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1.
Healthcare (Basel) ; 11(23)2023 Nov 28.
Article in English | MEDLINE | ID: mdl-38063628

ABSTRACT

BACKGROUND: The application of enhanced recovery after surgery principles decreases postoperative complications (POCs), length of stay (LOS), and readmissions. Pharmacoprophylaxis decreases morbidity, but the effect of specific regimens on clinical outcomes is unclear. METHODS AND MATERIALS: Records of 476 randomly selected adult patients who underwent elective colorectal surgeries (ECRS) at 10 US hospitals were abstracted. Primary outcomes were surgical site infection (SSI), venous thromboembolism (VTE), postoperative nausea and vomiting (PONV), pain, and ileus rates. Secondary outcomes included LOS and 7- and 30-day readmission rates. RESULTS: POC rates were SSI (3.4%), VTE (1.5%), PONV (47.9%), pain (58.1%), and ileus (16.1%). Cefazolin 2 g/metronidazole 500 mg and ertapenem 1 g were associated with the shortest LOS; cefotetan 2 g and cefoxitin 2 g with the longest LOS. No SSI occurred with ertapenem and cefotetan. More Caucasians than Blacks received oral antibiotics before intravenous antibiotics without impact. Enoxaparin 40 mg subcutaneously daily was the most common inpatient and discharge VTE prophylaxis. All in-hospital VTEs occurred with unfractionated heparin. Most received rescue rather than around-the-clock antiemetics. Scopolamine patches, spinal opioids, and IV lidocaine continuous infusion were associated with lower PONV. Transversus abdominis plane block with long-acting local anesthetics, celecoxib, non-anesthetic ketamine bolus, ketorolac IV, lidocaine IV, and pregabalin were associated with lower in-hospital pain severity rates. Gabapentinoids and alvimopan were associated with lower ileus rates. Acetaminophen, alvimopan, famotidine, and lidocaine patches were associated with shorter LOS. CONCLUSIONS: Significant differences in pharmacotherapy regimens that may improve primary and secondary outcomes in ECRS were identified. In adult ECRS, cefotetan or ertapenem may be better regimens for preventing in-hospital SSI, while ertapenem or C/M may lead to shorter LOS. The value of OA to prevent SSI was not demonstrated. Inpatient enoxaparin, compared to UFH, may reduce VTE rates with a similar LOS. A minority of patients had a documented PONV risk assessment, and a majority used as-needed rather than around-the-clock strategies. Preoperative scopolamine patches continued postoperatively may lower PONV and PDNV severity and shorter LOS. Alvimopan may reduce ileus and shorten LOS. Anesthesia that includes TAP block, ketorolac IV, and pregabalin use may lead to reduced pain rates. Acetaminophen, alvimopan, famotidine, and lidocaine patches may shorten LOS. Given the challenges of pain management and the incidence of PONV/PDNV found in this study, additional studies should be conducted to determine optimal opioid-free anesthesia and the benefit of newer antiemetics on patient outcomes. Moreover, future research should identify latent pharmacotherapy variables that impact patient outcomes, correlate pertinent laboratory results, and examine the impact of order or care sets used for ECRS at study hospitals.

2.
Eur Urol ; 82(5): 512-515, 2022 11.
Article in English | MEDLINE | ID: mdl-35688662

ABSTRACT

The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47-1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36-0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63-3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor-targeted agents, which should be evaluated in prospective trials. PATIENT SUMMARY: The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamides , Disease-Free Survival , Docetaxel/therapeutic use , Humans , Male , Nitriles/therapeutic use , Phenylthiohydantoin , Phosphatidylinositol 3-Kinases , Prospective Studies , Prostatic Neoplasms, Castration-Resistant/pathology , Proto-Oncogene Proteins c-akt , Pyrimidines , Pyrroles , Receptors, Androgen , Treatment Outcome
3.
Vasc Health Risk Manag ; 17: 771-778, 2021.
Article in English | MEDLINE | ID: mdl-34880620

ABSTRACT

INTRODUCTION: Neuromuscular stimulation (NMES) has been shown to improve peripheral blood flow in healthy people. We investigated the effect of bilateral leg NMES on the symptoms of chronic venous disease. METHODS: Forty subjects were recruited from four groups: healthy, superficial insufficiency, deep insufficiency, and deep obstruction. Haemodynamic venous measurements were taken from the right femoral vein with ultrasound, laser Doppler fluximetry from the left hand and foot. Devices were then worn for 4-6 hours per day, for 6 weeks. Haemodynamic measurements were repeated at week 6. Quality of life questionnaires were taken at week 0, 6 and 8. RESULTS: The mean age was 48.7, BMI 28.6kg/m2, and maximum calf circumference 39.0 cm. Twenty-four subjects were men. NMES increased femoral vein peak velocity, TAMV and volume flow by 55%, 20%, 36% at 20 minutes (all p<0.05), which was enhanced at week 6 (PV and TAMV p<0.05). Mean increases in arm and leg fluximetry were 71% and 194% (both p<0.01). Leg swelling was reduced by mean 252.7 mL (13%, p<0.05) overall; 338.9 mL (16%, p<0.05) in venous disease. For those with venous pathology, scores for disease specific and generic quality of life questionnaires improved. Those with C4-6 disease benefitted the most, with improvements in VDS score of 1, AVVQ of 6, and SF-12 of 10. CONCLUSION: NMES improves venous haemodynamic parameters in chronic venous disease, which is enhanced by regular use. NMES reduces leg oedema, improves blood supply to the skin of the foot, and may positively affect quality of life. CLINICAL TRIALS: This trial was registered with www.clinicaltrials.org.uk (NCT02137499).


Subject(s)
Electric Stimulation/methods , Leg/blood supply , Vascular Diseases/therapy , Venous Insufficiency/therapy , Adult , Chronic Disease , Female , Humans , Male , Middle Aged , Muscle Contraction/physiology , Pilot Projects , Quality of Life , Research Subjects , Ultrasonography , Venous Insufficiency/diagnostic imaging
4.
Psychooncology ; 29(10): 1514-1523, 2020 10.
Article in English | MEDLINE | ID: mdl-32458473

ABSTRACT

OBJECTIVE: Troublesome hot flushes and night sweats (HFNS) are experienced by many women after treatment for breast cancer, impacting significantly on sleep and quality of life. Cognitive behavioural therapy (CBT) is known to be effective for the alleviation of HFNS. However, it is not known if it can effectively be delivered by specialist nurses. We investigated whether group CBT, delivered by breast care nurses (BCNs), can reduce the impact of HFNS. METHODS: We recruited women with primary breast cancer following primary treatment with seven or more HFNS/week (including 4/10 or above on the HFNS problem rating scale), from six UK hospitals to an open, randomised, phase 3 effectiveness trial. Participants were randomised to Group CBT or usual care (UC). The primary endpoint was HFNS problem rating at 26 weeks after randomisation. Secondary outcomes included sleep, depression, anxiety and quality of life. RESULTS: Between 2017 and 2018, 130 participants were recruited (CBT:63, control:67). We found a 46% (6.9-3.7) reduction in the mean HFNS problem rating score from randomisation to 26 weeks in the CBT arm and a 15% (6.5-5.5) reduction in the UC arm (adjusted mean difference -1.96, CI -3.68 to -0.23, P = .039). Secondary outcomes, including frequency of HFNS, sleep, anxiety and depression all improved significantly. CONCLUSION: Our results suggest that specialist nurses can be trained to deliver CBT effectively to alleviate troublesome menopausal hot flushes in women following breast cancer in the NHS setting.


Subject(s)
Anxiety/therapy , Breast Neoplasms/complications , Breast Neoplasms/therapy , Cognitive Behavioral Therapy/methods , Depression/therapy , Hot Flashes/therapy , Nurses/psychology , Sweating , Adult , Aged , Anxiety/etiology , Anxiety/psychology , Breast Neoplasms/psychology , Depression/etiology , Depression/psychology , Female , Hot Flashes/etiology , Hot Flashes/psychology , Humans , Middle Aged , Psychotherapy, Group , Quality of Life , Sleep , Surveys and Questionnaires , Sweat , Treatment Outcome
5.
J Vasc Surg ; 71(6): 2170-2176, 2020 06.
Article in English | MEDLINE | ID: mdl-31882314

ABSTRACT

BACKGROUND: Median arcuate ligament syndrome (MALS) describes the clinical presentation associated with direct compression of the celiac artery by the median arcuate ligament. The poorly understood pathophysiologic mechanism, variable symptom severity, and unpredictable response to treatment make MALS a controversial diagnosis. METHODS: This review summarizes the literature pertaining to the pathophysiologic mechanism, presentation, diagnosis, and management of MALS. A suggested diagnostic workup and treatment algorithm are presented. RESULTS: Individuals with MALS present with signs and symptoms of foregut ischemia, including exercise-induced or postprandial epigastric pain, nausea, vomiting, and weight loss. Consideration of MALS in patients' diagnostic workup is typically delayed. Currently, no group consensus agreement as to the diagnostic criteria for MALS exists; duplex ultrasound, angiography, and gastric exercise tonometry are used in different combinations and with varying diagnostic values throughout the literature. Surgical management involves decompression of the median arcuate ligament's constriction of the celiac artery; robotic, laparoscopic, endoscopic retroperitoneal, and open surgical intervention can provide effective symptom relief, but long-term follow-up data (>5 years) are lacking. Patients treated nonoperatively appear to have worse outcomes. CONCLUSIONS: MALS is an important clinical entity with significant impact on affected individuals. Presenting symptoms, patient demographics, and radiologic signs are generally consistent, as is the short-to medium-term (<5 years) response to surgical intervention. Future prospective studies should directly compare long-term symptomatic and quality of life outcomes after nonoperative management with outcomes after open, laparoscopic, endoscopic retroperitoneal, and robotic celiac artery decompression to enable the development of evidence-based guidelines for the management of MALS.


Subject(s)
Celiac Artery , Decompression, Surgical , Ligaments/surgery , Median Arcuate Ligament Syndrome/surgery , Mesenteric Ischemia/surgery , Mesenteric Vascular Occlusion/surgery , Celiac Artery/diagnostic imaging , Celiac Artery/physiopathology , Constriction, Pathologic , Decompression, Surgical/adverse effects , Humans , Ligaments/diagnostic imaging , Median Arcuate Ligament Syndrome/complications , Median Arcuate Ligament Syndrome/diagnostic imaging , Median Arcuate Ligament Syndrome/physiopathology , Mesenteric Ischemia/diagnostic imaging , Mesenteric Ischemia/etiology , Mesenteric Ischemia/physiopathology , Mesenteric Vascular Occlusion/diagnostic imaging , Mesenteric Vascular Occlusion/etiology , Mesenteric Vascular Occlusion/physiopathology , Splanchnic Circulation , Treatment Outcome , Vascular Patency
6.
BMC Womens Health ; 18(1): 63, 2018 05 08.
Article in English | MEDLINE | ID: mdl-29739384

ABSTRACT

BACKGROUND: Women who have been treated for breast cancer may identify vasomotor symptoms, such as hot flushes and night sweats (HFNS), as a serious problem. HFNS are unpleasant to experience and can have a significant impact on daily life, potentially leading to reduced adherence to life saving adjuvant hormonal therapy. It is known that Cognitive Behavioural Therapy (CBT) is effective for the alleviation of hot flushes in both well women and women who have had breast cancer. Most women with breast cancer will see a breast care nurse and there is evidence that nurses can be trained to deliver psychological treatments to a satisfactory level, whilst also maintaining treatment fidelity. The research team will assess whether breast care nurses can effectively deliver a CBT intervention to alleviate hot flushes in women with breast cancer. METHODS: This study is a multi-centre phase III individually randomised controlled trial of group CBT versus usual care to reduce the impact of hot flushes in women with breast cancer. 120-160 women with primary breast cancer experiencing seven or more problematic HFNS a week will be randomised to receive either treatment as usual (TAU) or participation in the group CBT intervention plus TAU (CBT Group). A process evaluation using May's Normalisation Process Theory will be conducted, as well as practical and organisational issues relating to the implementation of the intervention. Fidelity of implementation of the intervention will be conducted by expert assessment. The cost effectiveness of the intervention will also be assessed. DISCUSSION: There is a need for studies that enable effective interventions to be implemented in practice. There is good evidence that CBT is helpful for women with breast cancer who experience HFNS, yet it is not widely available. It is not yet known whether the intervention can be effectively delivered by breast care nurses or implemented in practice. This study will provide information on both whether the intervention can effectively help women with hot flushes and whether and how it can be translated into routine clinical practice. TRIAL REGISTRATION: ISRCTN 12824632 . Registered 25-01-2017.


Subject(s)
Breast Neoplasms/complications , Cognitive Behavioral Therapy , Hot Flashes/therapy , Practice Patterns, Nurses' , Sweating , Breast Neoplasms/nursing , Breast Neoplasms/therapy , Cognitive Behavioral Therapy/economics , Cognitive Behavioral Therapy/standards , Cost-Benefit Analysis , Female , Humans , Psychotherapy, Group , Research Design
7.
Eur J Cancer ; 87: 75-83, 2017 12.
Article in English | MEDLINE | ID: mdl-29128692

ABSTRACT

BACKGROUND: Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. METHODS: A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. RESULTS: Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. CONCLUSIONS: Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.


Subject(s)
Antineoplastic Agents/adverse effects , Aspirin/administration & dosage , Cisplatin/adverse effects , Hearing Loss/prevention & control , Hearing/drug effects , Neoplasms/drug therapy , Protective Agents/administration & dosage , Adult , Aged , Aspirin/adverse effects , Audiometry, Pure-Tone , Cytoprotection , Double-Blind Method , Drug Administration Schedule , Female , Hearing Loss/chemically induced , Hearing Loss/diagnosis , Hearing Loss/physiopathology , Humans , Male , Middle Aged , Protective Agents/adverse effects , Time Factors , Treatment Outcome , United Kingdom , Young Adult
8.
Invest New Drugs ; 35(5): 599-607, 2017 10.
Article in English | MEDLINE | ID: mdl-28144789

ABSTRACT

Background Docetaxel and prednisolone chemotherapy (DP) extends survival in metastatic castration resistant prostate cancer (mCRPC). However, emergent clinical resistance is almost inevitable. AKT pathway activation is highly prevalent in mCRPC contributing to disease progression and DP resistance. AZD5363 is a potent oral pan-AKT inhibitor with pre-clinical data indicating activity in mCRPC and synergy with docetaxel. Methods This phase I trial was to determine an AZD5363 recommended phase II dose (RP2D) for combination with DP. Eligibility criteria included chemotherapy naive mCRPC, PSA or radiographic disease progression and ECOG performance status 0 or 1. Treatment comprised DP (75 mg/m2, IV, day 1 and 5 mg BID, PO, day 1-21 respectively for ten cycles) and AZD5363 to disease progression for all patients. We utilised a 3 + 3 dose escalation design to determine a maximum tolerated dose according to defined dose limiting toxicity criteria assessed using CTCAE version 4.03. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from day 2 of each cycle. Results 10 patients were treated. Dose limiting toxicities affected 2 patients (grade 3 rash ≥5 days; grade 3 diarrhoea) in DL2. The commonest grade 3 or 4, AZD5363 related, symptomatic adverse events were rash and diarrhoea. Hyperglycaemia affected all patients but was self-limiting. PSA reduction to <50% at 12 weeks occurred in 7 patients. Conclusions The RP2D for AZD5363 is 320 mg BID, 4 days on/3 days off, in combination with full dose DP for mCRPC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Aged , Docetaxel , Dose-Response Relationship, Drug , Humans , Male , Maximum Tolerated Dose , Middle Aged , Prednisolone/administration & dosage , Prostate-Specific Antigen/metabolism , Pyrimidines/administration & dosage , Pyrroles/administration & dosage , Taxoids/administration & dosage
9.
Tex Heart Inst J ; 42(6): 514-21, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26664302

ABSTRACT

Cardiopulmonary exercise testing provides oxygen pulse as a continuous measure of stroke volume, which is superior to other stress-testing methods in which systolic function is measured at baseline and at peak stress. However, the optimal peak oxygen pulse criterion for distinguishing cardiac from noncardiac causes of exercise limitation is unknown. In comparing several peak oxygen pulse criteria against the clinical standard of cardiopulmonary exercise testing, we retrospectively studied 54 consecutive patients referred for cardiopulmonary exercise testing. These exercise tests included measurement of oxygen consumption, carbon dioxide production, breathing reserve, arterial blood gases at baseline and at peak stress, exercise electrocardiogram, heart rate, and blood pressure response. Results were blindly interpreted and patients were categorized as members either of our Cardiac Group (abnormal result secondary to cardiac causes of exercise limitation) or of our Noncardiac Group (normal or abnormal result secondary to any noncardiac cause of exercise limitation). The accuracy of the peak oxygen pulse criteria ranged from 50% for univariate criterion (≤15 mL/beat), to 61% for oxygen pulse curve pattern, to 63% for bivariate criterion (≤15 mL/beat for men, ≤10 mL/beat for women), to as high as 81% for a multivariate criterion. All multivariate criteria outperformed oxygen pulse curve pattern, univariate, and bivariate criteria. This is the first study to evaluate the optimal peak oxygen pulse criterion for differentiating cardiac from noncardiac causes of exercise limitation. Multivariate criteria (especially a criterion incorporating age, sex, height, and weight) should be used preferentially, as opposed to the commonly used univariate and bivariate criteria.


Subject(s)
Dyspnea/etiology , Exercise Test , Heart Diseases/complications , Oxygen Consumption , Adult , Age Factors , Aged , Blood Gas Analysis , Blood Pressure , Body Height , Body Weight , Dyspnea/diagnosis , Dyspnea/physiopathology , Electrocardiography , Female , Heart Diseases/diagnosis , Heart Diseases/physiopathology , Heart Rate , Humans , Male , Middle Aged , Models, Biological , Multivariate Analysis , Predictive Value of Tests , Reproducibility of Results , Respiration , Retrospective Studies , Risk Factors , Sex Factors , Stroke Volume
10.
Phlebology ; 30(7): 455-61, 2015 Aug.
Article in English | MEDLINE | ID: mdl-24913776

ABSTRACT

OBJECTIVE: This study assessed patterns of superficial reflux in patients with primary chronic venous disease. METHODS: Retrospective review of all patient venous duplex ultrasonography reports at one institution between 2000 and 2009. Legs with secondary, deep or no superficial reflux were excluded. RESULTS: In total, 8654 limbs were scanned; 2559 legs from 2053 patients (mean age 52.3 years) were included for analysis. Great saphenous vein reflux predominated (68%), followed by combined great saphenous vein/small saphenous vein reflux (20%) and small saphenous vein reflux (7%). The majority of legs with competent saphenofemoral junction had below-knee great saphenous vein reflux (53%); incompetent saphenofemoral junction was associated with combined above and below-knee great saphenous vein reflux (72%). Isolated small saphenous vein reflux was associated with saphenopopliteal junction incompetence (61%), although the majority of all small saphenous vein reflux limbs had a competent saphenopopliteal junction (57%). CONCLUSION: Superficial venous reflux does not necessarily originate from a saphenous junction. Large prospective studies with interval duplex ultrasonography are required to unravel the natural history of primary chronic venous disease.


Subject(s)
Leg/blood supply , Saphenous Vein/diagnostic imaging , Venous Insufficiency/diagnostic imaging , Adolescent , Adult , Aged , Aged, 80 and over , Chronic Disease , Female , Humans , Leg/diagnostic imaging , Leg/physiopathology , Male , Middle Aged , Retrospective Studies , Saphenous Vein/physiopathology , Ultrasonography , Venous Insufficiency/epidemiology , Venous Insufficiency/physiopathology
11.
Ann Neurol ; 76(4): 594-608, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25088017

ABSTRACT

OBJECTIVE: Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. METHODS: By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. RESULTS: On average, BBB permeability increased 3.5-fold (p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died (p < 0.0001). INTERPRETATION: This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions.


Subject(s)
Cerebral Cortex/pathology , Encephalitis/etiology , Encephalomyelitis, Autoimmune, Experimental/complications , Encephalomyelitis, Autoimmune, Experimental/pathology , White Matter/pathology , 2',3'-Cyclic-Nucleotide Phosphodiesterases/metabolism , Analysis of Variance , Animals , Blood-Brain Barrier/physiopathology , Callithrix , Contrast Media , Disease Models, Animal , Female , Glial Fibrillary Acidic Protein/metabolism , Image Processing, Computer-Assisted , Leukocyte L1 Antigen Complex/metabolism , Magnetic Resonance Imaging , Male , Microfilament Proteins/metabolism , White Matter/metabolism
12.
PLoS Pathog ; 9(1): e1003138, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23382677

ABSTRACT

Human Herpesvirus 6 (HHV-6) is a ubiquitous virus with an estimated seroprevalence of 95% in the adult population. HHV-6 is associated with several neurologic disorders, including multiple sclerosis, an inflammatory demyelinating disease affecting the CNS. Animal models of HHV-6 infection would help clarify its role in human disease but have been slow to develop because rodents lack CD46, the receptor for cellular entry. Therefore, we investigated the effects of HHV-6 infections in a non-human primate, the common marmoset Callithrix jacchus. We inoculated a total of 12 marmosets with HHV-6A and HHV-6B intravenously and HHV-6A intranasally. Animals were monitored for 25 weeks post-inoculation clinically, immunologically and by MRI. Marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms and generated virus-specific antibody responses, while those inoculated intravenously with HHV-6B were asymptomatic and generated comparatively lower antibody responses. Viral DNA was detected at a low frequency in paraffin-embedded CNS tissue of a subset of marmosets inoculated with HHV-6A and HHV-6B intravenously. When different routes of HHV-6A inoculation were compared, intravenous inoculation resulted in virus-specific antibody responses and infrequent detection of viral DNA in the periphery, while intranasal inoculation resulted in negligible virus-specific antibody responses and frequent detection of viral DNA in the periphery. Moreover, marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms, while marmosets inoculated with HHV-6A intranasally were asymptomatic. We demonstrate that a marmoset model of HHV-6 infection can serve to further define the contribution of this ubiquitous virus to human neurologic disorders.


Subject(s)
Callithrix/physiology , Disease Models, Animal , Herpesvirus 6, Human/pathogenicity , Nervous System Diseases/immunology , Roseolovirus Infections , Administration, Intranasal , Animals , Brain/pathology , Brain/virology , DNA, Viral/analysis , Herpesvirus 6, Human/physiology , Humans , Injections, Intravenous , Magnetic Resonance Imaging , Nervous System Diseases/diagnosis , Nervous System Diseases/virology , Roseolovirus Infections/diagnosis , Roseolovirus Infections/immunology , Roseolovirus Infections/virology , Spinal Cord/pathology , Spinal Cord/virology
13.
Toxicol Pathol ; 41(7): 1016-27, 2013.
Article in English | MEDLINE | ID: mdl-23427274

ABSTRACT

Nonhuman primates, particularly rhesus macaques (Macaca mulatta), provide important model systems for studying human reproductive infectious diseases such as human immunodeficiency virus, human papillomavirus, and Chlamydia spp. An understanding of the spectrum of spontaneous cervical disease provides essential context for interpreting experimental disease outcomes in the female reproductive tract. This retrospective study characterizes the incidence of inflammatory and/or proliferative cervicovaginal lesions seen over a 14-year period in a multispecies nonhuman primate colony, focusing on rhesus macaques. The most common observations included a spectrum of lymphocytic accumulation from within normal limits to lymphoplasmacytic cervicitis, and suppurative inflammation with occasional squamous metaplasia or polyp formation. These inflammatory spectra frequently occurred in the context of immunosuppression following experimental simian immunodeficiency virus (SIV) infection. Cervical neoplasias were uncommon and included leiomyomas and carcinomas. Cervical sections from 13 representative cases, with an emphasis on proliferative and dysplastic lesions, were surveyed for leukocyte infiltration, abnormal epithelial proliferation, and the presence of papillomavirus antigens. Proliferative lesions showed sporadic evidence of spontaneous papillomavirus infection and variable immune cell responses. These results underscore the importance of pre screening potential experimental animals for the presence of preexisting reproductive tract disease, and the consideration of normal variability within cycling reproductive tracts in interpretation of cervical lesions.


Subject(s)
Primate Diseases/pathology , Uterine Cervical Neoplasms/veterinary , Vaginal Neoplasms/veterinary , Animals , Callitrichinae , Female , Immunohistochemistry , Macaca mulatta , Papillomaviridae/immunology , Primate Diseases/immunology , Retrospective Studies , Simian Immunodeficiency Virus/immunology , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/pathology , Vaginal Neoplasms/immunology , Vaginal Neoplasms/pathology
14.
Vasc Endovascular Surg ; 44(7): 586-93, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20675337

ABSTRACT

OBJECTIVE: Free-floating thrombus (FFT) of the carotid artery is a rare condition of currently unknown etiology. Less than 150 cases have been described in the published world literature to date. DESIGN AND SETTING: We present 6 consecutive cases of carotid FFT, identified prospectively from 5000 carotid duplex scans over a 34-month period in a single tertiary center for vascular surgery. RESULTS: All 6 cases involved the left carotid bifurcation in neurologically symptomatic individuals. In 5 of the 6 cases, FFT occurred in the absence of a significantly stenosing atheromatous plaque and was not associated with an elevation in velocity on duplex. The patients were all treated with surgical thromboendarterectomy, with good result. CONCLUSIONS: Duplex imaging can underestimate the degree of stenosis. Free-floating thrombus presents a challenge in diagnosis due to its rapidly evolving nature. The management of FFT by acute thromboendarterectomy appears to be safe and effective in limiting further focal neurological sequelae.


Subject(s)
Carotid Artery Thrombosis/diagnostic imaging , Carotid Artery Thrombosis/surgery , Carotid Stenosis/diagnostic imaging , Carotid Stenosis/surgery , Endarterectomy, Carotid , Ultrasonography, Doppler, Duplex , Adult , Aged , Carotid Artery Thrombosis/complications , Carotid Stenosis/complications , Cerebral Angiography/methods , Diffusion Magnetic Resonance Imaging , Female , Humans , Infarction, Middle Cerebral Artery/etiology , Infarction, Middle Cerebral Artery/pathology , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Severity of Illness Index , Tomography, X-Ray Computed , Treatment Outcome , Ultrasonography, Doppler, Color , Young Adult
15.
J Diabetes Sci Technol ; 4(3): 610-4, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20513327

ABSTRACT

INTRODUCTION: While the endogenous first-phase insulin response has disappeared by the time of diagnosis of type 1 diabetes mellitus (T1DM), anecdotal evidence suggests that these patients can continue to have a second-phase insulin response during the first 12 months after diagnosis. We hypothesized that patients who are started on continuous subcutaneous insulin infusion (CSII) at the time of diagnosis of T1DM would have a lower basal insulin requirement than the 40-60% usually expected. METHODS: We analyzed 38 patients with T1DM, age 9.9 +/- 6.4 years, 71% male, who were started on CSII within the first month of diagnosis. RESULTS: Average basal insulin requirements were 47-49% of total daily dose during the first 12 months after diagnosis and decreased from 0.30 U/kg/day at diagnosis to 0.20 U/kg/day by 12 months. Baseline percentage of basal insulin was significantly correlated with hemoglobin A1c at baseline and at six months. The percentage of basal insulin requirement at 12 months after diagnosis was significantly correlated with baseline body mass index (BMI) and current BMI. No other correlations between percentage of basal insulin requirements and any other factors were seen. CONCLUSION: Our data suggest that, even though some endogenous insulin production remains during the first year after diagnosis of T1DM, the distribution of basal versus total daily insulin requirements remains the same as in the general population of people with diabetes. There may be benefits to starting patients on a higher basal rate at time of diagnosis for overall glycemic control during the first six months. Further research is needed to optimize starting insulin doses to maximize their potential in preserving beta-cell function.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Hypoglycemic Agents/administration & dosage , Insulin Infusion Systems , Insulin/analogs & derivatives , Adolescent , Adult , Area Under Curve , Blood Glucose/analysis , Blood Glucose/drug effects , Body Mass Index , Child , Child, Preschool , Diabetes Mellitus, Type 1/blood , Female , Glycated Hemoglobin/analysis , Humans , Infant , Infusions, Subcutaneous , Insulin/administration & dosage , Insulin, Long-Acting , Male , Young Adult
17.
Am J Kidney Dis ; 46(5): 856-62, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16253725

ABSTRACT

BACKGROUND: Common carotid artery intima-media thickness (CCA-IMT) correlates with cardiovascular events in the general population and is an independent predictor of cardiovascular mortality in the hemodialysis population. It has not been evaluated extensively in patients with chronic kidney disease. METHODS: CCA-IMT was measured by using high-resolution B-mode ultrasonography, and glomerular filtration rate (GFR) was measured by means of EDTA clearance. Cardiovascular risk factors assessed included homocysteine and lipoprotein(a) levels, as well as smoking, blood pressure, and cholesterol level. RESULTS: One hundred fourteen patients were studied; mean measured GFR was 29.6 +/- 18.4 mL/min/1.73 m2 (0.49 +/- 0.31 mL/s). CCA-IMT was significantly elevated (0.59 +/- 0.22 cm) compared with a control group (0.44 +/- 0.08 cm; P = 0.0012). CCA-IMT increases with age (P < 0.0001) and low-density lipoprotein level (P = 0.048) and decreases with high-density lipoprotein level (P = 0.001) and being white (P = 0.014). CONCLUSION: This study suggests that arterial changes occur early in the course of renal disease progression and may be related to dyslipidemia in the early stages.


Subject(s)
Cardiovascular Diseases/epidemiology , Carotid Arteries/pathology , Carotid Artery Diseases/epidemiology , Kidney Diseases/epidemiology , Tunica Intima/pathology , Tunica Media/pathology , Adult , Aged , Aged, 80 and over , Carotid Arteries/diagnostic imaging , Carotid Artery Diseases/pathology , Chronic Disease , Diabetes Complications/epidemiology , Dyslipidemias/epidemiology , Ethnicity/statistics & numerical data , Female , Glomerular Filtration Rate , Humans , Hyperhomocysteinemia/epidemiology , Lipoprotein(a)/blood , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , London/epidemiology , Male , Middle Aged , Risk Factors , Smoking/epidemiology , Tunica Intima/diagnostic imaging , Tunica Media/diagnostic imaging , Ultrasonography
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