Interleukin-6 treatment augments cutaneous wound healing in immunosuppressed mice.

It has been postulated that the inflammatory response that occurs after cutaneous wounding is a prerequisite for healing and that inflammatory cytokines, such as interleukin-6 (IL-6) are involved in this process. We showed previously that IL-6-deficient mice display delayed wound healing, which could be reversed by administration of a murine IL-6 expression plasmid or recombinant murine IL-6 (rMuIL-6). In the present study, we observed that delayed cutaneous wound healing, which occurs as a result of glucocorticoid-induced immunosuppression, can also be reversed by rMuIL-6, as evidenced by epithelialization, granulation tissue formation, and wound closure. In vehicle control mice, rMuIL-6 did not augment healing but rather delayed the process. Immunochemical studies indicated that the expression of matrix metalloproteinase-10 (MMP-10) was increased in dexamethasone-treated mice and that rMuIL-6 treatment reduced its expression, indicating that IL-6 may influence dermal matrix formation and, specifically, collagen synthesis. These results demonstrate that IL-6 can restore abnormal wound repair that occurs in immunodeficiency and suggest its use as a potential therapy.

The role of tumor necrosis factor alpha in chemical-induced hepatotoxicity.

Only recently have toxicologists come to understand the role of inflammation, and TNFalpha specifically, in classical toxicological processes. This relationship appears fairly complex, as inflammation and proliferation may well be only one facet of a time- and dose-dependent continuum of toxicological and repair processes. Not surprisingly, considerable efforts are being undertaken using our newly found understanding of molecular control to develop specific and safe chemical, biological, and molecular regulators of TNFalpha for potential therapeutic use. Their effectiveness in controlling environmental or occupational diseases has yet to be established.

Effects of left temporal lobectomy and amygdalohippocampectomy on memory.

This study examined the effects of left (dominant) temporal lobe surgery on verbal and visual memory in 38 patients with temporal lobe epilepsy. Twenty-five patients had anterior temporal lobectomy (ATL) and 13 had selective amygdalohippocampectomy (AH). All were administered the Rey Auditory Verbal Learning Test and a Complex Figure Test preoperatively and 1 year after surgery. ATL resulted in better seizure control overall. The ATL group as a whole showed a greater postoperative decline of their verbal memory than the AH group. A closer examination of the ATL patients showed there was a subgroup (n = 11) with better preoperative memory functioning that had the most significant decline. In contrast, only three patients in the AH group had better preoperative memory, and the majority (n = 10) matched the 'memory impaired' ATL patients. The changes in memory performance of the 'memory impaired' ATL and AH patients did not reach statistical significance. Postoperatively all patient groups improved in their verbal fluency.

Epilepsy surgery in Sturge-Weber syndrome.

A patient with Sturge-Weber syndrome developed seizures at the age of 4 years. At 13 years of age, she had intractable complex partial seizures with marked visual symptomatology. Interictal encephalograms showed bilateral slow activity, more marked over the right hemisphere with epileptogenic activity maximal in the right temporal region. Serial computerized axial tomography scans demonstrated evolution of bilateral occipital lesions with calcification and adjacent low density areas that were more marked on the right. Magnetic resonance imaging, angiography and neuropsychological evaluations were performed. An extensive resection of the right occipital lobe was achieved. One year after surgery, the patient has had seven brief seizures. Delineation of an epileptogenic focus and surgical removal of the lesion in patients with intractable seizures can now be considered in selected patients with bilateral central nervous system pathology.

Hyperostosis of anterior cervical vertebrae: a rare cause of dysphagia.

Recently, we treated two cases of dysphagia as a result of anterior cervical osteophytes. The cases were the result of two different aetiologies. Referral was delayed in one case because a general practitioner was under the impression that the condition was untreatable. The aetiology, diagnosis and treatment are discussed.

Surgery for refractory epilepsy.

Over a six-year period, 130 patients with medically intractable epilepsy were assessed for possible surgical treatment. Initial assessment comprised full neurological and neuropsychological examination, computed tomographic and magnetic resonance imaging brain scanning, and simultaneous video and surface plus sphenoidal electroencephalographic (EEG) recordings of typical seizures. Forty-one patients (32%) underwent further video and EEG recordings of their seizures with depth (intracerebral) or strip (subdural) electrodes. After these assessments 46 patients (35%) underwent surgery, and follow-up for six months to six years is reported in 41 patients. Of 30 patients who underwent temporal lobe surgery, 21 (70%) are free of seizures and four have had significant seizure reduction, meaning that 83% benefited from surgery. Optimal results were obtained for complex partial seizures when depth electrode recordings were obtained and when abnormal tissue was removed. Six extratemporal resections abolished seizures in two patients, and four others showed worthwhile improvement. Five patients underwent corpus callosotomy, resulting in a worthwhile improvement in three and modest improvement in two patients. No deaths or major complications occurred. It is concluded that surgical intervention can be beneficial for up to 30% of patients with medically intractable epilepsy, and referral of these patients to an appropriate institution is encouraged.

Pro-inflammatory cytokines and interleukin 6 in the renal response to bacterial endotoxin.

Pro-inflammatory cytokines, including tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1 and IL-6 are thought to play important roles in the pathophysiology of chronic kidney disorders, including glomerulonephritis. In particular, IL-6 has received considerable attention as it appears at high concentrations to promote the progression of renal disease while at lower levels may be involved in regulating repair mechanisms. As such, cytokine profiles have been examined in the kidney by either examining secretion from isolated kidney cells or quantitating plasma and urinary levels in experimental models of glomerulonephritis. To examine the cytokine responses within the kidney, without the contribution of other organ systems, we used semi-quantitive polymerase chain reaction (RT-PCR) analysis and a recently developed kidney slice culture model from tissues of mice treated with combinations of endotoxin and neutralizing antibodies against TNF-alpha. The expression of IL-6, in addition to other pro-inflammatory cytokine genes, was increased by endotoxin treatment and reduced by pretreatment with neutralizing antibodies to TNF-alpha. Immunohistochemical staining revealed that IL-6 was expressed primarily in mesangial cells. Urinary IL-6 was also increased in endotoxin-treated mice and was inhibited by treatment with neutralizing TNF-alpha antibodies. Kinetics of the kidney-specific cytokine responses indicated that increase in TNF-alpha occurred initially, followed by IL-1 beta and finally IL-6. Furthermore, addition of TNF-alpha to glomerular mesangial cells induces IL-6 secretion. Taken together, these studies indicate that, like in the liver, a cytokine response occurs in the kidney from bacterial endotoxin and that TNF-alpha acts as a primary cytokine capable of stimulating additional cytokines, including IL-6.

Immunotoxicology: role of inflammation in chemical-induced hepatotoxicity.

The liver, which is the major organ responsible for the metabolism of drugs and chemicals, is also the primary target organ for many toxic chemicals. Increasing evidence has indicated that inflammatory processes are intimately involved in chemical-induced hepatotoxic processes, and like other inflammatory diseases, such as autoimmunity, are responsible for producing mediators which can effect liver damage or repair. This review will summarize the authors' current understanding of how inflammatory processes influence hepatic pathology and repair following exposure to established hepatotoxic chemicals including carbon tetrachloride (CCl4), an industrial chemical, and acetaminophen (APAP), a widely used analgesic.

Selective epilepsy surgery in tuberous sclerosis.

A patient with tuberous sclerosis diagnosed at the age of 5 years developed an intractable seizure disorder characterized by complex partial seizures numbering 10-20/day. Interictal electroencephalograms (EEG) showed a right frontal epileptogenic focus. A computerized tomography scan demonstrated calcification in the right frontal region at two sites, periventricular calcification and multiple low density lesions. Neuropsychological assessment showed a verbal intelligence quotient (IQ) of 69 and a performance IQ of 88. Telemetry and video monitoring recorded 10 seizures during which the EEG showed flattening of ongoing sharp wave activity in the right frontal region. Electrocorticography further identified and localized epileptogenic tissue in the right frontal cortex and surgical removal of involved tissue and the adjacent two tubers was carried out. Twelve months after surgery the patient has had only two brief seizures.

Hemispherectomy: a further modification using omentum vascularized free flaps.

This report describes the authors' technique designed to further prevent the late complications of hemispherectomy. A vascularized omental free flap is used to fill the extradural dead space left following the procedure advocated by Adams. This procedure may provide further stability to the residual brain and reduce infective complications.

Intracranial aneurysms--a survey of the results of surgical treatment at the Prince Henry Hospital, Sydney, 1972-1976.

In this paper, 124 intracranial aneurysms in 114 patients operated on during a five-year period, are reviewed, and the mortality is analysed in respect to factors of age, sex, duration of preoperative interval, site, and type of operation. A comparison with an earlier comprehensive ten-year cooperative study is attempted.

Importance of inflammatory and immune components in a mouse model of airway reactivity to toluene diisocyanate (TDI).

BACKGROUND: Nearly 9 million individuals are exposed to agents in the workplace associated with asthma, and isocyanates represent the most common cause of occupationally induced asthma. OBJECTIVES: Nonetheless, the immunological mechanisms responsible for isocyanate-induced asthma are not clear. A murine model for toluene diisocyanate (TDI) asthma is described and employed to examine inflammatory and immune components that may be involved in the disease. METHODS: Groups (n = 6) of C57BL/6J and athymic mice were sensitized by subcutaneous injection (20 microl on day 1, 5 microl on days 4 and 11), and 7 days later challenged by inhalation (100 p.p.b., days 20, 22 and 24) with TDI. Twenty-four hours following the last challenge the tracheae and lungs were examined for histological changes as well as for the expression of Th1, Th2 and pro-inflammatory cytokines. Mice were also examined for airway reactivity to methacholine challenge and for specific and total IgE and IgG antibodies. RESULTS: TDI sensitization resulted in increased reactivity to methacholine challenge as well as a significant inflammatory response in the trachea and nares of wild-type mice, but not in the athymic mice nor in the lungs of the C57BL/6J mice. Airway inflammation was characterized by inflammatory cell influx, goblet cell metaplasia and epithelial damage. Histological changes in the trachea were accompanied by increased mRNA expression of interleukin (IL)-4, tumour necrosis factor alpha, lymphotoxin beta, lymphotactin and Rantes, as well as TDI-specific IgG antibodies and elevated levels of total IgE. IgE-specific antibodies were not detected with this exposure regimen but were produced when the TDI concentrations were increased. CONCLUSIONS: These studies provide a unique murine model for occupational asthma that generates both inflammatory and immune mediators similar to those occurring in TDI-induced asthma in humans.

Results of ulnar neuropathy at the elbow treated by decompression or anterior transposition.

A retrospective study was conducted on 148 patients with ulnar neuropathy at the elbow, who underwent surgical treatment between 1981 and 1989. Of the 178 nerves operated on, 105 underwent subcutaneous anterior transposition, and 73 were decompressed without transposition. We compared the surgical results of these two groups, and factors influencing prognosis. Overall, 92% of patients improved postoperatively. Pre-operatively, electrophysiological assessment corresponded well to clinical findings, and to macroscopic findings at operation in 95% of cases. The severity of pre-operative clinical findings, advancing age, duration of symptoms and the presence of intraneural fibrosis did not predict an adverse outcome. A satisfactory outcome in 72% of those decompressed compared with 60% of those who were transposed was not statistically significant. However, there was a lower percentage of those with unsatisfactory results in the decompressed series. Thus, we advise that, except where there is persistent deformity or a mass lesion in the region of the ulnar groove, decompression is the operation of choice.

Thiopental sodium cerebral protection during carotid endarterectomy: perioperative disease and death.

PURPOSE: This study reports our experience with thiopental sodium (Pentothal) cerebral protection, without intraluminal shunting, during carotid endarterectomy. Only those complications that occurred during surgery or within 30 days of operation have been addressed. METHOD: A prospective, unselected, consecutive series of 621 carotid endarterectomies was done during a 7-year period, with electroencephalography-monitored, high-dose Pentothal for cerebral protection. RESULTS: Five ischemic strokes (0.8%), completion of two strokes-in-evolution (0.3%) and four strokes caused by cerebral hemorrhage (0.6%) occurred in 11 patients in the perioperative (30-day) period, for a combined cerebral morbidity-mortality rate of 1.7%. Four reversible ischemic neurologic deficits (0.6%) and two transient ischemic attacks (0.3%) in six patients produced a transient deficit rate of 0.9%. Symptomatic coronary artery disease coexisted in 37% of the patients but resulted in only five acute myocardial infarctions (0.7%), one of which was fatal (0.1%). Other perioperative complications in 10 patients (1.5%) were associated with the operative procedure. There were no complications directly attributable to the high-dose Pentothal. Prospective data collection has allowed definition of the disease and cause of all cerebral complications. CONCLUSION: The complications in this series have been related to surgical and clinical management problems rather than failure of cerebral protection. Cerebral protection with high-dose Pentothal under electroencephalographic control has been effective and complication free.

Retrospective survey of neurotraumatic admissions to a teaching hospital: comparison of data on head injuries after 10 to 16 years.

A retrospective survey of 1100 patients with head, spine, and cord injuries who were treated in The Prince Henry Hospital, and The Prince of Wales Hospital, Sydney, from January, 1960, to December, 1965, was published in The Medical Journal of Australia during 1967 and 1968. The present series of admissions from January, 1975, to December, 1976 comprises 179 head injury patients. The epidemiological data related to head injuries and specified in the two series are compared in the available details. The pattern of change in the structure of neurosurgical services is evaluated in relation to the ever-increasing neurological trauma on the roads of New South Wales. Growing numbers of patients with serious head injuries are treated in district and country hospitals in areas where neurosurgical consultative services cannot be obtained. The standards of treatment of these patients are unknown, and cannot be evaluated. The need for planning for better standards of care in district and country hospitals is stressed. A permanent system of statistical monitoring of all neurotrauma across the State is advocated. Organization of permanent postgraduate training courses in the management of acute neurotraumatic admissions, readily available to all those treating head injuries in the country hospitals is considered as a basic and imperative requirement.

Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice.

It has been postulated that an inflammatory response after cutaneous wounding is a prerequisite for healing, and inflammatory cytokines, such as interleukin-6 (IL-6), might be intimately involved in this process. IL-6-deficient transgenic mice (IL-6 KO) displayed significantly delayed cutaneous wound healing compared with wild-type control animals, requiring up to threefold longer to heal. This was characterized by minimal epithelial bridge formation, decreased inflammation, and granulation tissue formation. Using electrophoretic mobility shift assays of wound tissue from IL-6 KO mice, decreased AP-1 transcription factor activation was shown compared with wild-type mice 16 h after wounding. In situ hybridization of wound tissue from wild-type mice revealed IL-6 mRNA expression primarily in the epidermis at the leading edge of the wound. Delayed wound healing in IL-6 KO mice was reversed with a single dose of recombinant murine IL-6 or intradermal injection of an expression plasmid containing the full-length murine IL-6 cDNA. Treatment with rmIL-6 also reconstituted wound healing in dexamethasone-treated immunosuppressed mice. The results of this study may indicate a potential use for IL-6 therapeutically where cutaneous wound healing is impaired.