Novel pathologic scoring tools predict end-stage kidney disease in light chain (AL) amyloidosis

Background and objectives: Light chain (AL) amyloidosis frequently involves the kidney, causing significant morbidity and mortality. A pathologic scoring system with prognostic utility has not been developed. We hypothesized that the extent of amyloid deposition and degree of scarring injury on kidney biopsy, could provide prognostic value, and aimed to develop pathologic scoring tools based on these features.

Methods: This is a case-control study of 39 patients treated for AL amyloidosis with biopsy-proven kidney involvement at a large academic medical center. Our novel scoring tools, composite scarring injury score (CSIS) and amyloid score (AS) were applied to each kidney biopsy. The primary outcome was progression to dialysis-dependent end-stage kidney disease (ESKD) using a 12-month landmark analysis.

Results: At 12?months, nine patients had progressed to ESKD. Patients with an AS ≥7.5 had a significantly higher cumulative incidence of ESKD than those with AS <7.5 (p?=?.04, 95% CI 0.13–0.64).

Conclusions: Using a 12-month landmark analysis, AS correlated with progression to ESKD. These data suggest that a kidney biopsy, in addition to providing diagnostic information, can be the basis for a pathologic scoring system with prognostic significance.     

The folded postauricular flap: A novel approach to reconstruction of large full thickness defects of the conchal bowl

Extensive subtotal full-thickness auriculectomy defects pose a challenge for the reconstructive surgeon. The posterior island flap (PIF), based on the posterior auricular artery, has been described as a reconstructive option for auricular defects, with reports describing a “pull-through” or “revolving door” technique to reconstruct subtotal partial thickness and full thickness auricular defects. These techniques may result in posterior “pinning” of the auricle. This patient is an 87-year-old male who presented after Mohs excision of squamous cell carcinoma of the conchal bowl, which resulted in a 4x4cm subtotal auriculectomy defect. A folded PIF was used to reconstruct the large full thickness defect, in a multistage manor. Post-operatively, the patient had a reconstructed auricle that was suitable for wearing hearing aids and glasses. We describe a novel technique of the folded PIF for an extensive full-thickness auricular defect, which utilizes a single, well camouflaged donor site, provides well-vascularized local tissue with excellent color match, and allows for the restoration of the post-auricular sulcus.     

Pelvic inflammatory disease attributable to the IUD: modeling risk in West Africa

BACKGROUND: In Africa, use of the intrauterine device (IUD) is avoided because of perceived risk of pelvic inflammatory disease (PID) associated with sexually transmitted infections (STI). However, one recent model suggests that the risk of PID attributable to the IUD is very low, only 0.15% or less than 1 in 600. STUDY DESIGN: Using rates from a 2004 study of cervical STI prevalence in Benin, Burkina Faso, Ghana, Guinea, and Mali; we calculate PID risk attributable to the IUD in West Africa. RESULTS: Based on 4.4% combined prevalence of chlamydial and gonococcal infections, we estimate the risk is 0.075%, or less than 1 in 1,300. CONCLUSIONS: In West Africa, PID risk from IUDs is extremely low. This should be better communicated to family planning providers in the region who may under-provide the IUD based on erroneous perceptions of PID risk.     

In vitro and in vivo evaluation of 177Lu- and 90Y-labeled E. coli heat-stable enterotoxin for specific targeting of uroguanylin receptors on human colon cancers

The human E. coli heat-stable enterotoxin (ST(h), amino acid sequence N1SSNYCCELCCNPACTGCY19) binds specifically to the guanylate cyclase C (GC-C) receptor, which is present in high density on the apical surface of normal intestinal epithelial cells as well as on the surface of human colon cancer cells. Analogs of ST(h) are currently being used as vectors targeting human colon cancers. Previous studies in our laboratory have focused on development of 111Indium-labeled ST(h) analogs for in vivo imaging applications. Here, we extend the scope of this work to include targeting of the therapeutic radionuclides 90Y and 177Lu. The peptide DOTA-F19-ST(h)(1-19) was synthesized using conventional Fmoc-based solid-phase techniques and refolded in dilute aqueous solution. The peptide was purified by RP-HPLC and characterized by MALDI-TOF MS and in vitro receptor binding assay. The DOTA-conjugate was metallated with nonradioactive Lu(III)Cl3 and Y(III)Cl3, and IC50 values of 2.6+/-0.1 and 4.2+/-0.9 nM were determined for the Lu- and Y-labeled peptides, respectively. 177Lu(III)Cl3 and 90Y(III)Cl3 labeling yielded tracer preparations that were inseparable by C18 RP-HPLC, indicating that putative differences between Lu-, Y- and In coordination spheres are not observed in the context of labeled ST(h) peptides. In vivo biodistribution studies of the 177Lu-labeled peptide in severe combined immunodeficient (SCID) mice bearing T-84 human cancer tumor xenografts showed rapid clearance from the bloodstream, with >90 %ID in the urine at 1 h pi. Localization of the tracer within tumor xenografts was 1.86+/-0.91 %ID/g at 1 h pi, a value higher than for all other tissues with the exception of kidney (2.74+/-0.24 %ID/g). At 24 h pi, >98 %ID was excreted into the urine, and 0.35+/-0.23 %ID/g remained in tumor, again higher than in all other tissues except kidney (0.91+/-0.46 %ID/g). Biodistribution results at 24 h pi for the 90Y-labeled peptide mirrored those for the 177Lu analog, in agreement with the identical behavior of the labeled analogs by C18 RP-HPLC. These results demonstrate the ability of 177Lu- and 90Y-labeled ST(h) molecules to specifically target GC-C receptors expressed on T-84 human colon cancer cells.     

Artemin has potent neurotrophic actions on injured C-fibres

In this study, we have investigated the effects of artemin (ARTN), one of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, on C-fibres following nerve injury in the adult rat. GDNF family receptor alpha (GFRalpha) 3, the ligand binding domain of the ARTN receptor, is expressed in 34% of dorsal root ganglion (DRG) cells, predominantly in the peptidergic population of C-fibres and in a proportion of the isolectin B4 (IB4)-binding population. Interestingly, only 30% of GFRalpha3-expressing DRG cells co-expressed RET (the signal transducing domain). In agreement with previous studies, treatment with ARTN prevented many of the nerve injury-induced changes in the histochemistry of both the peptidergic and the IB4-binding populations of small, but not large, diameter DRG cells. In addition, ARTN treatment maintained C-fibre conduction velocity, and C-fibre evoked substance P release within the dorsal horn following nerve injury. ARTN was also protective following capsaicin treatment, which produces selective C-fibre injury. Given the potent neurotrophic actions of ARTN on C-fibres, it may therefore provide potential for the treatment of nerve injury, particularly in the maintenance of small fibre function.     

Use of treatment algorithms for depression

Depression continues to be a treatment challenge for many physicians-psychiatrists and primary care physicians alike-in part because of the nature of the disorder, but also because of the wide variety of medications and other treatments available, each with a distinct efficacy and safety profile. One way of negotiating treatment decisions is to use treatment guidelines and algorithms. This Commentary, which appears in the September 2006 issue of The Journal of Clinical Psychiatry (2006;67:1458-1465), provides the primary care clinician with insight into the pros and cons of using treatment algorithms to guide the treatment of depression. -Larry Culpepper, M.D.     

Static progressive stretch for the treatment of knee stiffness

Persistent knee stiffness is common after knee arthroplasties, cruciate ligament repairs, and trauma. Static progressive stretch protocols have shown success in treating contractures of the elbow, ankle, and knee in case reports and small case series. This study evaluated static progressive stretch as a treatment method for patients who had refractory knee stiffness, and compared the outcomes to published results of other therapeutic modalities. Forty-one patients who had knee stiffness and who had not improved with conventional physical therapy modalities were treated with a patient-directed orthosis that utilized the principles of static progressive stretch. After a mean of 9 weeks of use (range, 3 to 27 weeks), the total arc of motion increased by a mean of 33 degrees (range, 0 to 85 degrees ). Forty of 41 patients had increased motion at a mean final follow-up time of 1 year (range, 6 months to 2 years), and 93% were satisfied with the results. The outcomes were comparable to other nonoperative treatments reported in the literature, but the results in the present study occurred in a shorter mean treatment time. An orthosis that utilizes the principles of static progressive stretch may be a successful treatment for improving the range of motion and satisfaction of patients who have knee contractures.     

Evaluation of the in vitro skin permeation of antiviral drugs from penciclovir 1% cream and acyclovir 5% cream used to treat herpes simplex virus infection

Background

Herpes simplex virus infection (HSV) is a common and ubiquitous infection of the skin which causes mucocutaneous lesions called cold sores (herpes labialis) or fever blisters. It is estimated that approximately 80% of the population worldwide are carriers of the Herpes simplex virus, approximately 40% suffer from recurrent recurrent infections. This study evaluates the in vitro skin permeation and penetration of penciclovir and acyclovir from commercialized creams for the treatment of herpes labialis (cold sores), using non viable excised human abdominal skin samples, which were exposed to 5 mg/cm² of acyclovir 5% cream or penciclovir 1% cream.

Methods

After 24 h of cream application, excess cream was washed off and layers of stratum corneum were removed by successive tape stripping. Amounts of active ingredients having penetrated through the skin were measured, as well as the amounts in the washed-off cream, in skin strips and creams remaining in the skin. Molecular modelling was used to evaluate physico-chemical differences between the drugs. Western blot analysis enabled to determine whether the marker of basal cells keratin 5 could be detected in the various tape strips.

Results

Application of penciclovir 1% cream yielded higher concentration of drug in the deeper layers of the epidermis as well as a higher drug flux through the skin. Molecular modelling showed two higher hydrophobic moieties for acyclovir. Presence of the basal cell marker keratin 5 was underscored in the deeper tape strips from the skin, giving evidence that both drugs can reach their target cells.

Conclusion

Penciclovir 1% cream has the tendency to facilitate the diffusion of the drug through the stratum corneum into the deeper epidermis layers, in which it could reach the target basal cells at effective therapeutical concentration. The small difference in the surface properties between both molecules might also contribute to favour the passage of penciclovir through the epidermis into the deeper basal cells.