Effects of nifedipine on baroreflex modulation of vascular resistance in man

Studies in animals have demonstrated that, in addition to their vascular effects, calcium channel blockers have important effects on baroreceptor function. We performed a series of experiments to determine if nifedipine, in doses employed clinically, alters baroreflex control of vascular resistance in normal humans. Forearm vasoconstrictor responses of 14 normal subjects to unloading of baroreceptors with lower body negative pressure (LBNP), to a cold pressor test and during intra-arterial infusions of norepinephrine were studied in the control state and following administration of nifedipine. Nifedipine had no effect on baseline mean arterial pressure or central venous pressure. Heart rate and forearm blood flow (FBF) increased significantly following nifedipine: heart rate = 59.7 +/- 2.4 bpm before and 72.6 +/- 4.4 bpm after nifedipine (mean +/- SE, p less than 0.001, n = 14); FBF = 4.6 +/- 0.4 ml X min-1 X 100 ml-1 before and 6.7 +/- 1.0 ml X min1 X 100 ml-1 after nifedipine (p less than 0.02, n = 14). Forearm vascular resistance (FVR) tended to decrease following nifedipine but the difference was not significant: FVR = 21.1 +/- 1.4 units before and 17.8 +/- 2.3 units after nifedipine (p = 0.07, n = 14). Nifedipine attenuated forearm vasoconstrictor responses to cold pressor stimulus: delta FVR during cold pressor test = +10.3 +/- 2.4 units before and +4.7 +/- 1.4 units after nifedipine (p less than 0.02, n = 14). Likewise, nifedipine depressed vasoconstrictor responses to intra-arterial infusion of norepinephrine: delta FVR during norepinephrine = +15.5 +/- 3.4 units before and +10.2 +/- 2.9 units after nifedipine (p less than 0.05, n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone development and age-related bone loss in male C57BL/6J mice

The objective of this study was to examine changes in the long bones of male C57BL/6J mice with growth and aging, and to consider the applicability of this animal for use in studying Type II osteoporosis. Male C57BL/6J mice were aged in our colony between 4 and 104 weeks (n=9-15/group). The right femur and humeri were measured for length and subjected to mechanical testing (3-point flexure) and compositional analysis. The left femurs were embedded and thick slices at the mid-diaphysis were assessed for morphology, formation indices, and bone structure. In young mice, rapid growth was marked by substantial increases in bone size, mineral mass, and mechanical properties. Maturity occurred between 12 and 42 weeks of age with the maintenance of bone mass and mechanical properties. From peak levels, mice aged for 104 weeks experienced decreased whole femur mass (12.1 and 18.6% for dry and ash mass, respectively), percentage mineralization (7.4%), diminished whole bone stiffness (29.2%), energy to fracture (51.8%), and decreased cortical thickness (20.1%). Indices of surface-based formation decreased rapidly from the onset of the study. However, the periosteal perimeter and, consequently, the cross-sectional moments of inertia continued to increase through 104 weeks, thus maintaining structural properties. This compensated for cortical thinning and increased brittleness due to decreased mineralization and stiffness. The shape of the mid-diaphysis became increasingly less elliptical in aged mice, and endocortical resorption and evidence of subsequent formation were present in 20-50% of femurs aged > or =78 weeks. This, combined with the appearance of excessive endocortical resorption after 52 weeks, indicated a shift in normal mechanisms regulating bone shape and location, and was suggestive of remodeling. The pattern of bone loss at the femoral mid-diaphysis in this study is markedly similar to that seen in cortical bone in the human femoral neck in Type II osteoporosis. This study has thus demonstrated that the male C57BL/6J mouse is a novel and appropriate model for use in studying endogenous, aging-related osteopenia and may be a useful model for the study of Type II osteoporosis.     

Patient survival after renal transplantation: IV. Impact of post-transplant diabetes

BACKGROUND: The development of de novo diabetes mellitus is a serious complication of kidney transplantation. This study examined the cardiovascular risk profile of patients with post-transplant diabetes (PTDM) and assessed the impact of PTDM on patient survival. METHODS: This analysis included 1811 adult, renal allograft recipients, transplanted in a single institution between 1983 and 1998. Patient survival was analyzed by univariable and multivariable Cox regression considering PTDM as a time dependent variable. RESULTS: After a follow-up period of 8.3 +/- 4.5 years, 293 patients (20%) developed PTDM, 14% lost their graft, and 20% died. Compared to patients without DM (NoDM, N = 1186) patients with PTDM were significantly older (40 +/- 14 vs. 48 +/- 12 years, P < 0.001), heavier (76 +/- 23 vs. 86 +/- 25 kg, P < 0.001), and included more African Americans (18 vs. 28%, P = 0.001). In addition, the incidence of PTDM was significantly higher in patients who were transplanted after 1995 than prior to that year. In contrast, there were no significant differences between PTDM and patients who had DM before the transplant (DM; N = 332). Compared to NoDM, patients with PTDM had significantly higher total serum cholesterol and triglycerides (TG), higher systolic blood pressure and higher pulse pressure throughout the post-transplant period. Of interest, all of these abnormalities preceded the development of PTDM. Hypertriglyceridemia was particularly pronounced in PTDM and elevated TG levels correlated with the subsequent development of PTDM, independent of other risk factors (P = 0.001 by multivariate Cox). Compared to NoDM (16% mortality) a significantly higher percent of DM (31%, P < 0.001) and PTDM (22%, P = 0.005) patients died. By Cox regression, PTDM correlated with reduced patient survival (hazard ratio = 1.80, CI 1.35 to 2.41, P = 0.001), and that relationship was independent of other correlates of reduced survival that included: increasing age; transplant year; reduced serum albumin; and male sex. CONCLUSION: s: PTDM is associated with an unfavorable cardiovascular risk profile that precedes the development of hyperglycemia. PTDM is an independent predictor of reduced survival in renal allograft recipients.     

Outcomes in surgical treatment of "idiopathic-like" scoliosis associated with syringomyelia

Patients with "idiopathic-like" spinal deformities associated with syringomyelia were retrospectively reviewed. Ten patients had surgical stabilization of their curvatures with at least a 2-year follow-up, and an additional five patients were evaluated for deformity pattern with <2 years of follow-up. Paralytic curve patterns, scoliosis associated with spina bifida, congenital scoliosis, or other associated syndromes were discarded. All 10 patients with surgery who were followed for an average of 46 months lost 10 degrees correction above, through, or below the instrumented segments. A total of 50% lost correction through the instrumented segments. Anterior fusion stabilized the instrumented portion of the spine better than posterior instrumentation alone. Eighty percent of the 15 patients had thoracic kyphosis >40 degrees. Only one patient was lordoscoliotic. Syringomyelia deformities tend to be kyphoscoliotic in 80% of cases and behave more like paralytic curvatures postoperatively. MRI is recommended for apparent idiopathic scoliotic curvatures that are kyphoscoliotic and not lordoscoliotic.     

Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring.

Keloids are benign skin tumours occurring during wound healing in genetically predisposed patients. They are characterised by an abnormal deposition of extracellular matrix components, in particular collagen. There is evidence that transforming growth factor-beta (TGFbeta) is involved in keloid formation. SMAD proteins play a crucial role in TGFbeta signaling and in terminating the TGFbeta signal by a negative feedback loop through SMAD6 and 7. It is unclear how TGFbeta signaling is connected to the pathogenesis of keloids. Therefore, we investigated the expression of SMAD mRNA and proteins in keloids, in normal skin and in normal scars. Dermal fibroblasts were obtained from punch-biopsies of keloids, normal scars and normal skin. Cells were stimulated with TGFbeta1 and the expression of SMAD2, 3, 4, 6 and 7 mRNA was analysed by real time RT-PCR. Protein expression was determined by Western blot analysis. Our data demonstrate a decreased mRNA expression of the inhibitory SMAD6 and 7 in keloid fibroblasts as compared to normal scar (p<0.01) and normal skin fibroblasts (p<0.05). SMAD3 mRNA was found to be lower in keloids (p<0.01) and in normal scar fibroblasts (p<0.001) compared to normal skin fibroblasts. Our data showed for the first time a decreased expression of the inhibitory SMAD6 and SMAD7 in keloid fibroblasts. This could explain why TGFbeta signaling is not terminated in keloids leading to overexpression of extracellularmatrix in keloids. These data support a possible role of SMAD6 and 7 in the pathogenesis of keloids.     

Evaluation of a novel precision template-guided biopsy system for detecting prostate cancer

OBJECTIVE

To explore the ability of a novel transrectal ultrasonography (TRUS) device (TargetScan^TM, Envisioneering Medical Technologies, St. Louis MO) that creates a three‐dimensional map of the prostate and calculates an optimal biopsy scheme, to accurately sample the prostate and define the true extent of disease, as standard TRUS‐guided prostate biopsy relies on the operator to distribute the biopsy sites, often resulting in under‐ and oversampling regions of the gland.

PATIENTS AND METHODS

In a multicentre retrospective chart review evaluating patients who had a TargetScan prostate biopsy between January 2006 and June 2007, we determined the overall cancer detection rate in all patients and in subgroups based on prostate specific antigen level, digital rectal examination, and indication for biopsy. We assessed the pathological significance of cancer detected, defined as a Gleason score of ≥7, positive margins, extracapsular disease or >20% tumour volume in the prostatectomy specimen. We also evaluated the concordance in Gleason score between the biopsy and prostatectomy specimen.

RESULTS

Cancer was detected in 50 (35.7%) of the 140 patients biopsied, including 39 (47.6%) with no previous biopsies. Of 23 prostatectomy specimens, 20 (87%) had pathologically significant disease. The biopsy predicted the prostatectomy Gleason score in 12 patients (52%), overestimated in two (9%), underestimated in eight (35%), and biopsy Gleason score could not be assigned in one (4%).

CONCLUSIONS

Template‐guided biopsy potentially produces a higher cancer detection rate and more accurate assessment of grade. Prostatectomy specimens did not have a high rate of pathologically insignificant disease.     

Variable impairment of wound healing in the heterozygous collagenase-resistant mouse

Collagen undergoes dramatic reorganization during wound repair. Matrix metalloproteinases degrade and remodel collagen in a tightly controlled process. The collagenase-resistant mouse, Col1a1(tm1Jae), produces type I collagen, which is resistant to degradation by human matrix metalloproteinase 1. These mice grow normally but develop thickened skin with age. We have previously reported that the early wound repair response in homozygous mutant (Col1a1(r/r)) mice is delayed compared to wild type (Col1a1(+/+)). However, the late-stage scar of Col1a1(r/r) wounds was not significantly altered compared to Col1a1(+/+). Here we have investigated the response of heterozygous mice (Col1a1(+/r)) to wounding, not previously reported. Wound reepithelialization was delayed to a similar degree to wounds in the Col1a1(r/r) mice. However, the recovery of impaired wound contraction was faster in Col1a1(+/r) than in Col1a1(r/r) mice, but still slower than in wild-type animals. Analysis of wound protein extracts showed expression of some matrix metalloproteinases was prolonged in both the Col1a1(r/r) and Col1a1(+/r) wounds compared to wild type. We suggest the partial resistance of collagen to collagenase-mediated degradation in the heterozygous animals causes equivalent impairment of keratinocyte migration compared to homozygous collagenase-resistant mice, but that wound contraction during late-stage healing is only partially retarded.     

Demonstration of biofilm in human bacterial chronic rhinosinusitis

BACKGROUND: Bacterial biofilms may explain why some patients with bacterial chronic rhinosinusitis (CRS) improve while on antibiotics but relapse after completion of the antibiotic. In the human host, biofilms exist as a community of bacteria surrounded by a glycocalyx that is adherent to a foreign body or a mucosal surface with impaired host defense. Biofilms generate planktonic, nonadherent bacterial forms that may metastasize infection and generate systemic illness. These planktonic bacteria are susceptible to antibiotics, unlike the adherent biofilm. METHODS: We reviewed four cases of CRS using transmission electron microscopy (TEM) to assay for typical colony architecture of biofilms. Bacterial communities surrounded by a glycocalyx of inert cellular membrane materials consistent with a biofilm were shown in two patients. RESULTS: In the two patients without biofilm, a nonbacterial etiology was discovered (allergic fungal sinusitis) in one and in the other there was scant anaerobic growth on culture and the Gram stain was negative. Culture of the material from the biofilm grew Pseudomonas aeruginosa in both patients. Pseudomonas from the biofilm showed a glycocalyx, not present in Pseudomonas cultured for 72 hours on culture media. Both patients' symptoms with bacterial biofilms were refractory to culture-directed antibiotics, topical steroids, and nasal lavages. Surgery resulted in cure or significant improvement. CONCLUSION: Biofilms are refractory to antibiotics and often only cured by mechanical debridement. We believe this is the first TEM documentation of bacterial biofilms in CRS in humans.     

TINEA VERSICOLOR: HISTOLOGIC AND ULTRASTRUCTURAL INVESTIGATION OF PIGMENTARY CHANGES

A comparative histopathologic study is made between the hypopigmented and hyperpigmented skin lesions of pityriasis versicolor and normal skin areas utilizing histochemical stains and electron microscopy. There were no differences found between the population of Dopa-positive melanocytes within the hypopigmented and hyperpigmented lesions and the normal skin areas. The total epidermal pigmentation was diminished in hypopigmented lesions. The keratin layer was found to be significantly thicker in hyperpigmented lesions and contained more organisms. In hypopigmented lesions, melanocytes contained fewer and smaller melanosomes and exhibited signs of degenerative cellular changes.