Miliary tuberculosis and acquired immunodeficiency syndrome - 'a cursed duet'.

Tuberculous osteomyelitis is rare and usually involves the vertebrae but is seldom found in the foot. The uncommon site and ability to mimic other disorders clinically and radiographically leads to diagnostic and therapeutic delays. We report a case of a 40-year-old man who initially presented to his podiatrist with intermittent pain and swelling of his right ankle and foot that lasted for a year. He also started to exhibit significant weight loss and unexplained fevers and was subsequently hospitalized for cellulitis of his right foot. On further workup, patient was found to have miliary tuberculosis (TB) and acquired immunodeficiency syndrome (AIDS). Patient was treated with anti-TB therapy for 9 months and highly active anti-retroviral therapy. Our patient presented with ongoing chronic right foot and ankle pain that was proven to be secondary to TB osteomyelitis of cuneiform bones of the right ankle in the setting of AIDS. The patient's clinical presentation was unusual due to symptom duration and lack of systemic characteristics. Like our case, reported incidence of osteomyelitis of bone/joint in extrapulmonary TB is estimated to be 10%, and out of all bones/joint TB cases, only 1% are found to be in the foot.

Role of Therapeutic Plasma Exchange in Treatment of Tumefactive Multiple Sclerosis-Associated Low CD4 and CD8 Levels.

We report a 35-year-old healthy male who developed central nervous system inflammatory demyelinating disease consistent with tumefactive multiple sclerosis. About 2 weeks after onset of symptoms and prior to initiation of therapy, the patient had lymphopenia and low CD4 and CD8 levels. His lymphocyte count was 400 cells/µl (850-3,900 cells/µl), CD4 was 193 cells/µl (490-1,740 cells/µl) and CD8 was 103 cells/µl (180-1,170 cells/µl). He was treated with intravenous methylprednisolone followed by therapeutic plasma exchange, the levels of CD4 and CD8 normalized, and ultimately, he recovered completely.

Whole blood viscosity and microvascular abnormalities in Alzheimer's Disease.

We hypothesized that abnormalities in hemorheologic parameters, including vessel diameter, flow velocity, and whole blood viscosity (WBV), would be present in Alzheimer's Disease (AD) and would correlate with microvascular abnormalities (vasculopathy). Using the Rheolog, we obtained WBV profiles, measured at shear rates of 1-1,000 s-1, for 10 AD subjects and age matched non-AD controls. Vessel diameter, flow velocity, and microvascular abnormalities were quantified using computer-assisted intravital microscopy (CAIM) of the conjunctival microcirculation. A Severity Index (SI), scale 0-15, was computed to reflect degree/severity of vasculopathy. AD subjects compared to controls had significantly higher WBV (3.96+/-0.29 cP vs. 3.34+/-0.05 cP, sheared at 300 s-1; P<0.05) and SI (7.00+/-2.36 vs. 0.30+/-0.70; P<0.05). WBV was correlated (rhos=0.648; P<0.05) with SI in AD subjects. These results strongly suggest the simultaneous involvement of hemorheologic abnormalities and systemic vasculopathy in AD.

Comparison of treatment modalities for hemorrhagic shock.

Allogeneic blood resuscitation is the treatment of choice for hemorrhagic shock. When blood is unavailable, plasma expanders, including crystalloids, colloids, and blood substitutes, may be used. Another treatment modality is vasopressin, a vasoconstrictor administered to redistribute blood flow, increase venous return, and maintain adequate cardiac output. While much information exists on systemic function and oxygenation characteristics following treatment with these resuscitants, data on their effects on the microcirculation and correlation of real-time microvascular changes with changes in systemic function and oxygenation in the same animal are lacking. In this study, real-time microvascular changes during hemorrhagic shock treatment were correlated with systemic function and oxygenation changes in a canine hemorrhagic shock model (50-55% total blood loss with a MAP of 45-50 mmHg as a clinical criterion). Following splenectomy and hemorrhage, the dogs were assigned to five resuscitation groups: autologous/shed blood, hemoglobin-based oxygen carrier/Oxyglobin, crystalloid/saline, colloid/Hespan (6% hetastarch), and vasopressin. Systemic function and oxygenation changes were continuously monitored and periodically measured (during various phases of the study) using standard operating room protocols. Computer-assisted intravital video-microscopy was used to objectively analyze and quantify real-time microvascular changes (diameter, red-cell velocity) in the conjunctival microcirculation. Measurements were made during pre-hemorrhagic (baseline), post-hemorrhagic (pre-resuscitation), and post-resuscitation phases of the study. Pre-hemorrhagic microvascular variables were similar in all dogs (venular diameter = 42+/-4 microm, red-cell velocity = 0.55+/-0.5 mm/sec). All dogs showed significant (P < 0.05) post-hemorrhagic microvascular changes: approximately 20% decrease in venular diameter and approximately 30% increase in red-cell velocity, indicative of sympathetic effects arising from substantial blood loss. Microvascular changes correlated with post-hemorrhagic systemic function and oxygenation changes. All resuscitation modalities except vasopressin restored microvascular and systemic function changes close to pre-hemorrhagic values. However, only autologous blood restored oxygenation changes to pre-hemorrhagic levels. Vasopressin treatment resulted in further decreases in venular diameter (approximately 50%) as well as red-cell velocity (approximately 70%) without improving cardiac output. Our results suggested that volume replenishment - not oxygen-carrying capability - played an important role in pre-hospital/en route treatment for hemorrhagic shock. Vasopressin treatment resulted in inadvertent detrimental outcome without the intended benefit.

Effects of poloxamer 188 treatment on sickle cell vaso-occlusive crisis: computer-assisted intravital microscopy study.

Nine patients with sickle cell disease (SCD) who were hospitalized at UC Davis Medical Center for vaso-occlusive crisis (VOC) were studied as part of a randomized double-blind phase III clinical trial to investigate the real-time effects of poloxamer 188 on VOC. All patients showed significant microvascular changes from normal (steady-state) values during VOC (diminished venular diameter and red cell velocity). The patients were randomly assigned to be treated with poloxamer 188 or placebo. Poloxamer 188 (n = 4) but not placebo (n = 5) significantly reversed these microvascular changes approximately 2 hours postinitiation of loading infusion (100 mg/kg in 1 hour). Further significant improvement induced by poloxamer 188 but not placebo was observed > or = 7 hours postinfusion, resulting in a significant reversal of the microvascular changes to steady-state values.

The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo.

Microvascular occlusion in sickle cell disease can be initiated by adhesion of sickle red blood cells (RBCs) to the endothelium. Our objective in this study was to verify the relevance in vivo of our discovery that sickle RBCs adhere abnormally to endothelial P-selectin in vitro. We used computer-assisted intravital microscopy to characterize RBC flow velocity (V(RBC)) in mice. We found faster V(RBC) of sickle RBCs in P-selectin knock-out and control mice than in sickle cell mice, which have increased endothelial cell P-selectin expression. Agonist peptide for murine protease-activated receptor-1 (PAR-1), which selectively activates mouse endothelial cells but not platelets, was used to assess the effects of endothelial cell P-selectin on microvascular flow. Suffusion of venules with this agonist stopped flow promptly in normal and sickle mice but not in P-selectin knock-out mice or in control mice pretreated with anti-P-selectin monoclonal antibody or unfractionated heparin (UFH). Agonist-induced slowing of flow was reversed rapidly by suffusion with UFH, provided flow had not already stopped. We conclude that endothelial cell P-selectin contributes to the microcirculatory abnormalities in sickle cell disease and that blocking P-selectin may be useful for preventing painful vasoocclusion in sickle cell disease.

Blood substitute resuscitation as a treatment modality for moderate hypovolemia.

Blood substitute resuscitation as a treatment modality for moderate hypovolemia (approximately 40% blood loss) in a canine model has been evaluated using Oxyglobin (Biopure Hemoglobin Glutamer-200/ Bovine; a hemoglobin-based oxygen-carrier) and Hespan (6% hetastarch; a nonoxygen-carrier) as resuscitants. Autologous (shed) blood served as control. Nine dogs were studied--after splenectomy, each dog was hemorrhaged (32-36 mL/kg; MAP = approximately 50 mmHg) and randomly assigned to the three resuscitation groups. Microvascular, systemic function and oxygenation characteristics were monitored and/or measured simultaneously in prehemorrhagic (baseline), posthemorrhagic and postresuscitation phases for correlation-real-time microvascular changes in the bulbar conjunctiva were noninvasively measured via computer-assisted intravital microscopy and systemic function and oxygenation changes were monitored and/or measured via instrumentation and devices incorporated into our bioengineering station in an operating room setting. Blood chemistry was also studied for relevant measurements. Prehemorrhagic microvascular characteristics were similar in all animals (venular diameter = 41 +/- 12 microm, A:V ratio = approximately 1:2, red-cell velocity = 0.5 +/- 0.3 mm/s). All animals also showed similar prehemorrhagic systemic function and oxygenation measurements comparable to a previous study and were consistent with normal measurements in dogs. At the completion of hemorrhaging to achieve moderate hypovolemia (approximately 40% blood loss with MAP at approximately 50 mmHg), all nine animals showed similar significant (P < 0.01) posthemorrhagic microvascular changes, including approximately 17% decrease in diameter (34 +/- 7 microm), A:V ratio = variable, and approximately 80% increase in velocity (0.9 +/- 0.5 mm/s). All animals also showed similar significant (P < 0.01) posthemorrhagic systemic function and oxygenation changes, with decreases in Hct, aHb(total), MPAP, MAP, SAP, DAP, CO, SVI, CaO2, and CvO2 and increases in HR and lactic acidosis. Shed blood (control) resuscitation restored posthemorrhagic microvascular changes close to prehemorrhagic values (diameter = 39 +/- 6 microm, A:V ratio = approximately 1:2, velocity = 0.6 +/- 0.4 mm/s). Oxyglobin and Hespan restored microvascular changes in similar manner close to prehemorrhagic values (Oxyglobin: diameter = 38 +/- 3 microm, A:V ratio = approximately 1:2, velocity = 0.6 +/- 0.4 mm/s; Hespan: diameter = 38 +/- 7 microm, A:V ratio = 1:2, velocity = 0.5 +/- 0.4 mm/s). After resuscitation, shed blood (control) restored all systemic function and oxygenation changes close to prehemorrhagic values. However, both Oxyglobin and Hespan resuscitation restored systemic function changes, but not oxygenation changes, to prehemorrhagic values. This was an interesting finding because of the different oxygen-carrying capability of Oxyglobin (oxygen-carrying) and Hespan (nonoxygen-carrying). The result suggests that either volume replenishment alone (and not oxygen-carrying capability) is needed to treat moderate hypovolemia or oxygenation measurements obtained by standard methods (oximetry, blood chemistry) may not reflect tissue oxygenation levels.

Microvascular abnormalities in sickle cell disease: a computer-assisted intravital microscopy study.

The conjunctival microcirculation of 18 homozygous sickle cell disease (SCD) patients during steady-state, painful crisis, and postcrisis conditions was recorded on high-resolution videotapes using intravital microscopy. Selected videotape sequences were subsequently coded, frame-captured, studied, and blindly analyzed using computer-assisted image analysis protocols. At steady-state (baseline), all SCD patients exhibited some of the following morphometric abnormalities: abnormal vessel diameter, comma signs, blood sludging, boxcar blood flow phenomenon, distended vessels, damaged vessels, hemosiderin deposits, vessel tortuosity, and microaneurysms. There was a decrease in vascularity (diminished presence of conjunctival vessels) in SCD patients compared with non-SCD controls, giving the bulbar conjunctiva a "blanched" avascular appearance in most but not all SCD patients during steady-state. Averaged steady-state red cell velocity in SCD patients was slower than in non-SCD controls. During painful crisis, a further decrease in vascularity (caused by flow stoppage in small vessels) and a 36.7% +/- 5.2% decrease in large vessel (mostly venular) diameter resulted. In addition, the conjunctival red cell velocities either slowed significantly (6.6% +/- 13.1%; P <.01) or were reduced to a trickle (unmeasurable) during crisis. The microvascular changes observed during crisis were transient and reverted to steady-state baseline after resolution of crisis. When combined, intravital microscopy and computer-assisted image analysis (computer-assisted intravital microscopy) represent the availability of a noninvasive tool to quantify microvascular abnormalities in vascular diseases, including sickle cell disease. The ability to identify and relocate the same conjunctival vessels for longitudinal studies uniquely underscores the applicability of this quantitative real-time technology.

Microvascular abnormalities in pediatric diabetic patients.

Microvascular abnormalities are associated with and causative of the development of end-stage organ complications in adult diabetic patients. Whether the same microvascular abnormalities are present in pediatric patients is not known and has not been studied because of a lack of real-time technology, methodology to study young patients, and availability of an appropriate noninvasive site for in vivo studies. We hypothesized that microvascular abnormalities should be present in pediatric patients despite their young age and the relatively short durations of the disease. In this study, computer-assisted intravital microscopy (CAIM) was adapted to blindly quantify microvascular abnormalities in 12 pediatric type 1 diabetic mellitus (T1DM) patients (ages = 6-16 years; mean +/- SD = 11.42 +/- 3.42; duration since diagnosis = 2-14 years; mean +/- SD = 6.75 +/- 3.79) in vivo, using the microcirculation of the bulbar conjunctiva as a noninvasive site. Microvascular abnormalities, commonly found in adult patients, existed in the conjunctival microcirculation of all pediatric T1DM patients in varying degrees despite their relatively young age. A severity index (SI) was developed to reflect the cumulative severity of the microvascular abnormalities and was computed as the summation of all microvascular abnormalities found in each patient. SI for the 12 T1DM patients (mean +/- SD = 7.42 +/- 1.88; median = 8; mode = 9) differed significantly from that for the nondiabetic controls (mean +/- SD = 0.67 +/- 0.78; median = 0.5; mode = 0; P < 0.0001). In addition, SI correlated with hemoglobin A1c levels (mean +/- SD = 9.18 +/- 1.57) of T1DM patients but did not correlate with the duration of disease since diagnosis of the same patients. This observation raises the possibility that diabetic pathogenesis may precede the onset of overt disease or clinical diagnosis. This study confirms that CAIM may represent the availability of a useful real-time technology to study conjunctival microvascular abnormalities in vascular diseases in juvenile as well as adult patients.