Spinal epidural empyema concurrent with sequestrum in a cat: a case report.

A 5-month-old intact female mixed cat presented with repetitive paraplegia and drainage of pus from the back despite continuous antibiotic medication. Neurologic examination was consistent with below T3-L3 myelopathy. Computed tomography and magnetic resonance imaging revealed a contrast-enhanced mass in the L1-3 spinal canal, and bone fragments in the T13 and L1 spinal canal. Spinal epidural empyema was suspected, and hemilaminectomy was performed for T12-L2 on the right side and T11-12 on the left side. Bone fragments were diagnosed as sequestrum infected with Bacteroides sp. The cat recovered enough to ambulate next day. One month after surgery, there was no deficit in neurological function. This is the first report of spinal epidural empyema concurrent with sequestrum in a cat.

Tracheobronchial chondritis as an immune-related adverse event occurring during the administration of nivolumab for recurrent hypopharyngeal squamous cell carcinoma.

Tracheobronchial chondritis is a rare immune-related adverse event (irAE) associated with immune checkpoint inhibitors. We report a case wherein tracheobronchial chondritis occurred while administering nivolumab for recurrent hypopharyngeal squamous cell carcinoma (SCC) in a man diagnosed with T2N3bM0 stage IVB hypopharyngeal SCC. After treatment with cisplatin and radiotherapy followed by left and right neck dissection, local recurrence was observed in the hypopharynx. Because of the difficulty of salvage surgery, we administered 240 mg/body of nivolumab. After 9 cycles of nivolumab, the patient was judged to have complete response. After 10 cycles, he had cough and sputum, for which prompting us to perform imaging tests. Computed tomography (CT) showed edematous thickening around the trachea and bilateral bronchi and elevated amounts of adjacent subcutaneous fat tissue. Positron emission tomography-CT showed diffuse fluorodeoxyglucose uptake in the trachea and bilateral bronchi, bronchial endoscopy showed redness and swelling throughout the bronchi, and biopsy showed partial mucosal erosion, inflammatory cell (lymphocyte) infiltration, interstitial edema, and desmoplasia. The patient was diagnosed with tracheobronchial chondritis as an irAE resulting from administering anti-programmed death-1 monoclonal antibody. After four-day prednisolone treatment, his cough and sputum disappeared; after two weeks, tracheobronchial chondritis no longer appeared on CT.

Minocycline-induced black thyroid with black pigmentation of the thyroid cartilage, cricoid cartilage, and trachea found during reconstructive surgery for hypopharyngeal cancer.

Black thyroid is characterized by a rare pigment change observed almost exclusively in patients taking minocycline. We present the case of a 72-year-old man diagnosed with T3N3bM0 stage IVB hypopharyngeal squamous cell carcinoma who had been taking minocycline for approximately 18 months as a treatment for prurigo chronica multiformis. Initial treatment consisted of total pharyngolaryngoesophagectomy, bilateral neck dissection, total thyroidectomy, pharyngeal reconstruction using a free jejunal autograft, and creation of a permanent tracheostoma. During surgery, black discoloration of the thyroid and trachea was observed. Postoperative histological findings confirmed the black discoloration, with deposits of dark-brown, melanin-like granules observed in the thyroid, trachea, thyroid cartilage, and cricoid cartilage. Therefore, the black discoloration of the thyroid associated with the use of minocycline can extend to the thyroid cartilage, cricoid cartilage, and trachea. This information is important for surgeons to recognize in order to prevent unnecessary resection due to misdiagnosis.

Nivolumab for recurrent/metastatic hypopharyngeal squamous cell carcinoma in a liver transplant recipient.

Nivolumab administration to patients with organ transplantation history requires careful management. Herein, we report the case of a living-donor liver-transplant recipient, a 52-year-old man, with recurrent and metastatic hypopharyngeal cancer treated with nivolumab. He was diagnosed with T2N2bM0 stage IVA hypopharyngeal squamous cell carcinoma. While using oral immunosuppressants (cyclosporine and mycophenolate mofetil), the patient underwent right neck dissection followed by radiotherapy as an initial treatment. Three months after radiotherapy, positron emission tomography scans revealed multiple bone metastases. We administered two courses of the EXTREME regimen, comprising cisplatin, 5-fluorouracil, and cetuximab, as the first-line treatment for distal metastasis, but the patient presented with progressive disease. The patient was administered nivolumab as the second-line treatment. The programmed death-ligand 1 (PD-L1) expression level in a biopsy specimen of the primary hypopharyngeal tumor and resected specimen of the cervical lymph node metastasis was 40% and 10%, respectively. PD-L1 expression was not detected in hepatocytes of the liver biopsy sample obtained before nivolumab introduction. The patient received four courses of nivolumab 240 mg. Although liver dysfunction was alleviated by adjusting the dose of the hepatoprotective agent and cyclosporine, the progressive disease status persisted after completing nivolumab courses. The patient died of hypopharyngeal cancer progression.

Electronystagmography in 166 patients with acoustic neuroma before and after surgery.

OBJECTIVE: To analyze the preoperative patterns of caloric test, eye tracking test (ETT), and optokinetic pattern (OKP) in patients with acoustic neuroma (AN) and compare them with the postoperative patterns of ETT and OKP results METHODS: A total of 166 patients with AN (102 women; mean age: 41 years, range: 11-79 years) who were being treated at our hospital between 2013 and 2016 were enrolled. Preoperatively, a detailed history was taken regarding the presence of subjective symptoms of equilibrium dysfunction, and the patients underwent caloric test, ETT, and OKP. They were classified into three groups based on the preoperative ETT and OKP results as follows: Group A, normal ETT and OKP; Group B, either ETT or OKP was abnormal; and Group C, both ETT and OKP were abnormal. All patients were evaluated for subjective symptoms of vestibular dysfunction and were also grouped based on the tumor size on imaging. All surgeries were performed by a neurosurgeon using the lateral suboccipital retrosigmoid approach. About one month later after surgery, postoperatively ETT was performed on 150 patients and OKP was performed on 148 patients. The preoperative and postoperative ETT and OKP results were compared. The same two specialists analyzed the postoperative ETT and OKP findings as improved, unchanged, or worse. Student t-test was used for statistical analysis and a P-value of <0.05 was considered to indicate a statistically significant difference. RESULTS: The average canal paresis(CP) % was 65.8%. No correlation was found between tumor size and CP%. The other side, the average tumor size in each group was 26.6 mm, 28.7 mm, and 37.8 mm in the Group A, B, and C, respectively. The average tumor size in Group C was significantly greater than those of Group A and B (P<0.01). The presence of gait disturbance in Group C was significantly higher than the other groups (P<0.01). The other side, abnormal ETT and OKP were seen in 32.5% and 31.9% of all patients, respectively. ETT and OKP results improved postoperatively in 67.4% and 68.9% of these patients. CONCLUSIONS: Abnormal ETT and OKP results showed positive correlations with the tumor size and presence of subjective symptoms. Further, dysfunction of cerebellum and brain stem owing to tumor compression was observed to recover in many cases after surgery.

Laryngeal Cancer With Lung Metastases Showing Long-Term Complete Response and Delayed Immune-Related Adverse Event After Nivolumab Discontinuation.

We report a case of laryngeal cancer with multiple lung metastases that maintained a complete response (CR) for 18 months after discontinuing nivolumab treatment, with colitis developing 5 months after drug discontinuation. A 65-year-old man was diagnosed with T3N2cM0 stage IVA right supraglottic squamous cell carcinoma that progressed after 1 course of TPF (cisplatin, docetaxel, and 5-fluorouracil) as induction chemotherapy. He underwent total laryngectomy, bilateral neck dissection, pharyngeal reconstruction with anterolateral thigh flap, and creation of a permanent tracheostoma; extranodal extension was detected in the right cervical lymph node metastasis, and the patient underwent adjuvant radiotherapy. Multiple lung metastases occurred during radiotherapy, and the patient was deemed platinum refractory; nivolumab treatment was thus initiated. The tumor proportion score for programmed death-ligand 1-evaluated via antibody testing of the laryngeal tumor-was <1. The patient received 240 mg/body nivolumab every 2 weeks; a computed tomography performed after course 16 of nivolumab treatment confirmed a CR. He exhibited grade 2 thyroid dysfunction, grade 1 interstitial pneumonia, and grade 2 colitis after 6, 7, and 14 months of receiving nivolumab, respectively; treatment was discontinued as despite maintaining a CR, interstitial pneumonia occurred twice. Colitis appeared 5 months after nivolumab discontinuation; nevertheless, a CR was maintained after 18 months.

Predicting the efficacy of chemoradiotherapy for locally advanced human papilloma virus-related oropharyngeal squamous cell carcinoma using one course of TPF chemotherapy.

PURPOSE: The standard induction chemotherapy for head and neck cancer is TPF [cisplatin (CDDP), docetaxel (DOC), and 5-fluorouracil (5-FU)]. We assessed whether one course of TPF could predict the efficacy of chemoradiotherapy for human papilloma virus (HPV)-related oropharyngeal squamous cell carcinoma. METHODS: We retrospectively reviewed 51 patients with stage III-IV HPV-related oropharyngeal squamous cell carcinoma who received one course of TPF with CDDP 60 mg/m2, DOC 60 mg/m2, and 5-FU 600 mg/m2. We recommended chemoradiotherapy for patients with complete or partial response (CR/PR), and surgery for those with stable or progressive disease (SD/PD). The endpoints were TPF-related adverse events and efficacy, chemoradiotherapy efficacy, and 2-year survival. RESULTS: Neutropenia was the most common grade ≥ 3 adverse event (88%). No grade 5 adverse events occurred. TPF achieved CR in 4% of patients (2/51), PR in 73% (37/51), SD in 20% (10/51), and PD in 4% (2/51). Concurrent cetuximab and radiotherapy (bio-radiotherapy, BRT) were administered to 61% of patients (31/51), concurrent CDDP and radiotherapy (CDDP-RT) to 16% (8/51), RT alone to 2% (1/51), and surgery was performed for 22% (11/51). CR was achieved in 85% of the chemoradiotherapy group, and the rate tended to increase with TPF efficacy. CR was achieved in 84% (26/31) of patients receiving BRT, 88% (7/8) receiving CDDP-RT, and 100% (1/1) receiving RT. The 2-year survival rates were 92% overall, and 97% and 79% in the chemoradiotherapy and surgery groups, respectively. CONCLUSIONS: When facing difficulty in deciding between chemoradiotherapy and surgery, one course of TPF may be an effective option.

Occult Papillary Thyroid Carcinoma without Detection of the Primary Tumor on Preoperative Ultrasonography or Postoperative Pathological Examination: A Case Report.

Herein, we report a case of an occult thyroid cancer that was not detected as a primary tumor on preoperative ultrasonography or postoperative pathological examination, although a diagnosis of papillary thyroid carcinoma metastasis was made owing to the presence of a mass in the right upper neck. Needle biopsy of the mass in the right upper neck revealed positive results for thyroglobulin and TTF-1 on immunostaining, and a papillary thyroid carcinoma was observed with papillary and follicular patterns. We suspected papillary thyroid carcinoma (T0N1bM0) or ectopic papillary thyroid carcinoma. Accordingly, we performed total thyroidectomy, central lymph node dissection, right lateral neck dissection, and resection of the superficial lobe of the right parotid. A postoperative pathological examination of 5-mm slices of the specimen revealed no primary tumor in the thyroid. However, a hyalinized image of the thyroid indicated that a micropapillary thyroid carcinoma might have spontaneously disappeared. As there was no normal thyroid tissue in the metastasis to the superior internal jugular lymph node, the tumor was unlikely to be an ectopic papillary thyroid carcinoma. Therefore, we made a diagnosis of a papillary thyroid carcinoma (pT0N1bM0). After surgery, we determined that the tumor belonged to a high-risk group of papillary thyroid carcinomas and a poor-prognosis group of symptomatic papillary thyroid microcarcinomas; accordingly, ablation was performed with 30 mCi iodine-131. There was no recurrence or metastasis 24 months after the first surgery.

Simultaneous metastasized primary unknown signet ring cell carcinoma of the cervical lymph node and mucoepidermoid carcinoma of the parotid gland as double cancers.

Lymph node metastasis from signet ring cellcarcinoma (SRCC) primary unknown is extremely rare. We here report a case of primary-unknown SRCC that metastasized to the cervical lymph nodes, co-existing with mucoepidermoid carcinoma (MEC) of the parotid gland as a simultaneous double cancer. A 68-year-old female patient with right swollen cervical lymph nodes consulted our medical center. A diagnosis of bilateral cervical lymph node metastasis and a right parotid tumor was made. After bilateral neck dissection and right parotidectomy, the pathological diagnosis was SRCC of primary unknown with metastasis to the cervical lymph node and MEC of the parotid gland. Examination of the CRTC1/3-MAML2 fusion gene showed no relation between SRCC of primary unknown with metastasis to the cervical lymph node and MEC of the parotid gland. Ten months after the first treatment, there was recurrence in the left neck lymph node, and left neck dissection was performed. Fourteen months after the first treatment, the patient is alive and cancer-free. This case is the fourth report of SRCC with lymph node metastasis, and highlights the value of fusion gene detection to determine relatedness between simultaneous cancers. Moreover, such cases should be closely monitored for the subsequent appearance of distant metastases.

Comparison of cervical vestibular evoked potentials evoked by air-conducted sound and bone-conducted vibration in vestibular Schwannoma patients.

OBJECTIVE: The vestibular evoked myogenic potential (VEMP) is associated with otolithic afferents and can be used to evaluate the function of the saccule and utricle. In this study, we compared cervical VEMP evoked by stimulation with Air-conducted sound (ACS) and bone-conducted vibration (BCV) to the forehead and investigated whether BCV can be used as a substitute for ACS. METHODS: Data were obtained from 33 patients with vestibular schwannoma. Vestibular examinations were performed preoperatively. VEMP was obtained upon stimulation with ACS (ACS cVEMP) and BCV to the forehead using a minishaker (BCV cVEMP). Vestibular function was also analyzed using the caloric test and ocular VEMP (oVEMP) testing. oVEMP was measured using bone-conductive vibration to the forehead. The results of BCV cVEMP, ACS cVEMP, and oVEMP were compared by the caloric test. RESULTS: Rates of patients with abnormal ACS cVEMP, BCV cVEMP, oVEMP, and caloric test results were 78.8%, 75.8%, 78.8%, and 69.7%, respectively. BCV cVEMP did not correlate with ACS cVEMP, but correlated with oVEMP and caloric test results. CONCLUSION: BCV cVEMP did not correlate with ACS cVEMP. Therefore, BCV cVEMP cannot be used as a substitute for ACS cVEMP.

Prevention of anastomotic leak using an advanced pectoral flap in total pharyngolaryngectomy and free jejunal reconstruction for hypopharyngeal or laryngeal carcinoma.

BACKGROUND: We devised an advanced pectoral flap (APF) to prevent anastomotic leak after total pharyngolaryngectomy (TPL) and free jejunal reconstruction (FJR) in patients with hypopharyngeal or laryngeal carcinoma. The APF alleviates tension on the skin in the neck, reduces the subcutaneous dead space, and promotes adhesion between the neck skin and the anastomosis. OBJECTIVE: To investigate whether an APF is effective for prevention of anastomotic leak associated with TPL/FJR. PATIENTS AND METHODS: Anastomotic leak was compared between APF (n = 65) and non-APF groups (n = 25). Patients who had received preoperative radiotherapy or undergone tracheostomy or skin infiltration requiring neck reconstruction using a pedicle flap were excluded. RESULTS: There were significantly fewer cases of anastomotic leak in the APF group than in the non-APF group (1.5% [1/65] vs. 16.0% [4/25]; p = .02). An APF could be created bilaterally within approximately 15 minutes. Unlike a deltopectoral flap, an APF does not require a skin graft. CONCLUSIONS: The postoperative anastomotic leak rate was 1.5% in patients who underwent TPL and FJR for hypopharyngeal or laryngeal carcinoma with an APF. SIGNIFICANCE: An APF is easily created and can reduce the incidence of anastomotic leak after TPL and FJR.

Extent of thyroid resection and thyroid function after postoperative radiotherapy following total laryngectomy or total pharyngo-laryngo-esophagectomy.

OBJECTIVE: Concurrent chemoradiotherapy (CCRT) is often performed after total pharyngo-laryngo-esophagectomy (TPLE) or total laryngectomy (TL). Hypothyroidism is one of the side-effects of CCRT. The objective of this study was to ascertain the timing of onset and severity of latent hypothyroidism among patients who underwent radiotherapy (RT) or CCRT after TPLE or TL, using thyroid-stimulating hormone (TSH) as a biomarker, and to explore methods of preventing its development. METHODS: Participants comprised 21 patients who underwent these treatments at Tokyo Medical University Hachioji Medical Center between May 2009 and December 2013. TSH, free thyroxine 3, and free thyroxine 4 levels were used as indicators of thyroid function, and thyroid hormone was administered for TSH levels ≥15 µU/mL. RESULTS: Post-radiotherapeutic TSH levels in 17 of the 21 patients (81%) were not within the reference value, and 10 (48%) required thyroid hormone therapy. Pharmacotherapy was initiated within 1 year in 5 of these 10 patients (50%), and between 1 and 3 years in the remaining 5 patients. No patient who did not undergo thyroidectomy required hormone therapy. Early evaluation of thyroid function appears important when postoperative RT, including CCRT, is performed in combination with TPLE or TL. CONCLUSION: Our study suggested that postoperative CCRT or RT after TPLE or TL, especially hemithyroidectomy, carries a high risk for hypothyroidism.

A case of nasal glial heterotopia in an adult.

We report a rare case of nasal glial heterotopia in an adult. After the surgery, frontal lobe cerebral hemorrhage developed. A 58-year-old man had unilateral nasal obstruction that progressed for one year. He had been treated for hypertension, chronic heart failure, and cerebral infarction with aspirin and warfarin. A computed tomography scan showed that the tumor occupied the right nasal cavity and the sinuses with small defect in the cribriform plate. The tumor was removed totally with endoscopy. After the operation, the patient developed convulsions and frontal lobe cerebral hemorrhage. The hemorrhage site was located near a defect in the cribriform plate. Nasal glial heterotopia is a rare developmental abnormality, particularly rare in adult. Only few cases were reported. We could not find any report of adult nasal glial heterotopias that developed cerebral hemorrhage as a complication of the surgery.

Stapes fixation accompanied with abnormal facial nerve pathway.

The patient was a 52-year-old woman. She had been aware of her bilateral hearing loss since she was 20 years old. The hearing in her left ear started to deteriorate at the age of 49. Pure-tone audiometry showed a bilateral mixed hearing loss. The hearing levels for the right ear and the left ear were 52 dB and 68 dB, respectively. There were no remarkable findings in a computed tomography (CT) scan of the temporal bone. We suspected that she had otosclerosis, and an operation was performed on her left ear. When the incudostapedial joint (I-S joint) was exposed to investigate the movement of the stapes, a soft white band that ran under the superstructure of the stapes was noted. By using a nerve monitoring system, we confirmed that the white band was the bare facial nerve. The ossicular chain was normal, except for a malformed stape due to the facial nerve, and the footplate of the stapes was fixed. Therefore, she was diagnosed as having otosclerosis with an abnormal facial nerve pathway. The malformed superstructure of the stapes was removed carefully. When the ectopic facial nerve was shifted to anteroinferior side, the oval window could be seen. Stapedotomy using a Teflon piston prosthesis was performed with no complications.

Osteoma of the pharynx that developed from the hyoid bone.

This paper reports on apparently the first case of a pharyngeal osteoma that developed from the hyoid bone. An 84-year-old man's, presenting symptom was a slight throat pain. Endoscopic examination revealed a huge mass occluding the pharyngeal space. CT scan of the neck showed a large osseous mass adjacent to the hyoid bone. Transoral resection with tracheostomy was performed. Histopathologically, the tumor consisted of mature lamellar bone without a fibrous component. For two years postoperatively, the patient has been free from throat symptoms and signs of recurrence. Osteomas are benign, slow-growing tumors. They rarely develop symptoms or cause functional disturbance. We performed total resection to avoid further functional disturbance as the osteoma was huge. To the best of our knowledge, this is the first report on an osteoma that occupied the pharyngeal space and developed from the hyoid bone.

Role of amino-terminal half of the S4-S5 linker in type 1 ryanodine receptor (RyR1) channel gating.

The type 1 ryanodine receptor (RyR1) is a Ca(2+) release channel found in the sarcoplasmic reticulum of skeletal muscle and plays a pivotal role in excitation-contraction coupling. The RyR1 channel is activated by a conformational change of the dihydropyridine receptor upon depolarization of the transverse tubule, or by Ca(2+) itself, i.e. Ca(2+)-induced Ca(2+) release (CICR). The molecular events transmitting such signals to the ion gate of the channel are unknown. The S4-S5 linker, a cytosolic loop connecting the S4 and S5 transmembrane segments in six-transmembrane type channels, forms an α-helical structure and mediates signal transmission in a wide variety of channels. To address the role of the S4-S5 linker in RyR1 channel gating, we performed alanine substitution scan of N-terminal half of the putative S4-S5 linker (Thr(4825)-Ser(4829)) that exhibits high helix probability. The mutant RyR1 was expressed in HEK cells, and CICR activity was investigated by caffeine-induced Ca(2+) release, single-channel current recordings, and [(3)H]ryanodine binding. Four mutants (T4825A, I4826A, S4828A, and S4829A) had reduced CICR activity without changing Ca(2+) sensitivity, whereas the L4827A mutant formed a constitutive active channel. T4825I, a disease-associated mutation for malignant hyperthermia, exhibited enhanced CICR activity. An α-helical wheel representation of the N-terminal S4-S5 linker provides a rational explanation to the observed activities of the mutants. These results suggest that N-terminal half of the S4-S5 linker may form an α-helical structure and play an important role in RyR1 channel gating.

Subjective visual vertical in patients with ear surgery.

CONCLUSION: Dysequilibrium is one of the most important side effects of ear surgery. The subjective visual vertical can be used as a good indicator for the evaluation of otolithic function in patients with ear surgery. OBJECTIVE: To investigate the influence of various types of ear surgery on the otolithic organs. METHODS: Seventy-one patients underwent ear surgery. Subjective visual vertical (SVV) test was performed before and after ear surgery. We investigated the directional changes of SVV before and after the ear surgery. RESULTS: The postoperative SVV of two patients who underwent translabyrinthine removal of vestibular schwannoma shifted toward the operated side, but following other surgical procedures the SVV tended to shift toward the healthy side.

Distinct mechanisms for dysfunctions of mutated ryanodine receptor isoforms.

Ryanodine receptor (RyR) is the Ca(2+)-induced Ca(2+) release channel in cells. RyR1 and RyR2 are its isoforms expressed in the skeletal and cardiac muscles, respectively. Their missense mutations, which are clustered in three regions that correspond to each other, cause hereditary disorders such as malignant hyperthermia and central core disease in skeletal muscle and catecholaminergic polymorphic ventricular tachycardia in cardiac muscle. Their pathogeneses, however, are not well understood. The following hypotheses are favorably discussed in this article: phenotypes with RyR1 and RyR2 mutations are mainly caused by dysregulations of their functions through the interdomain interaction and luminal Ca(2+), respectively.

Postulated role of interdomain interaction between regions 1 and 2 within type 1 ryanodine receptor in the pathogenesis of porcine malignant hyperthermia.

We have demonstrated recently that CICR (Ca2+-induced Ca2+ release) activity of RyR1 (ryanodine receptor 1) is held to a low level in mammalian skeletal muscle ('suppression' of the channel) and that this is largely caused by the interdomain interaction within RyR1 [Murayama, Oba, Kobayashi, Ikemoto and Ogawa (2005) Am. J. Physiol. Cell Physiol. 288, C1222-C1230]. To test the hypothesis that aberration of this suppression mechanism is involved in the development of channel dysfunctions in MH (malignant hyperthermia), we investigated properties of the RyR1 channels from normal and MHS (MH-susceptible) pig skeletal muscles with an Arg615-->Cys mutation using [3H]ryanodine binding, single-channel recordings and SR (sarcoplasmic reticulum) Ca2+ release. The RyR1 channels from MHS muscle (RyR1MHS) showed enhanced CICR activity compared with those from the normal muscle (RyR1N), although there was little or no difference in the sensitivity to several ligands tested (Ca2+, Mg2+ and adenine nucleotide), nor in the FKBP12 (FK506-binding protein 12) regulation. DP4, a domain peptide matching the Leu2442-Pro2477 region of RyR1 which was reported to activate the Ca2+ channel by weakening the interdomain interaction, activated the RyR1N channel in a concentration-dependent manner, and the highest activity of the affected channel reached a level comparable with that of the RyR1MHS channel with no added peptide. The addition of DP4 to the RyR1MHS channel produced virtually no further effect on the channel activity. These results suggest that stimulation of the RyR1MHS channel caused by affected inter-domain interaction between regions 1 and 2 is an underlying mechanism for dysfunction of Ca2+ homoeostasis seen in the MH phenotype.