The structure and mode of action of different botulinum toxins

The seven serotypes (A–G) of botulinum neurotoxin (BoNT) are proteins produced by Clostridium botulinum and have multifunctional abilities: (i) they target cholinergic nerve endings via binding to ecto‐acceptors (ii) they undergo endocytosis/translocation and (iii) their light chains act intraneuronally to block acetylcholine release. The fundamental process of quantal transmitter release occurs by Ca²⁺‐regulated exocytosis involving sensitive factor attachment protein‐25 (SNAP‐25), syntaxin and synaptobrevin. Proteolytic cleavage by BoNT‐A of nine amino acids from the C‐terminal of SNAP‐25 disables its function, causing prolonged muscle weakness. This unique combination of activities underlies the effectiveness of BoNT‐A haemagglutinin complex in treating human conditions resulting from hyperactivity at peripheral cholinergic nerve endings. In vivo imaging and immunomicroscopy of murine muscles injected with type A toxin revealed that the extended duration of action results from the longevity of its protease, persistence of the cleaved SNAP‐25 and a protracted time course for the remodelling of treated nerve–muscle synapses. In addition, an application in pain management has been indicated by the ability of BoNT to inhibit neuropeptide release from nociceptors, thereby blocking central and peripheral pain sensitization processes. The widespread cellular distribution of SNAP‐25 and the diversity of the toxin's neuronal acceptors are being exploited for other therapeutic applications.     

Effects of acetaminophen on adverse effects of influenza vaccination in health care workers.

OBJECTIVE: To evaluate the effects of acetaminophen on the incidence of adverse effects to, and the immunogenicity of, whole-virus influenza vaccine in health care workers. DESIGN: Prospective, randomized, double-blind placebo-controlled trial. SETTING: Health Sciences Centre, an acute care teaching hospital in Winnipeg. PARTICIPANTS: Of 474 hospital personnel who agreed to undergo influenza vaccination during the 1990-91 season 262 volunteered to participate in the study. INTERVENTIONS: A dose of 0.5 mL of inactivated trivalent whole-virus influenza vaccine was injected into the deltoid muscle. Volunteers were randomly assigned to ingest two capsules of acetaminophen in a half dose (162.5 mg per capsule) or a full dose (325 mg per capsule) or two identical placebo capsules. Capsules were to be taken at vaccination and at 4, 8 and 12 hours afterward. Subjects were asked to answer questions regarding six symptoms in a diary for the 3 days after vaccination and to record their ingestion of the study medication. MAIN OUTCOME MEASURES: Incidence of local (sore arm) and systemic (headache, fever, muscle ache, nausea and diarrhea) side effects as well as serum titres of hemagglutination inhibition (HAI) antibody to vaccine antigens before vaccination and 2 weeks and 6 months afterward. RESULTS: A total of 87, 87 and 88 subjects received the half dose, full dose and placebo respectively; 96% returned the diaries, 83% ingested all four doses of medication, and 87% volunteered all blood samples. Compared with the placebo group the incidence of sore arm was 25% to 28% lower in the half-dose and full-dose groups respectively at 24 hours after vaccination, and the rate of nausea was 90% lower in the full-dose group. The HAI titres were similar among the groups at the three test times. CONCLUSIONS: The full dose of acetaminophen significantly reduced the incidence of sore arm and nausea without affecting the antibody response. Acetaminophen use may increase the acceptance of influenza vaccine by health care workers in whom concern about side effects is an impediment to vaccination.     

Long-term results of open reduction for residual subluxation in congenital dislocation of the hip: A new open reduction method involving 360° circumferential capsulotomy

We report satisfactory results with a new operative treatment, conducted via an extensive anterolateral approach, involving 360 degree circumferential capsulotomy, for residual subluxation in congenital dislocation of the hip (CDH). Long-term radiographic results of this procedure (group A) were compared retrospectively with the results of partial capsulotomy (group B), which preserved the posteroinferior joint capsule. The mean center edge angle in group A (22.5°) was greater than that in group B (16.0°). Satisfactory results were achieved in 11 of 15 hips (73%) (Severin class I or II) in group A, and in 5 of 12 hips (42%) in group B. These results suggest that whole circumferential capsulotomy can remove obstacles to complete reduction, and that acetabular development can be expected in hips reduced by the procedure, without the performance of innominate osteotomy. We believe that our technique is a useful alternative for the treatment of residual subluxation in CDH.     

Mechanisms of pinacidil-induced vasodilatation

The mechanism of the vasodilator effect of pinacidil was examined. Pinacidil (0.1–100 μM) inhibited the increases in cytosolic Ca²⁺ ([Ca²⁺]_i) and muscle tension due to norepinephrine in rat aorta. In contrast, a Ca²⁺ channel blocker, verapamil, inhibited the norepinephrine-stimulated [Ca²⁺]_i more strongly than the contraction. Higher concentrations of pinacidil (3–100 μM) inhibited the verapamil-insensitive portion of the contraction and [Ca²⁺]_i. An inhibitor of ATP-sensitive K⁺ channels, glibenclamide, antagonized the inhibitory effect of low concentrations ( 10 pM) of pinacidol. Pinacidil did not change the contraction induced by Ca²⁺ in vascular smooth muscle permeabilized with Staphylococcus aureus -toxin. Norepinephrine (in the presence of GTP), 12-deoxyphorbol 13-isobutyrate (in the absence of GTP), and treatment with GTP_γS potentiated the contraction of permeabilized smooth muscle induced by the addition of Ca²⁺. Pinacidil (100 μM) inhibited the potentiation due to GTP_γS or noepinephrine but not to phorbol ester. These results suggest that pinacidil has dual effects on vascular smooth muscle contraction. At lower concentrations (>0.1 μM), it decreases [Ca²⁺]_i, possibly by activating ATP-sensitive K+ channels. At higher concentrations (> 3 μM), it may additionally inhibit the receptor-mediated, GTP-binding protein-coupled phosphatidyl inositol turnover.     

Transient Brain Ischaemia Provokes Ca2+, PIP2 and Calpain Responses Prior to Delayed Neuronal Death in Monkeys

To clarify the mechanism of postischaemic delayed cornu Ammonis (CA)-1 neuronal death, we studied correlations among calpain activation and its subcellular localization, the immunoreactivity of phosphatidylinositol 4,5-bisphosphate (PIP₂) and Ca²⁺ mobilization in the monkey hippocampus by two independent experimental approaches: in vivo transient brain ischaemia and in vitro hypoxia-hypoglycaemia of hippocampal acute slices. The CA-1 sector undergoing 20 min of ischaemia in vivo showed microscopically a small number of neuronal deaths on day 1 and almost global neuronal loss on day 5 after ischaemia. Immediately after ischaemia, CA-1 neurons ultrastructurally showed vacuolation and/or disruption of the lysosomes. Western blotting using antibodies against inactivated or activated μ-calpain demonstrated μ-calpain activation specifically in the CA-1 sector immediately after ischaemia. This finding was confirmed in the perikarya of CA-1 neurons by immunohistochemistry. CA-1 neurons on day 1 showed sustained activation of μ-calpain, and increased immunostaining for inactivated and activated forms of μ- and m-calpains and for PIP₂. Activated μ-calpain and PIP₂ were found to be localized at the vacuolated lysosomal membrane or endoplasmic reticulum and mitochondrial membrane respectively, by immunoelectron microscopy. Calcium imaging data using hippocampal acute slices showed that hypoxia-hypoglycaemia in vitro provoked intense Ca²⁺ mobilization with increased PIP₂ immunostaining specifically in CA-1 neurons. These data suggest that transient brain ischaemia increases intracellular Ca²⁺ and PIP₂ breakdown, which will activate calpain proteolytic activity. Therefore, we suggest that activated calpain at the lysosomal membrane, with the possible release of biodegrading enzyme, will cause postischaemic CA-1 neuronal death.     

Computed tomography features immediately after replacement of haematoma with oxygen through percutaneous subdural tapping for the treatment of chronic subdural haematoma in adults

Summary In an effort to achieve a simple and less invasive method for the treatment of chronic subdural haematoma, replacement of the haematoma with oxygen by percutaneous subdural tapping was employed in 36 patients. This study was conducted on 23 haematomas in 20 patients, whose computed tomography (CT) scans immediately following the treatment were available for evaluation, with particular regard to distinguishing between their findings and those seen with tension pneumocephalus. The CT features werde divided into two patterns according to the location of oxygen; a convexity type (19 haematomas) and an interhemispheric type (4 haematomas). Analysis of the CT appearances revealed the oxygen was exclusively confined to the haematoma cavity, distinguishing it from the findings in tension pneumocephalus. This observation indicates the safety of replacement of the haematoma with oxygen when combined with our percutaneuous subdural tapping technique which prevents lesions of the inner haematoma membrane.     

Jejunal carcinoma with adenoma —Report of a case and review of the Japanese literature—

A rare case of jejunal carcinoma coexisting with adenoma, situated 120 cm distal to the ligament of Treitz in a 53 year old male, is reported herein. We also review cases of adenoma and carcinoma in the jejunum and ileum from the Japanese literature, and discuss the histogenesis of carcinoma of the jejunum and ileum.     

The role of magnetic resonance cholangiopancreatography (MRCP) after resection of the pancreas

Magnetic resonance cholangiopancreatography (MRCP) was performed in 35 patients to evaluate the feasibility of its use as a postsurgical imaging technique after resection of the pancreas. The surgical procedures performed were: pancreatoduodenectomy in 22 patients, segmental pancreatectomy in 1, distal pancreatectomy in 7, and pyroluspreserving pancreatoduodenectomy in 5. The pancreatic duct was shown in its entirety in 24 of the 35 patients (68.6%) and was partially visualized in 8 patients (22.9%), but the intrahepatic and extrahepatic bile ducts were visualized completely in all patients. Furthermore, MRCP was able to demonstrate lesions in 3 of 6 patients who had shown clinical evidence of recurrence. The visualization of the pancreatic and bile duct system was satisfactory despite anatomical changes brought about by resection of the pancreas. Thus, we conclude that MRCP is an appropriate follow-up screening test for patients with suspected abnormalities of the biliary and pancreatic duct system.     

Maffucci’s syndrome associated with spindle cell hemangioendothelioma

 The case of a 49-year-old man with Maffucci’s syndrome, who developed multiple spindle cell hemangioendotheliomas, is presented. The case provides support for recent reports suggesting an association between this peculiar vascular lesion and skeletal enchondromatosis.     

EFFECTS OF ACUTE SUPERIOR CERVICAL GANGLIONECTOMY ON CEREBRAL BLOOD FLOW AND METABOLISM IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS SUBJECTED TO CEREBRAL ISCHAEMIA

1. The effects of acute bilateral superior cervical ganglionectomy on cerebral blood flow and metabolism were investigated in stroke-prone spontaneously hypertensive rats (SHRsp), before and during cerebral ischaemia. 2. The resting cerebral blood flow was comparable between the control and denervated animals. 3. There was no significant difference in cerebral blood flow or concentration of tissue energy metabolites (adenosine triphosphate [ATP], lactate and pyruvate) between the sham-operated control and denervated animals during ischaemia. 4. The results suggest that sympathetic innervation of cerebral vessels originating from superior cervical ganglia may not play a major role in the progression of cerebral ischaemia in SHRsp.