Discovery of novel and potent benzhydryl-tropane trypanocides highly selective for Trypanosoma cruzi.

A benzhydryl tropinone oxime that is potently toxic to Trypanosoma cruzi has been previously identified. An SAR investigation determined that no part of the original compound was superfluous and all early SAR probes led to significant drops in activity. The only alteration that could be achieved without loss of activity was replacement of the aryl chloride substituent with chloro homologues. This led to the discovery of a trifluoromethyl-containing analogue with an EC(50) against T. cruzi of 30 nM and a cytotoxicity selectivity index of over 1000 relative to rat skeletal myoblast L-6 cells.

The effect of pressure loading on the blood flow rate in human skin.

The effect of pressure on the blood flow in skin is of considerable clinical interest. Methods are described for the estimation of skin blood flow from the disappearance rate of an injection of 133Xe in saline. The flow rate may be monitored for a period long enough to establish the normal flow and the reduced flow resulting from a constant pressure load. Initial results indicate that the flow is reduced greatly by pressures up to 10 mmHg. This result is interpreted as a demonstration of an auto regulatory mechanism of skin blood flow. Above 30 mmHg the flow continues to decrease essentially to zero as systolic pressure is approached.

Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo.

OBJECTIVE: To assess the efficacy of topically applied CT-102 APST for treating diabetic neurotrophic foot ulcers. RESEARCH DESIGN AND METHODS: Thirteen patients entered a randomized, double-blind trial of topically applied CT-102 APST vs. placebo (normal saline) gauze dressings for the treatment of nonhealing diabetic neurotrophic foot ulcers. CT-102 APST (Curative Technologies, Setauket, NY) was prepared from homologous platelets and contained multiple growth factors including PDGF, PDAF, EGF, PF-4, TGF-beta, aFGF, and bFGF. Inclusion criteria for subjects included diabetes, ulcer of > 8 wk duration, peri-wound transcutaneous oxygen tension > 30 mmHg, platelet count > 100,000/mm3, and no wound infection. Wounds were excised before entry and were > 700 mm3 but < 50,000 mm3 in volume, < 100 cm2 in area, and involved subcutaneous tissue. RESULTS: In the CT-102 group, 5 of 7 ulcers were healed (100% epithelialized) by 15 wk, but only 1 of 6 ulcers was healed by 20 wk with placebo (P < 0.05). Average percent reduction in ulcer area at 20 wk was 94% for CT-102 vs. 73% for placebo. Daily reduction in ulcer volume was 73.8 +/- 42.4 mm3/day (mean +/- SE) for CT-102 vs. 21.8 +/- 8.1 mm3/day for placebo (P < 0.05). Daily reduction in ulcer area was 6.2 +/- 1.8 mm2/day for CT-102 vs. 1.8 +/- 0.4 mm2/day for placebo (P < 0.05). CONCLUSIONS: CT-102 significantly accelerated wound closure in diabetic leg ulcers when administered as part of a comprehensive program for the healing of chronic ulcers.

Cutaneous blood flow responses to injection trauma measured by laser Doppler velocimetry.

The question has been raised repeatedly: what is the effect of an intracutaneous injection on skin blood flow? This is particularly relevant where radioisotope clearance techniques are used for its measurement. This study was performed to measure these changes. Using the noninvasive technique of laser Doppler velocimetry to measure cutaneous blood flow, injections were made in the forearm skin with a needle alone, and with 20 microliter of saline, histamine or epinephrine. In each case, measurements were made of resting flow and elevated flow levels, the latter produced by heating the site to 44 degrees C for 5 min prior to the study. At resting flow levels, insertion of the needle or injection of saline produced approximately a sevenfold increase in flow over the base line; the flow increase remained elevated for periods of at least 20 min. Histamine produced a much smaller increase, and epinephrine a decrease as compared to the base line. In the heated sites, vasodilatation was already present, and flow levels decreased in all cases, slightly with the needle and saline, more with histamine, and most with epinephrine. It is concluded that there is a significant increase in skin blood flow caused by injections into the skin, but this response is progressively more masked as base line flow levels increase.

Laser Doppler measurement of cutaneous blood flow.

This work describes an instrument for the noninvasive measurement of cutaneous blood flow velocity. The system utilizes the Doppler shift of laser light backscattered from moving red blood cells in the cutaneous microcirculation, the shift being obtained by an optical heterodyning technique. Comparison is made between this technique and the 133xenon clearance technique in measuring cutaneous flow in the forearms of normal volunteers. Variations in flow were obtained by inducing different degrees of solar erythema with an ultraviolet sunlamp. A Y on X linear regression yielded a regression coefficient = 0.89 (p less than 0.001, n = 16) between the two methods. The laser Doppler method appear to represent a practical technique for clinical evaluation of cutaneous blood flow in any skin surface.

Effect of fluocinolone acetonide cream on human skin blood flow.

Blood flow rate was measured in the forearm skin of human subjects exposed to ultraviolet irradiation. Blood flow was determined by the 133Xe disappearance technique 18 hr after ultraviolet (UV) irradiation with a Westinghouse RS sunlamp held 10 inches from the skin for 10 min. Ultraviolet irradiation caused skin blood flow to increase. Application of fluocinolone acetonide cream, 0.025%, 4 times in the 16 hr following UV irradiation had no effect on either control skin blood flow or the UV-induced hyperemia.

Estimation of blood flow with radioactive tracers.

The techniques of tracer dilution in the circulation, and of tracer uptake by and washout from an orgen, may be described using expressions that are general and are not dependent on specific models such as exponentials. The expressions have been applied to the measurement of cardiac output using impulse and constant rate injection techniques. Further expressions have been given for estimating organ blood flow from inflow/outflow concentration-time curves, and from the distribution of deposited tracer. Some problems with respect to the use of deposition techniques as they are ordinarily applied to the estimation of regional blood flow must be considered, particularly when there are capillary beds in series or where there is countercurrent diffusional shunting of diffusible tracers between inflow and outflow. This review deals with these various aspects of tracer theory as they relate to the measurement of blood flow.

Effect of internal mammary artery mobilization on sternal blood flow.

Use of the internal mammary artery as a conduit for coronary artery bypass has enhanced this procedure in terms of prolonged graft patency. An earlier warning that use of both arteries would devascularize the sternum was based on postmortem radiologic imaging. This was complemented by a subsequent animal study employing isotopic microspheres. In the present clinical study, laser Doppler flowmetry was adapted to identify changes in blood supply to the left half of the divided manubrium sternum during separation of the left internal mammary artery from its chest wall attachment. Our finding of continued blood flow after this event suggests that complete devascularization of the sternum does not take place. Quality of sternal bone and surrounding tissues and clinical indications should remain as factors influencing use of one or both internal mammary arteries.

Prevention of amputation by diabetic education.

This prospective randomized study evaluated the influence of a simple education program on the incidence of lower extremity amputation in diabetic patients. Two hundred three patients were randomized into two groups: Group 1, education (103 patients, 203 limbs) and Group 2, no education (100 patients, 193 limbs). There were no significant differences in medical management or clinical risk factors between the two groups. The amputation rate was three times higher in Group 2 (21 of 177 limbs versus 7 of 177 limbs; p less than or equal to 0.025), the ulceration rate was three times higher in Group 2 (26 of 177 limbs versus 8 of 177 limbs; p less than or equal to 0.005), and there was no difference in the overall incidence of infection (2 of 177 limbs). Overall success in Group 1 was highly significantly different from Group 2 (160 of 177 limbs versus 128 of 177 limbs; p less than or equal to 0.0005). This study demonstrated that a simple education program significantly reduced the incidence of ulcer or foot and limb amputation in diabetic patients.

Wound tension and blood flow in skin flaps.

The relationship between wound-closing tension, blood flow, and flap viability is examined using piglets as an experimental model. Twenty-seven rectangular skin flaps with random-pattern blood flow were created and closed under varying tensions. Closing tensions were accurately measured using a stabilized mechanical force gauge. In flaps with an impaired blood supply, there was a statistically significant increase in flap necrosis for those flaps closed with greater than 250 g of tension. The laser Doppler demonstrated a clear-cut inverse relationship between flap tension and blood flow in these flaps which correlated well with the experimental flap necrosis seen.

Interval insertion of an intrauterine contraceptive device following cesarean section.

Two previous studies of interval insertion of intrauterine contraceptive devices (IUCD) in women with previous cesarean delivery produced conflicting results. We studied the first and subsequent segment IUCD performance in 215 women with one or more cesarean deliveries. All the insertions were performed by doctors in the outpatient department of the hospital. The follow-up rate at 6 months was over 80%. There was a higher than expected expulsion rate of 19 per 100 insertions in the first 12 months, in both the first and subsequent segments. Other IUCD related problems were in keeping with expectations. The IUCD nonetheless remains a useful contraceptive option for these women.

PIP: 2 previous studies of interval insertion of intrauterine contraceptive devices (IUD) in women with previous cesarean delivery produced conflicting results. We studied the 1st and subsequent segment IUD performance in 215 women with 1 or more cesarean deliveries. All the insertions were performed by doctors in the outpatient department of the hospital. The follow-up rate at 6 months was over 80%. There was a higher than expected expulsion rate of 19/100 insertions in the first 12 months, in both the 1st and subsequent segments. Other IUD related problems were in keeping with expectations. The IUD nonetheless remains a useful contraceptive option for these women. (Author's).

Laser Doppler monitoring of microcirculatory changes in acute burn wounds.

Because burns are dynamic wounds that can change in apparent depth during the first 72 hours, we asked whether measuring changes in cutaneous blood flow might help predict the ultimate fate of burns that were not obviously shallow or deep. A laser Doppler flowmeter was used to study cutaneous perfusion for at least 72 hours in partial-thickness wounds on patients with burns of less than 15% TBSA and in experimental wounds of similar size on rats. Clinical wounds that healed without grafting consistently showed elevated perfusion levels which increased further within 72 hours, whereas wounds eventually requiring grafting experienced lower perfusion levels with no obvious pattern of increase. Differences between average flow levels for healing and nonhealing burns were statistically significant throughout the study period. Perfusion levels in experimental wounds were stratified according to burn severity, with shallower wounds showing a pattern of increase similar to the clinical wounds.

Laser Doppler flowmetry for the early detection of hypertrophic burn scars.

In this preliminary study it was hypothesized that patients with hypertrophic scars have increased microcirculatory perfusion in the areas of scarring. Sixteen former patients whose burn injuries involved less than 30% TBSA and who required autologous skin grafting were evaluated using laser Doppler flowmetry. Data grouped at three-week intervals showed higher flow values in patients with hypertrophic scarring than in those with non-hypertrophic scars. These initial data suggest that hypertrophic scars may be associated with increased microcirculatory blood flow. These values are elevated early and could possibly serve as an early indicator for the occurrence of hypertrophic scarring.

Arterial ulcers: assessment and diagnosis.

Arterial ulcers occur because of inadequate perfusion of skin and subcutaneous tissue at rest. Arterial occlusive disease, common among smokers, diabetics and the elderly, can lead to claudication, rest pain and gangrene, in addition to localized ulceration. Other processes, such as venous stasis, pressure, trauma, and vasculitis, can also cause ischemia. However, a thorough patient history and physical assessment can help discriminate between ischemic ulcers caused by arterial disease and other types of ulcers. The key to the diagnosis of arterial occlusive disease is the patient history. Pain while walking is the most common presenting complaint and can indicate intermittent claudication. Physical assessment should include both a general exam, looking for problems relating to lungs, heart and nervous system, and a focused exam of the affected extremities and arterial pulses. Vascular laboratory findings can also help confirm a diagnosis of arterial ischemic ulceration. The key to treatment is improvement in the vascular perfusion to the affected area. Surgical revascularization is the mainstay of treatment, with some interventional procedures becoming accepted. Medical options, in addition to correction of underlying medical problems, include good wound and supportive care, but pharmaceutical interventions have generally not proven effective, and should be considered only if interventional procedures are not possible. With an adequate blood supply reestablished, most arterial ulcers will progress to healing unless there are complicating factors.

A comparison of wound environments.

A comparison of a system of moist wound dressings to traditional normal saline wet-to-dry dressings was conducted on OB/GYN patients with open abdominal incisions. The moist wound products included in this study were a hydrogel (Intrasite Gel) and a foam wound cavity filler (Allevyn), manufactured by Smith & Nephew United, Inc. of Largo, FL, and a transparent cover (Bioclusive), manufactured by Johnson & Johnson Medical, Inc. of Arlington, TX. The results indicated that those incisions treated with the moist wound environment dressings experienced fewer complaints of pain, a decrease in healing time and a significant cost savings.

Preliminary experiences with laser Doppler velocimetry for the determination of amputation levels.

Laser Doppler velocimetry is a newly available technique for the continuous and non-invasive measurement of capillary perfusion. The technique is presented and preliminary results of its use in the evaluation of amputation levels in 16 patients discussed.

Spinal cord stimulation for relief of ischemic pain in end-stage arterial occlusive disease.

A total of 41 patients with end-stage arterial occlusive disease not treatable by surgery were enrolled in a study after implantation of a spinal cord stimulator. To date, a total of 25 patients have been followed up to 6 months after surgery. Patients were classified as grade I to grade III based on the scale developed by the Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery/Society for Cardiovascular Surgery (1986). Sixty-seven percent of patients with rest pain who did not have ulcers (grade II) were successfully treated with a spinal cord stimulator. The success rate among patients who had rest pain and foot lesions was only 38%. Failure is defined as foot amputation or heroic bypass surgery. This study was conducted at six centers in North America.

Placental haemangioma associated with acute fetal anemia in labour.

A case of pregnancy complicated by a placental hemangioma is presented. This was unassociated with any of the complications commonly coexistant with this tumor, and presented with fetal anemia due to a fetomaternal transfusion.