been suggested to work as a mechanosensory conductor, and in response to, e. The organic cation transporter 3 subtype has been demonstrated in and suggested to be involved in the nonneuronal release from rat urothelium [148]. Most investigators agree on that there is a low expression of these receptors in the detrusor muscle [149–152]. In addition, in functional experiments, they found a small response to phenylephrine at high 361 drug concentrations with no difference between normal and obstructed bladders. In the bladder, the function of the detrusor muscle is dependent on the vasculature and the perfusion. Hypoxia induced by partial outlet obstruction is believed to play a major role in both the hypertrophic and degenerative effects of partial outlet obstruction. They found that 4 weeks treatment with doxazosin increased bladder blood flow in both controlled and obstructed rats. Furthermore, doxazosin treatment reduced the severity of the detrusor response to partial outlet obstruction. It should be remembered that in women these drugs may produce stress incontinence [162]. Pharmacokinetics Mirabegron is rapidly absorbed after oral administration, and maximum plasma concentration (Tmax) is reached in about 2 hours [182,183]. The drug circulates in the plasma as the unchanged active form and inactive metabolites. Most of an administered dose is excreted in urine, mainly as the unchanged form, and one-third is recovered in feces, almost entirely as the unchanged form [184]. Mechanism(s) of Action Filling of the bladder initiates activity in “in-series”-coupled, low-threshold mechanoreceptive (Aδ) afferents [188]. This implies that, if the compliance of the bladder is increased, the response to distension is decreased and, to recruit sufficient afferent activity needed to initiate micturition, greater filling volumes are needed—thus, bladder capacity increases. One determinant of bladder compliance is the spontaneous (autonomous) bladder activity during filling. Mirabegron inhibited only nonvoiding activity in rat, while tolterodine (antimuscarinic) inhibited nonvoiding activity as well as the amplitude of voiding contractions [191]. Mirabegron did not adversely affect flow rate, detrusor pressure at maximum flow rate, or bladder contractile index and was well tolerated. The safety and efficacy of long-term administration of mirabegron 50 and 100 mg was compared to that of tolterodine in a 12-month, 3-armed, parallel group study (no placebo arm). Tolerability and Adverse Effects In the clinical studies performed, the tolerability of mirabegron has been good as well as the adverse effect close to those of placebo [201]. The most common (≥3%) adverse effects in any treatment group were hypertension (6. However, in the clinical efficacy and safety studies, the change from baseline in mean pulse rate for mirabegron 50 mg was approximately 1 bpm and reversible upon discontinuation of treatment. This was a randomized, placebo-, and active-controlled (moxifloxacin 400 mg), four-treatment-arm, parallel crossover study in 352 healthy subjects [202]. Even if the cardiovascular effects of mirabegron observed in clinical studies have been minimal and clinically not relevant, effects on heart rate and blood pressure need to be monitored when the drug is generally prescribed and patients with cardiovascular morbidities are treated. They were randomized to 12 weeks of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2. It was found that compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved mean volume voided per micturition (the primary end point), micturition frequency, and urgency. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo. They concluded that both cyclic nucleotides can produce relaxation of the urethra. They found no differences between the treatments but did not exclude that changes in blood flow may have occurred, which for several reasons could not be detected. Located within the plasma membrane, they control the permeability of different ions. The two most thoroughly investigated classes of ion channels are calcium channels and potassium channels [164]. In smooth muscle, increased intracellular calcium concentrations activate the contractile mechanisms, and in nerve terminals, calcium influx in response to action potentials is an important mechanism for neurotransmitter release. Calcium channels can be divided into at least four different subtypes: L, N, P, and Q channels. The calcium channels present in smooth muscles are L-type (dihydropyridine sensitive) calcium channels and seem to be involved in contraction of the human bladder irrespective of the mode of activation [225]. A decrease of the membrane potential (depolarization) increases the open probability for calcium channels, thereby increasing the calcium influx. Elevated intracellular calcium levels are also believed to initiate release of calcium from intracellular stores, a mechanism called calcium-induced calcium release [226,227].