In depth analysis of kinase cross screening data to identify chemical starting points for inhibition of the Nek family of kinases.

Potent, selective, and cell active small molecule kinase inhibitors are useful tools to help unravel the complexities of kinase signaling. As the biological functions of individual kinases become better understood, they can become targets of drug discovery efforts. The small molecules used to shed light on function can also then serve as chemical starting points in these drug discovery efforts. The Nek family of kinases has received very little attention, as judged by number of citations in PubMed, yet they appear to play many key roles and have been implicated in disease. Here we present our work to identify high quality chemical starting points that have emerged due to the increased incidence of broad kinome screening. We anticipate that this analysis will allow the community to progress towards the generation of chemical probes and eventually drugs that target members of the Nek family.

Non-invasive investigation of chronic stable angina--a practical overview for medical practitioners.

How does one decide on the best non-invasive test to investigate stable coronary ischaemia? This is a very common question faced by many medical practitioners. Chronic stable angina is a common presentation encountered in general practitice. Upon clinical assessment and risk stratification the patient needs to be investigated further to confirm the diagnosis. The first investigational modality involves a non-invasive test. It is important that practitioners possess a practical knowledge of the array of different tests that are available so that the best suited one for each patient can be chosen. This article aims to compare the efficacy and accuracy and the practical utility of the different non-invasive tests for coronary ischaemia and aid the practitioner in making sound decisions in this regard.

Feasibility and efficacy of upper limb robotic rehabilitation in a subacute cervical spinal cord injury population.

STUDY DESIGN: Multi-center pilot study. OBJECTIVES: To investigate the use of an upper limb robotic rehabilitation device (Armeo Spring, Hocoma AG, Switzerland) in a subacute cervical spinal cord injury (SCI) population. SETTING: Two Canadian inpatient rehabilitation centers. METHODS: Twelve subjects (motor level C4-C6, ASIA Impairment Scale A-D) completed the training, which consisted of 16.1±4.6 sessions over 5.2±1.4 weeks. Two types of outcomes were recorded: (1) feasibility of incorporating the device into an inpatient rehabilitation program (compliance with training schedule, reduction in therapist time required and subject questionnaires) and (2) efficacy of the robotic rehabilitation for improving functional outcomes (Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP), action research arm test, grip dynamometry and range of motion). RESULTS: By the end of the training period, the robot-assisted training was shown to require active therapist involvement for 25±11% (mean±s.d.) of the total session time. In the group of all subjects and in a subgroup composed of motor-incomplete subjects, no statistically significant differences were found between intervention and control limbs for any of the outcome measures. In a subgroup of subjects with partial hand function at baseline, the GRASSP-Sensibility component showed a statistically significant increase (6.0±1.6 (mean±s.e.m.) point increase between baseline and discharge for the intervention limbs versus 1.9±0.9 points for the control limbs). CONCLUSION: The pilot results suggest that individuals with some preserved hand function after SCI may be better candidates for rehabilitation training using the Armeo Spring device.

Effects of modified sample collection technique on fungal culture yield: nail clipping/scraping versus microdrill.

OBJECTIVE: Onychomycosis requires accurate diagnosis but fungal culture yield is frequently low by routine sampling techniques. The aim of this study was to investigate the utility of nail plate/subungual microdrilling as an alternative to conventional nail clipping/subungual scraping. METHODS: Patients with clinical evidence of onychomycosis (n=46) were prospectively evaluated for fungal potassium hydroride (KOH) microscopy and culture comparing two sampling techniques: nail clipping versus microdrilling. RESULTS: Fungal cultures were positive in 48% with 2 additional cases detected by combining both methods. KOH microscopy was positive in 17% cases. Specimen obtained via the microdrill technique gave consistent heavier fungal growth on culture media. Candida species were the most common isolates (82.7% of cases) and were negative on KOH microscopy in 95 % of culture proven cases. The microdrill technique yielded consistent heavier growth on culture media CONCLUSION: Microdrill technique improves laboratory diagnosis and ultimately treatment of onychomycosis, particularly in patients with repeated KOH microscopy and culture failure despite strong clinical suspicion.

Gabapentin for chronic pain in spinal cord injury: a case report.

A 30-year-old white woman with an L1 complete spinal cord injury (SCI) secondary to a gunshot wound in 1985, presented to a chronic pain service for evaluation. She had a 13-year history of chronic lower extremity pain. She described her discomfort as "throbbing, aching, and stabbing." She had tried many different medications, including opioids, Tegretol, and tricyclic antidepressants, without success. During the evaluation process, she admitted to being "angry, frustrated, and anxious." She was diagnosed with central pain after SCI. She was placed on gabapentin 300 mg 3 times daily; within 1 week, her visual analog pain scale fell from 95 mm to 27 mm, and her McGill Short Form pain score fell from 13 to 3. Her mood also vastly improved. This case report suggests that gabapentin should be studied as a therapeutic option for treating central pain post-SCI and should be considered as a viable, well-tolerated, low-toxicity tool.

Endothelial dysfunction in cerebral microcirculation during hypothermic cardiopulmonary bypass in newborn lambs.

OBJECTIVES: Inflammatory stimuli or mechanical stresses associated with hypothermic cardiopulmonary bypass could potentially impair cerebrovascular function, resulting in inadequate cerebral perfusion. We hypothesize that hypothermic cardiopulmonary bypass is associated with endothelial or vascular smooth muscle dysfunction and associated cerebral hypoperfusion. Therefore we studied the cerebrovascular response to endothelium-dependent vasodilator, acetylcholine, endothelium-independent nitric oxide donor, sodium nitroprusside, and vasoactive amine, serotonin, in newborn lambs undergoing hypothermic cardiopulmonary bypass (nasopharygeal temperature = 18 degrees C). METHODS: Studies were performed on 13 newborn lambs equipped with a closed cranial window, allowing for direct visualization of surface pial arterioles. Six animals were studied while undergoing hypothermic cardiopulmonary bypass, whereas seven served as nonbypass, warm (37 degrees C) controls. Pial arteriolar caliber (range = 111 to 316 microm diameter) was monitored using video microscopy. RESULTS: Topical application of acetylcholine caused a dose-dependent increase in arteriolar diameter in the control group that was absent in animals undergoing hypothermic cardiopulmonary bypass. Hypothermic cardiopulmonary bypass did not alter the vasodilation in response to sodium nitroprusside. Furthermore, the contractile response to serotonin was fully expressed during hypothermic cardiopulmonary bypass. CONCLUSIONS: The specific loss of acetylcholine-induced vasodilation suggests endothelial cell dysfunction rather than impaired ability of vascular smooth muscle to respond to nitric oxide. It is speculated that loss of endothelium-dependent regulatory factors in the cerebral microcirculation during hypothermic cardiopulmonary bypass may enhance vasoconstriction, and impaired cerebrovascular function may be a basis for associated neurologic injury during or after hypothermic cardiopulmonary bypass.

Open label trial of the efficacy and tolerability of Lamisil (Terbinafine) 500 mg once daily in the treatment of onychomycosis due to candida.

An open label trial of Lamisil (Terbinafine) 500 mg daily for 16 weeks was conducted on 20 patients with Onychomycosis due to candida. Of these, 15 patients could complete the trial. Total number of target nails infected was 21. The follow-up period was from 16 to 52 weeks. At 16 weeks, 71% cases showed clinical improvement and 67% had mycological cure. Thirty-three percent had complete cure at 52 weeks. The results show that Terbinafine is effective against candida but requires a longer duration of treatment. The drug was well tolerated.

Nifedipine, captopril, metoprolol and nifedipine with metoprolol in hypertensive crisis in non-intensive care setting.

In 102 cases of severe hypertension (DBP > or = 115 mm Hg), with or without acute complications, efficacy and safety of SL Nifedipine 10 mg (NIF), SL Captopril 25 mg (CAP), IV Metoprolol 15 mg (MET) and SL NIF + IV MET were studied in an inpatient trial. Maximum mean percent reduction in SBP was 13.3, 9.7, 15.7 and 19.9 and in DBP was 21.2, 13.9, 12.5 and 20.4 with NIF, CAP, MET and NIF + MET respectively. A safe DBP of < or = 110 mm Hg (Kaplan) was achieved in 90, 61, 72.2 and 95.2 percent of patients. A statistically significant fall in DBP was observed at 5 minutes with all regimens except CAP which was at 15 minutes. Mild side effects observed were palpitations and flushing (NIF n = 4), taste disturbances (CAP n = 3), heaviness of head (CAP n = 1) and giddiness (MET n = 2, NIF + MET n = 2). The trial data suggest that hypertensive crisis can be managed, without intensive care facility, with all four regimens; this implies significant cost containment.

Cutaneous manifestations of systemic lupus erythematosus: study from Lahore, Pakistan.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder in which cutaneous lesions occur in 85% of patients. This study from Lahore, Pakistan, was conducted to determine the pattern and incidence of such lesions in SLE. METHODS: Forty patients with SLE fulfilling the clinical and laboratory criteria of the American Rheumatism Association (ARA) (1982) were examined between October 1992 and September 1993 for the presence of cutaneous manifestations. RESULTS: Skin changes noted were: noncicatricial diffuse alopecia (82.5%), malar rash (60%), mucosal lesions (60%), discoid eruption (57.5%), photosensitivity (60%), nail involvement (55%), vascular lesions (50%), pruritus (45%), and pigmentary changes (37.5%). Peripheral gangrene, chronic ulcers, Raynaud's phenomenon, urticaria, chilblains, thrombophlebitis, palmar erythema, and erythema multiforme were rare. Antinuclear antibody reaction was positive in 80% and anti-dSDNA antibodies in 70%. CONCLUSION: A different clinical pattern was noted in our patients than reported previously.

Aortopulmonary fistula: an uncommon complication in dystrophic aortic aneurysm.

Wall dissection is a typical complication in the evolution of Marfan aortic aneurysm and usually is associated with valve regurgitation. Formation of a fistula with adjacent structures is very uncommon. We report the case of a 32-year-old man who presented with the typical features of Marfan's syndrome, with chronic aneurysm of the ascending aorta and acute aortopulmonary fistula. Diagnosis was made preoperatively by aortography; operation was performed successfully. A review of the literature only shows a few cases of aortopulmonary fistula in atherosclerotic, syphilitic, or postendocarditis disease.

Acute myocarditis presenting as acute myocardial infarction.

Myocarditis, often caused by an infectious agent, may have a presentation mimicking that of acute myocardial infarction. The authors describe a young man who, when first seen in the emergency department, appeared to have an acute myocardial infarction with normal coronary arteries. At autopsy, the histologic findings were diagnostic of active myocarditis, mixed-cell type. Neutrophilic infiltration with microabscess suggested an infectious cause, although the etiology was uncertain. The patient's clinical course, pathologic findings, and several treatment modalities are discussed. The differentiation between acute myocardial infarction and acute myocarditis can be difficult. Electrocardiographic changes and enzyme elevations are common in both. Therefore, clinicians should consider myocarditis in all patients--particularly young patients--with normal coronary arteries and suspected myocardial infarction.

[Value of the posterior route in the surgical treatment of popliteal aneurysm]. / Intérêt de la voie postérieure dans la cure chirurgicale des anévrysmes poplités.

The authors report about 4 cases of surgical treatment of popliteal aneurysms through a strictly posterior approach. In all cases, the aneurysm was asymptomatic and diagnosed during the assessment of a controlateral symptomatic popliteal aneurysm that was treated in a conventional manner (exclusion and interposition of a femoropopliteal prosthetic tube through a medial approach). The procedure is carried out with the patient in ventral decubitus, and it consists in a debridement and graft with direct anatomical interposition of a straight PTFE tube. The posterior approach has limitations as it does not allow craniad extension and applies only to sacciform or short fusiform aneurysms the upper pole of which does not extend beyond Hunter's canal. The graft was an 8-mm PTFE straight tube in all 4 cases. All patients had a dynamic bilateral control angiography made and none of them presented with symptoms. Three conventional restorations required later embolectomy for thrombosis of the prosthesis. In our opinion, the use of the posterior approach for the surgery of popliteal aneurysm is appealing-provided strict criteria (aneurysm size, scheduled surgery, prosthesis) are complied with--as it reduces morbidity, restores the anatomical course and allows reducing the rate of postoperative thrombosis, thus ensuring better long-term patency.

Sublingual nifedipine and captopril in hypertensive urgencies and emergencies.

Fifty two patients of severe hypertension, diastolic blood pressure > or = 115 mmHg, with or without acute complications, were treated with sublingual nifedipine 10 mg or sublingual captopril 25 mg in a randomized prospective in patient study with careful clinical monitoring. Both the drugs were safe and effective in rapidly lowering blood pressure. Nifedipine appeared to be superior to captopril with earlier onset of action, greater magnitude of response and longer duration of action. No significant side effects were observed in either of the two groups.