Long-term changes in adipose tissue gene expression following bariatric surgery.

OBJECTIVE: Patients undergoing bariatric surgery present long-term metabolic improvements and reduced type 2 diabetes risk, despite long-term weight regain. We hypothesized that part of these protective effects could be linked to altered gene expression in white adipose tissue (WAT). METHODS: Transcriptomic profiling by gene microarray was performed in abdominal subcutaneous WAT from women before (n = 50) and two (n = 49) and five (n = 38) years after Roux-en-Y gastric bypass (RYGB) surgery as well as in 28 age-matched nonoperated women. RESULTS: In the obese women, the average body weight decrease was 38 kg 2 years postsurgery followed by an 8 kg weight regain between 2 and 5 years. Most of the long-term changes in WAT gene expression occurred during the first 2 years. However, a subset of genes encoding proteins involved in inflammation displayed a continued decrease between baseline, 2 and 5 years, respectively; that is an expression pattern independent of body weight regain. Expression of 71 of these genes correlated with measurements of adipocyte morphology or serum adipokine levels. CONCLUSION: The continuous improvement in WAT inflammatory gene expression, despite body weight relapse, may contribute to the sustained effects on adipose morphology after bariatric surgery.

Epigenetic regulation of diabetogenic adipose morphology.

OBJECTIVE: Hypertrophic white adipose tissue (WAT) morphology is associated with insulin resistance and type 2 diabetes. The mechanisms governing hyperplastic versus hypertrophic WAT expansion are poorly understood. We assessed if epigenetic modifications in adipocytes are associated with hypertrophic adipose morphology. A subset of genes with differentially methylated CpG-sites (DMS) in the promoters was taken forward for functional evaluation. METHODS: The study included 126 women who underwent abdominal subcutaneous biopsy to determine adipose morphology. Global transcriptome profiling was performed on WAT from 113 of the women, and CpG methylome profiling on isolated adipocytes from 78 women. Small interfering RNAs (siRNA) knockdown in human mesenchymal stem cells (hMSCs) was used to assess influence of specific genes on lipid storage. RESULTS: A higher proportion of CpG-sites were methylated in hypertrophic compared to hyperplastic WAT. Methylation at 35,138 CpG-sites was found to correlate to adipose morphology. 2,102 of these CpG-sites were also differentially methylated in T2D; 98% showed directionally consistent change in methylation in WAT hypertrophy and T2D. We identified 2,508 DMS in 638 adipose morphology-associated genes where methylation correlated with gene expression. These genes were over-represented in gene sets relevant to WAT hypertrophy, such as insulin resistance, lipolysis, extracellular matrix organization, and innate immunity. siRNA knockdown of ADH1B, AZGP1, C14orf180, GYG2, HADH, PRKAR2B, PFKFB3, and AQP7 influenced lipid storage and metabolism. CONCLUSION: CpG methylation could be influential in determining adipose morphology and thereby constitute a novel antidiabetic target. We identified C14orf180 as a novel regulator of adipocyte lipid storage and possibly differentiation.

Assessment of vertigo.

Vertigo is defined as a subjective sense of imbalance and includes unsteadiness as well as a sensation of rotation. Vertiginous symptoms may arise from defects in the labyrinth, the visual system, or the central nervous system, although in most patients presenting with balance problems, the lesion lies within the labyrinth or its central connections. The most important step in the diagnosis is an unhurried and detailed history, bearing in mind that many patients will have difficulty in describing their symptoms. A detailed neurological examination is usually unnecessary but one must examine the ears, cranial nerves, cerebellum, and balance function, and look for the presence of nystagmus. The common error of carrying out investigations in place of a detailed history is to be avoided. In many cases, investigations are not required at all, although it is the author's practice to do a routine pure tone audiogram with basic assessment of speech discrimination. There is no indication for routine caloric testing, imaging or blood analysis, each of which should be carried out only when there are specific indications. In the routine clinical care of patients, it is only in exceptional situations that specialised vestibular testing is required, although these are often necessary in research projects.

Cerebrospinal fluid rhinorrhea following surgery for acoustic neurinoma. Report of two cases.

In a series of 48 patients with acoustic neurinoma removed by the suboccipital route, one patient developed cerebrospinal fluid rhinorrhea and another patient had delayed-onset meningitis. Each complication was attributed to opening the posteromedial air-cell tract in the posterior wall of the internal auditory meatus. In operations requiring removal of the posterior meatal wall, it is important to look for the air-cell tract which may not be apparent on computerized tomography. If the tract is opened the cells should be occluded by bone wax.

Ganglion cell populations in normal and pathological human cochleae. Implications for cochlear implantation.

A histological study of 100 hearing ears showed that some capability for speech discrimination requires at least 10,000 spiral ganglion cells. The spiral ganglion cell populations were then estimated in another group of 62 ears which were profoundly deaf for a variety of causes and it was found that 45% of these met the criterion of having 10,000 ganglion cells. The ganglion cell populations were largest in ears deafened by sudden deafness, Meniere's Disease, and ototoxic drugs; they were somewhat less for those with vascular occlusion, temporal bone fracture, otosclerosis, and cochlear dysplasias; they were least in those with measles, bacterial labyrinthitis and congenital syphilis. The data is of relevance in the selection of patients for cochlear implantation.

Ossiculotympanic transplantation.

Continued investigations into current tympanoplasty problems have been carried out in the Eye and Ear Clinic, Royal Victoria Hospital, Belfast. Retrospective studies have been helpful in identifying some of the main problems responsible for many of our unsatisfactory results, both in the irradication of disease and the restoration of aural function. Prospective studies into the behavior of grafting materials for tympanic reconstruction in the experimental animal have led us to an overwhelming preference for natural materials as opposed to plastics or stainless steel. Both homologous and autologous bone and cartilage appear to offer good prospects in ossicular replacement techniques. The most satisfactory material we have used for repair of tympanic membrane defects continues to be either autologous or homologous temporalis fascia. The long-term success of these materials in functional restoration is utterly dependent on continued aeration of the tubotympanic cleft.

Operations on the saccus endolymphaticus and vestibular nerve: have they fulfilled their promise?

The rationale for operations on the saccus and vestibular nerve in patients incapacitated by Meniere's disease as a replacement for total labyrinthectomy, has been the expectancy that less radical procedures will protect these patients from total auditory incapacity. Aware of postoperative hearing losses in some patients after 3 years, we have studied the results in 21 Shambaugh saccus decompression (SD) and 29 middle fossa vestibular nerve section (VNS) operations, in order to assess the claims made for these procedures. We found that while control of vertigo was similar to that reported elsewhere, worse hearing (AAOO criteria) developed in many cases. With SD this increased from 14% at 1 year to 58% at 10 years, and with VNS it increased from 17% at 1 year to 48% at 10 years, when the worse preoperative audiogram was used. Only 17% of SD and 11% VNS ears with serviceable best preoperative hearing had retained this at 10 years. Nineteen percent developed audiometric evidence of contralateral disease during the first 10 postoperative years. It is concluded that although, regrettably, neither of these surgical therapies appears to have the capability of preventing the progress of hearing loss, the reality of bilateral disease justifies the continued use of SD or VNS by adequately trained surgeons.

Small vestibular schwannomas in the elderly: a management dilemma.

Small vestibular schwannomas were diagnosed in two elderly patients and, for different reasons, a policy of watch and wait was instituted. One was reliable in attending for follow-up and lived for over 20 years without surgical intervention. The other was unreliable in follow-up, there was an unexpected and undetected acceleration of the growth rate and urgent surgery became imperative at the age of 77 years. This provided to be unsuccessful. A watch and wait policy is acceptable in the elderly but only if the patient can be relied upon to co-operate in follow-up attendance and imaging.

Familial stapes superstructure fixation.

Congenital stapes superstructure fixation was found in a mother in both ears and her daughter in one ear. The head of the stapes was fixed to the pyramid by a bony bar which lay immediately superior to a normal stapedius muscle. Removal of the bony bar resulted in normal hearing, which has been maintained. We believe that these are the first reported cases of this abnormality.

Artificial tympanic membrane and ossiculoplasty.

We report an unusual case of a subjective hearing improvement, confirmed by audiometry, in a patient using a paper towel prosthesis.

Disability after labyrinthectomy.

A labyrinthectomy is known to relieve vertigo successfully in the majority of patients who suffer from Menière's disease and have non-serviceable hearing in the affected ear. It is assumed that the procedure reduces disability, helps the patient to return to work and improves the quality of life. Eighteen patients who underwent a transmastoid drill-out labyrinthectomy between 1980 and 1990 were interviewed and an attempt was made to evaluate the success of the operation in accordance with the guidelines set out by the AAO-HNS 1985. In the present series it was noted that although vertigo was relieved in 89 per cent of patients after labyrinthectomy, only 50 per cent of them returned to work. In this study, the age and occupation of the patient at the time of surgery and the relief of vertigo did not accurately predict whether or not a patient returned to work.

Destruction of the endolymphatic sac in the cat.

The endolymphatic duct and sac were destroyed by drilling in a cat that was sacrificied after 2 3/4 years. Histological examination of the temporal bones showed marked endolymphatic hydrops; degeneration of the stria vascularis in the upper coil; degeneration of the organ of Corti and spiral ganglion in the upper and middle coils; and degeneration of the macula of the saccule. It is probable that, in some cases at least, the primary pathology of Menière's disease is in the endolymphatic sac.

Long-term viability of transplanted ossicles.

Doubt has been raised about the long-term suitability of ossicular implants in tympanoplasty. Twenty-three ossicular implants that had been in the middle ear for a mean duration of 9.6 years were examined histologically by light microscopy. Although there were only two specimens showing subtotal replacement of the dead ossicular implant by new bone, the structural integrity of all implants was maintained and there was no evidence of overt osteoclastic bone resorption. Therefore our findings support the concept of prolonged survival of ossicular implants in the middle ear and we do not see any good reason for abandoning their use in reconstructive tympanoplasty.

Long-term results of vestibular nerve section.

Records are available on 27 patients who had vestibular nerve section between 1975 and 1987 giving a follow-up time of 10 to 22 years with a mean of 16 years. Episodic vertigo was fully controlled in 26 patients, one needing a labyrinthectomy 18 months later. In addition to the patient who had labyrinthectomy, one patient had immediate post-operative profound hearing loss so that long-term follow-up of hearing was possible in 25 patients. After six months there was an overall average improvement in hearing of 1 dB. Thereafter there were average deterioration of 7 dB at two years, 15 dB at 10 years, 23 dB at 15 years and 29 dB at 20 years. This deterioration was more marked in those who had better hearing at the time of surgery, with all 10 whose hearing was classified as good deteriorating to poor by 15 years. At 10 years hearing deteriorated by 25 dB in those with good hearing and by 7 dB in those with poor hearing. In 20 per cent of patients there was audiological evidence of eventual involvement of the other ear. Tinnitus became worse in five patients but was a major problem in only one patient. One patient suffered a facial paralysis with partial recovery and, in addition, in one the frontal branch was divided in the incision.

Transplanted ossicles after two decades.

The authors now report on the histological appearance of two very long-term ossicles, an autologous incus removed from the middle ear at revision surgery 21 years after repositioning and a homologous incus removed from the middle ear after 20 years. Having been placed in formalin immediately after removal from the ear, both specimens were later decalcified by ethylene diamine tetra-acetic acid, embedded in paraffin wax, serially sectioned and stained with haematoxylin and eosin.

Realities in ossiculoplasty.

The results of ossiculoplasty are frequently reported in terms of closure of the air-bone gap. This parameter is a reliable indicator of the degree of technical success, and is useful in comparing different materials and types of reconstructions. However, assessment of the operated ear alone does not evaluate the effect of surgery on binaural hearing ability, leading to the situation where sub-optimal advice may be given to patients pre-operatively. This article advocates a more patient orientated method of assessing the results of ossiculoplasty. Previous studies have indicated that the operated ear must reach an air conduction level of 30 dB for the speech frequencies, or be within 15 dB of the other ear, to ensure that the patient will gain significant benefit. A graphical method for the prediction of patient benefit is presented, and compared to the rule of thumb quoted above. The implications for surgeons and patients considering ossiculoplasty are obvious. Many statements routinely made to patients prior to surgery for conductive hearing loss are unduly optimistic and unrelated to the realities of reported results. There is a need to determine what types of such hearing losses can be helped surgically, and more importantly to what extent the patients hearing disability can be relieved.

Syphilitic labyrinthitis--an update.

Forty-eight patients with syphilitic labyrinthitis have been treated and followed up for periods of six months to 25 years; interpretation of the hearing results must be in the light of the natural history of this condition which is perceived to be progression of hearing loss to profound deafness. At the beginning of the series treatment was with ampicillin alone and on this treatment 11 ears with useful hearing were maintained at this level. The group with combined ampicillin and prednisone treatment, which included some failures from ampicillin alone, maintained useful hearing in 28 out of 29 ears. Those treated initially with ampicillin and prednisone and later also given regular injections of ACTH, maintained hearing in 16 out of 17 ears. At the outset, there were 29 profoundly deaf ears. One of these recovered some useful hearing but two ears with useful hearing at the outset became profoundly deaf so that at the end there were 30 profoundly deaf ears. However, all patients as opposed to ears, with useful hearing at the outset were left with some hearing; no patient became profoundly deaf.

Second ear stapedectomy--a continued controversy.

This paper presents the results of an investigation into the effects of stapedectomy on vestibular function. We detected a disturbingly high incidence of vestibular abnormality in the results of caloric tests at three months postoperatively. Surprisingly, this was not usually accompanied by concurrent vestibular symptoms and there was no evidence of cochlear dysfunction in most cases. Although the caloric response at 12 months postoperatively showed an improvement in most instances, the responses rarely became symmetrical. We believe that a long-term alteration in vestibular response is not uncommon following stapedectomy. Although most patients will compensate quite quickly after unilateral stapedectomy we suspect that this occurs much less readily after bilateral stapedectomy and not at all should bilateral impairment of vestibular function occur. On the basis of this evidence, we submit that bilateral stapedectomy is justified only when vestibular function can be shown to be normal prior to the second ear operation.

Vestibular nerve section for Ménière's disease.

In summary: (i) the fact that VNS spares auditory function makes it preferable to labyrinthectomy. A comparison of VNS and the "conservative" operations on the inner ear shown that they have much the same effect on hearing. VNS by controlling vertigo may also provide an additional benefit by eliminating one of the stress factors concerned in the perpetuation of hydrops; (2) in the treatment of vertigo, VNS is now the most effective method of treatment. Because of elimination of vertigo is what chiefly concerns most of our patients, we suggest that when medical treatment fails to control vertigo, VNS is the surgical method of choice.

Otological manifestations of a new familial polyostotic bone disorder.

Fifty members of a family with a unique autosomal dominant bone disease were investigated. Nineteen of the family members were either known to have, or were strongly suspected of having the disease. All but one of these had a hearing loss which was conductive in the younger age group and mixed in the older members. The common finding in those who had middle ear surgery was replacement of the long process of incus by a fibrous band. The histological features were similar to those found in Paget's disease. The age of onset, distribution of lesions and radiographic findings, however, were not typical of this disorder.