Biomedical subjects
Publications and source records attributed to N K Patel.
This paper describes a new application for radiofrequency ablation in head and neck surgery. Two patients with extensive laryngeal papillomata were successfully treated using this technology. The technique is described in detail, highlighting the main benefits of this approach as compared with existing techniques. These advantages include limited damage to underlying tissues and a bloodless field.
A novel hydrocolloidal polymer, methylcellulose glutarate (MC-GA), was prepared by esterifying methylcellulose with glutaric anhydride. The formation of ester was confirmed by FTIR and NMR spectroscopy, DSC and elemental analysis. The physicochemical properties such as, rate of swelling in water, viscosity and hygroscopicity of MC-GA were determined and compared with those of methycellulose A (MC). Aspirin, theophylline and atenolol tablets were compacted on a Carver press using the wet granulation method. Each tablet contained: 200 mg active, 80 mg anhydrous lactose, 8 mg povidone, 4 mg magnesium stearate, 4 mg talc, 50mg MC or MC-GA (drug-to-polymer ratio, 4:1). Contrary to the first-order release profile of all the drugs from the MC matrix tablets, a zero-order release was obtained from the MC-GA matrix tablets in water.
The role of trigeminal ganglion percutaneous injection and radio-frequency lesioning procedures for the treatment of trigeminal neuralgia (TGN) in multiple sclerosis (MS) is well established. There is general acceptance that microvascular decompression (MVD) cannot be an appropriate treatment due to the view that the underlying aetiology is a demyelinating plaque affecting the root entry zone of the trigeminal pathway. Recently, MR-imaging has been used in the preoperative investigation of this group of patients demonstrating that neurovascular compression can occasionally be the responsible mechanism and that MVD can be the treatment of choice. We present five cases with MS and TGN. All the patients had failed to respond to medical treatment or percutaneous procedures. Magnetic resonance imaging demonstrated evidence of neurovascular compression in four cases. All the patients underwent MVD. Postoperatively four of the five patients made an uncomplicated recovery, were pain-free and fully satisfied with the result (mean follow-up 38.75 months; range 8-59 months). One patient developed recurrent pain 1 week following surgery and went on to have a total sensory rhizotomy. TGN in MS can be caused by neurovascular compression, which may be identified on MR-imaging. MVD has offered satisfactory short-term outcome for at least 2 years and does not inflict sensory loss. Longer follow-up will determine whether the outcome in MS patients will be as successful as in the TGN patients who do not suffer from MS.
OBJECTIVE: Bilateral chronic high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as an appropriate therapy for patients with advanced Parkinson's disease refractory to medical therapy. Advances in neuroimaging and neurophysiology have led to the development of varied targeting methods for the delivery of this treatment. Intraoperative neurophysiological and clinical monitoring is regarded by many to be mandatory for accurate STN localisation. We have examined efficacy of bilateral STN stimulation using a predominantly magnetic resonance imaging (MRI)-directed technique. METHODS: DBS leads were stereotactically implanted into the STN using an MRI directed method, with intraoperative macrostimulation used purely for adjustment. The effects of DBS were evaluated in 16 patients followed up to 12 months, and compared with baseline assessments. Assessments were performed in both off and on medication states, and were based on the Unified Parkinson's Disease Rating Scale (UPDRS) and timed motor tests. Functional status outcomes were examined using the PDQ-39 quality of life questionnaire. A battery of psychometric tests was used to assess cognition. RESULTS: After 12 months, stimulation in the off medication state resulted in significant improvements in Activities of Daily Living and Motor scores (UPDRS parts II and III) by 62% and 61% respectively. Timed motor tests were significantly improved in the off medication state. Motor scores (UPDRS part III) were significantly improved by 40% in the on medication state. Dyskinesias and off duration were significantly reduced and the mean dose of L-dopa equivalents was reduced by half. Psychometric test scores were mostly unchanged or improved. Adverse events were few. CONCLUSIONS: An MRI directed targeting method for implantation of DBS leads into the STN can be used safely and effectively, and results are comparable with studies using intraoperative microelectrode neurophysiological targeting. In addition, our method was associated with an efficient use of operating time, and without the necessary costs of microelectrode recording.
Ninety-two patients with trigeminal neuralgia (TGN) were investigated prior to posterior fossa surgery with magnetic resonance imaging (MRI) and contrast-enhanced magnetic resonance angiography (MRA). The preoperative investigation was matched to one consultant neuroradiologist (co-author) who was blinded to the side of symptomotology. The imaging results were compared with the operative findings in all patients. In 76 patients MRA showed present neurovascular compression in accordance with surgical findings. Eight cases had no compression either on MRA or intraoperatively. Eight predictions of no compression were false and there was no false positive. Based on surgical findings, the sensitivity of MRA was 90.5% and the specificity 100%. In 19 cases MRA predicted bilateral compression of the trigeminal nerves. Only two cases had clinically bilateral TGN. We conclude that MRA with gadolinium enhancement is an extremely sensitive and specific method for demonstrating compression in TGN. As a result posterior fossa surgery can be recommended with confidence, and microvascular decompression remains the treatment of choice for TGN at the authors' centre.
AIMS: To determine whether the presence and location of giant cells or granulomas in relation to crypts distinguishes between ulcerative colitis and Crohn's disease. METHODS AND RESULTS: Twenty-nine large bowel mucosal biopsy specimens showing giant cells and/or granulomas in a background more typical of ulcerative colitis than Crohn's disease were collected between 1986 and 1996. Each was subject to detailed independent analysis by three histopathologists. Follow-up of the cases was by examination of all previous and subsequent gastrointestinal surgical or biopsy material and by scrutiny of the clinical notes by a gastroenterologist. On the basis of the accumulated histological data 10 of these 29 cases were accorded the diagnosis of ulcerative colitis. In nine of these 10 cases the clinical diagnosis, where known, was in keeping with this and all nine contained only crypt-associated giant cells and/or granulomas. The tenth case contained a solitary free-standing granuloma and clinically the patient had perianal disease, suggesting that the true diagnosis was Crohn's disease. CONCLUSIONS: Isolated giant cells and well-defined epithelioid granulomas distant from crypts do not, as a rule, occur in ulcerative colitis, and hence their presence in a colonoscopic biopsy showing features of chronic inflammatory bowel disease is a strong pointer towards the diagnosis of Crohn's disease. Crypt-associated giant cells and granulomas can occur in ulcerative colitis and in themselves are unreliable features for the discrimination between Crohn's disease and ulcerative colitis.
Consent to autopsy is usually obtained by a doctor other than the one who will perform the procedure. There is an argument that, for proper informed consent, a pathologist should participate. We ascertained the views of consultant pathologists in south-east England. 53 (87%) of 61 consultants responded, of whom 50 currently do autopsies. Only 2 at present participate directly in obtaining consent, and 10 of the remaining 48 expressed willingness to do so. The general view was that consent is best obtained by a senior clinician from the team that has looked after the patient. Pathologists see their primary role as to provide guidance to clinicians. Few see it as their function to obtain consent for autopsy.
Decorin binding protein A (DbpA) has been shown by several laboratories to be a protective antigen for the prevention of experimental Borrelia burgdorferi infection in the mouse model of Lyme borreliosis. However, different recombinant forms of the antigen having either lipidated amino termini, approximating the natural secretion and posttranslational processing, or nonprocessed cytosolic forms have elicited disparate levels of protection in the mouse model. We have now used the unique functional properties of this molecule to investigate the structural requirements needed to elicit a protective immune response. Genetic and physicochemical alterations to DbpA showed that the ability to bind to the ligand decorin is indicative of a potent immunogen but is not conclusive. By mutating the two carboxy-terminal nonconserved cysteines of DbpA from B. burgdorferi strain N40, we have determined that the stability afforded by the putative disulfide bond is essential for the generation of protective antibodies. This mutated protein was more sensitive to thermal denaturation and proteolysis, suggesting that it is in a less ordered state. Immunization with DbpA that was thermally denatured and functionally inactivated stimulated an immune response that was not protective and lacked bactericidal antibodies. Antibodies against conformationally altered forms of DbpA also failed to kill heterologous B. garinii and B. afzelii strains. Additionally, nonsecreted recombinant forms of DbpA(N40) were found to be inferior to secreted lipoprotein DbpA(N40) in terms of functional activity and antigenic potency. These data suggest that elicitation of a bactericidal and protective immune response to DbpA requires a properly folded conformation for the production of functional antibodies.
Injecting drug users frequently use accident and emergency (A&E) departments to access emergency care for local and systemic infections. Clostridium novyi type A is a bacterium that has recently been associated with a number of fatalities among drug injecting addicts. The clinical course is described of a patient who attended an A&E department with septicaemia who was found at postmortem examination to have been infected with Clostridium novyi type A. Doctors working in A&E departments should be aware of the existence of this infection and be vigilant when treating injecting drug users with localised infection.
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The urokinase-type plasminogen activator (uPA) system has been implicated in tumor spread. We have used immunohistochemistry to examine three components of this system, ie, uPA, uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1), in a pilot study on 142 cases of breast carcinoma. We wished to determine whether there were any relationships between expression of the proteins in either tumor cells or fibroblasts and clinical and pathological features. Strong uPA expression in each cell type was significantly related to high tumor grade (P = 0.013 and 0.008, respectively), and was more common in invasive than in in situ carcinomas (P < 0.0001). Fibroblastic expression of uPAR was only related to the presence of invasion (P < 0.0001). Strong PAI-1 expression in both cell types was seen in high-grade tumors (tumor cells, P = 0.012; fibroblasts, P < 0.001), but only fibroblastic expression was related to the presence of invasion (P = 0.042). Fibroblastic expression of both uPA and uPAR were positively correlated with tumor size. Although patients with strong fibroblastic expression of uPA showed a tendency toward a shorter time to relapse, none of the plasminogen activator proteins were significantly associated with relapse-free survival. These results suggest that strong expression of uPA, uPAR, and PAI-1 in fibroblasts rather than in tumor cells have the most impact on the clinical behavior of breast cancer. Larger prospective studies are needed to confirm these findings.
Mice immunized with either the predominantly vector-stage lipoprotein outer surface protein A (OspA) or the in vivo-expressed lipoprotein decorin binding protein A (DbpA) are protected against Borrelia burgdorferi challenge. DbpA-OspA combinations protected against 100-fold-higher challenge doses than did either single-antigen vaccine and conferred significant protection against heterologous B. burgdorferi, B. garinii, and B. afzelii isolates, suggesting that there is synergy between these two immunogens.
BACKGROUND: Premenopausal breast carcinoma patients who undergo tumor excision during the follicular phase of their menstrual cycle may have a significantly worse prognosis than those whose tumors are excised in other phases of the menstrual cycle. METHODS: Outcome was determined in a series of 112 premenopausal women with operable breast carcinoma in relation to the timing of surgery within the menstrual cycle and the estrogen receptor (ER) and progesterone receptor (PR) status of their primary tumors as determined by immunohistochemistry. RESULTS: Those patients with ER positive tumors who underwent surgery in the early and luteal phase of the cycle had a significantly better survival than women with ER negative tumors (chi-square test = 15.56; P < 0.001). This also was true for PR status (chi-square test = 18.21; P < 0.001). After follicular phase surgery, tumor receptor status had no effect on overall survival. Patients with the best prognosis had ER/PR positive tumors excised on Days 0-2 and 13-32 but even those women with ER or PR negative tumors removed during the luteal phase of their menstrual cycle fared better than patients whose tumors were removed during the follicular phase. CONCLUSIONS: There was a better survival rate for patients with both ER/PR positive and negative tumors treated during the luteal phase of the menstrual cycle. This could be the result of progesterone acting on the surrounding peritumoral normal tissue, thereby exerting a straitjacket effect and improving cohesion of the primary carcinoma. Unopposed estrogen in the follicular phase of the cycle may enable more tumor emboli to escape and successfully establish micrometastases.
The study was designed to investigate the feasibility of developing a transdermal drug dosage form of promethazine hydrochloride (PMH). The in vitro release and diffusion characteristics of PMH from various dermatological polymeric bases were studied using cellulose membrane and hairless mouse skin as the diffusion barriers. These included polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), cross-linked microcrystalline cellulose, and carboxyl methyl cellulose sodium (Avicel CL-611), and a modified hydrophilic ointment USP. In addition, the effects of several additive ingredients known to enhance the drug release from topical formulations were evaluated. The general rank order for the drug release from these formulations using cellulose membrane was observed to be PEG > HMPC > Avicel CL-611 > hydrophilic ointment base. The inclusion of the additives had little or no effect on the drug diffusion from these bases, except for the hydrophilic ointment formulation containing 15% ethanol, which provided a significant increase in the drug release. However, when these formulations were studied for drug diffusion through the hairless mouse skin, the Avicel CL-611 base containing 15% ethanol exhibited the optimum drug release. The data also revealed that this formulation gave the highest steady-state flux, diffusion, and permeability coefficient values and correlated well with the amount of drug release.
The cell cycle-associated retinoblastoma protein (pRb) and p16 protein were demonstrated using immuno-histochemistry on paraffin sections from 192 cases of invasive breast carcinoma. Abnormal expression of pRb was defined as negative staining and was seen in 17% of tumours. Such abnormal expression was significantly more frequent in tumours with negative oestrogen receptor (ER) status. There was also a trend for tumours which were negative for pRb to be grade III ductal carcinomas. There was no association between p16 staining and any histopathological parameter, though, surprisingly, log-rank analysis showed that strong staining was associated with a poor outcome. There was a significant inverse relationship between pRb and p16 expression and a significant positive association between pRb and cyclin D1. In a Cox multivariate analysis, which included cyclin D1, neither pRb nor p16 was an independent predictor of patient outcome.
Epithelioid hemangioendothelioma arising in the skin is extremely rare, and the majority of documented cases have developed in association with an underlying bone tumor. We report eight patients with an age range of 29-84 years (mean 53), who presented with primary cutaneous tumors at a variety of sites including the palm, shin, neck, knee, nose, back, and penis with a duration of between 6 and 12 months. Histologically, all eight cases presented as circumscribed nodules with an overlying acanthotic epidermis, three showing striking acrosyringeal proliferation, reminiscent of eccrine syringofibroadenoma. The tumors were composed of an admixture of slightly pleomorphic spindle and epithelioid cells with abundant, sharply defined eosinophilic cytoplasm and vesicular nuclei containing single nucleoli. Mitoses were generally sparse. All tumors showed intracytoplasmic lumina and intraluminal erythrocytes were occasionally apparent. The tumor cells were embedded in a myxoid or hyaline matrix. In contrast to visceral lesions, a vascular origin was not evident in any of our cases. The tumor cells variably expressed CD31, CD34, factor VIII-Rag, and smooth-muscle actin but not pankeratin or epithelial membrane antigen. Follow-up ranged from 4 months to 3 years. None of the lesions has thus far recurred and there have been no metastases.
DbpA is a target for antibodies that protect mice against infection by cultured Borrelia burgdorferi. Infected mice exhibit early and sustained humoral responses to DbpA and DbpB, suggesting that these proteins are expressed in vivo. Many antigens expressed in mammals by B. burgdorferi are repressed in vitro at lower growth temperatures, and we have now extended these observations to include DbpA and DbpB. To confirm that the protective antigen DbpA is expressed in vivo and to address the question of its accessibility to antibodies during infection, we examined B. burgdorferi in blood samples from mice following cutaneous inoculation. B. burgdorferi was visualized by dark-field microscopy in plasma samples from spirochetemic mice, and an indirect immunofluorescence assay showed that these spirochetes were DbpA positive and OspA negative. We developed an ex vivo borreliacidal assay to show that hyperimmune antiserum against DbpA, but not OspA, killed these plasma-derived spirochetes, demonstrating that DbpA is accessible to antibodies during this phase of infection. Blood transferred from spirochetemic donor mice readily established B. burgdorferi infection in naive recipient mice or mice hyperimmunized with OspA, while mice hyperimmunized with DbpA showed significant protection against challenge with host-adapted spirochetes. Antiserum from persistently infected mice had borreliacidal activity against both cultured and plasma-derived spirochetes, and adsorption of this serum with DbpA substantially depleted this killing activity. Our observations show that immunization with DbpA blocks B. burgdorferi dissemination from the site of cutaneous inoculation and suggest that DbpA antibodies may contribute to control of persistent infection.
Borrelia burgdorferi, the spirochete that causes Lyme disease, binds decorin, a collagen-associated extracellular matrix proteoglycan found in the skin (the site of entry for the spirochete) and in many other tissues. Two borrelial adhesins that recognize this proteoglycan, decorin binding proteins A and B (DbpA and DbpB, respectively), have recently been identified. Infection of mice by low-dose B. burgdorferi challenge elicited antibodies against DbpA and DbpB that were sustained at high levels, suggesting that these antigens are expressed in vivo. Scanning immunoelectron microscopy showed that DbpA was surface accessible on intact borreliae. Passive administration of DbpA antiserum protected mice from infection following challenge with heterologous B. burgdorferi sensu stricto isolates, even when serum administration was delayed for up to 4 days after challenge. DbpA is the first antigen target identified that is capable of mediating immune resolution of early, localized B. burgdorferi infections. DbpA immunization also protected mice from B. burgdorferi challenge; DbpB immunization was much less effective. DbpA antiserum inhibited in vitro growth of many B. burgdorferi sensu lato isolates of diverse geographic, phylogenetic, and clinical origins. In combination, these findings support a role for DbpA in the immunoprophylaxis of Lyme disease and suggest that DbpA vaccines have the potential to eliminate early-stage B. burgdorferi infections.