Metabolic physiology in age related macular degeneration

Ischemia and hypoxia have been implicated in the pathophysiology of age related macular degeneration (AMD). This has mostly been based on studies on choroidal perfusion, which is not the only contributor to retinal hypoxia found in AMD eyes. Other features of AMD may also interfere with retinal oxygen metabolism including confluent drusen, serous or hemorrhagic retinal detachment, retinal edema and vitreoretinal adhesion. Each of these features contributes to retinal hypoxia: the drusen and retinal elevation by increasing the distance between the choriocapillaris and retina; vitreoretinal adhesion by reducing diffusion and convection of oxygen towards and vascular endothelial growth factor (VEGF) away from hypoxic retinal areas. Hypoxia-inducible-factor is known to exist in subretinal neovascularization and hypoxia is the main stimulus for the production of VEGF. Each feature may not by itself create enough hypoxia and VEGF accumulation to stimulate wet AMD, but they may combine to do so. Choroidal ischemia in AMD has been demonstrated by many researchers, using different technologies. Choroidal ischemia obviously decreases oxygen delivery to the outer retina. Confluent drusen, thickening of Bruch's membrane and any detachment of retina or retinal pigment epithelium, increases the distance between the choriocapillaris and the retina and thereby reduces the oxygen flux from the choroid to the outer retina according to Fick's law of diffusion. Retinal elevation and choroidal ischemia may combine forces to reduce choroidal oxygen delivery to the outer retina, produce retinal hypoxia. Hypoxia leads to production of VEGF leading to neovascularization and tissue edema. A vicious cycle may develop, where VEGF production increases effusion, retinal detachment and edema, further increasing hypoxia and VEGF production. Adhesion of the viscous posterior vitreous cortex to the retina maintains a barrier to diffusion and?convection currents in the vitreous cavity according to the laws of Fick's, Stokes-Einstein and Hagen-Poiseuille. If the vitreous is detached from the surface of the retina, the low viscosity fluid transports oxygen and nutrients towards an ischemic area of the retina, and cytokines away from the retina, at a faster rate than through attached vitreous gel. Vitreoretinal adhesion can exacerbate retinal hypoxia and accumulation of cytokines, such as VEGF. Vitreoretinal traction can also cause hypoxia by retinal elevation. Conceivably, the basic features of AMD, drusen, choroidal ischemia, and vitreoretinal adhesion are independently determined by genetics and environment and may combine in variable proportions. If the resulting hypoxia and consequent VEGF accumulation crosses a threshold, this will trigger effusion and neovascularization.     

Performance of Interferon-Gamma and IP-10 Release Assays for Diagnosing Latent Tuberculosis Infections in Patients with Concurrent Malaria in Tanzania

Interferon-gamma (IFN-γ) release assays (IGRAs) are used to detect cellular immune recognition of Mycobacterium tuberculosis. The chemokine IFN-γ-inducible protein 10 (IP-10) is an alternative diagnostic biomarker to IFN-γ. Several conditions interfere with IGRA test performance. We aimed to assess the possible influence of Plasmodium falciparum infection on the IGRA test QuantiFERON-TB GOLD^® In-Tube (QFT) test and an in-house IP-10 release assay. In total, 241 Tanzanian adults were included; 184 patients with uncomplicated malaria (88 human immunodeficiency virus [HIV] coinfected) and 57 HIV-infected patients without malaria infection. Malaria was treated with artemether–lumefantrine (Coartem^®). QFT testing was performed before initiation of malaria treatment and at days 7 and 42. In total, 172 patients completed follow-up. IFN-γ and IP-10 was measured in QFT supernatants. We found that during malaria infection IFN-γ and IP-10 levels in the unstimulated samples were elevated, mitogen responsiveness was impaired, and CD4 cell counts were decreased. These alterations reverted after malaria treatment. Concurrent malaria infection did not affect QFT test results, whereas there were more indeterminate IP-10 results during acute malaria infection. We suggest that IGRA and IP-10 release assay results of malaria patients should be interpreted with caution and that testing preferably should be postponed until after malaria treatment.     

A survey of the use of mandibular implant overdentures in 10 countries

PURPOSE: This preliminary international survey compared provision of implant-retained overdentures to fixed implant-supported prostheses for edentulous mandibles. MATERIALS AND METHODS: Questionnaires based on a 2001 Swedish study were sent to prosthodontists and specialist clinics in nine additional countries. RESULTS: Response rate varied from 53% to 100% in 10 national surveys and should allow careful comparison of results. The relationship between implant overdentures and fixed implant-supported prostheses in treatment of edentulous mandibles varied much; in Sweden, the proportion of overdentures was 12%, whereas it was 93% in The Netherlands. In all countries, the most common reason for choice of the overdenture was reduced cost. In all but two countries, the majority of respondents thought that patients with implant overdentures were equally or more satisfied with overdentures as those with fixed implant-supported prostheses. CONCLUSION: There were great differences among the 10 countries in choice of implant treatment of the edentulous mandible. The relative proportion of mandibular overdentures to fixed prostheses was low in Sweden and Greece and varied from one to two thirds in the other countries, except The Netherlands.     

Surgical reconstruction is a cost-efficient treatment option for isolated PCL injuries

Purpose and hypothesis

The main purpose of the study is to put focus on the costs related to treating posterior cruciate ligament (PCL) injuries and the possible implications of chosen treatment strategy to the respective institutions and society.

Methods

Costs of treating PCL injuries nonoperatively and for both single-bundle (SB) and double-bundle (DB) reconstruction were estimated. These costs were translated into equivalent quality-adjusted life years (QALY) given a threshold value of Euro (€) 70,000 per QALY. Expected gain in knee osteoarthritis outcome score (KOOS) quality of life (QoL) following surgery based on KOOS data from 112 patients was used as a basis for calculating the cost efficiency ratio.

Results

The average calculated cost of nonoperative treatment was €3382. Incremental cost for SB PCLR was €8585 (154%) and another increment of €5220 (61%) for DB PCLR using numbers from a European hospital. This is equivalent to increments of 0.074 (SB) and another 0.075 (DB) QALYs given the €70,000 threshold. For DB to be as cost efficient as SB reconstruction, the incremental gain in KOOS QoL has to be at the same level as for SB reconstruction compared to nonoperative treatment.

Conclusion

Though surgical reconstruction adds a substantial cost to nonoperative treatment alone, it can be considered cost-effective. Double-bundle reconstruction is less cost efficient than SB reconstruction, but should probably still be considered the treatment of choice for certain patient categories. Randomized controlled trials looking at outcome following nonoperative, SB and DB PCL reconstruction are needed. The clinical relevance of this is that surgical reconstruction of PCL injuries is a cost-efficient treatment alternative in patients with an isolated PCL injury. This finding should be taken into consideration when deciding on how to treat these injuries.

Level of evidence

III.

     

Microfracture is more cost-effective than autologous chondrocyte implantation: a review of level 1 and level 2 studies with 5 year follow-up

Purpose

Focal cartilage defects in the knee may have devastating effect on the knee joint, where two of the main surgical treatment options are microfracture and autologous chondrocyte implantation. Comparative studies have failed to establish which method yields the best clinical results. A cost-effectiveness analysis of microfracture and autologous chondrocyte implantation would contribute to the clinical decision process.

Methods

A PubMed search identifying level I and level II studies with 5 year follow-up was performed. With the data from these studies, decision trees with associated service provision and costs connected to the two different techniques were designed. In addition to hospital costs, we included costs connected to physiotherapy following surgery. To paint a broader cost picture, we also included indirect costs to the society due to productivity loss caused by work absence.

Results

Four high-quality studies, with a follow-up of 5 years, met the inclusion criteria. A total of 319 patients were included, 170 undergoing microfracture and 149 autologous chondrocyte implantation. The re-operation rate was 23 (13.5%) following microfracture, and 18 (12.1%) for autologous chondrocyte implantation. Both groups achieved substantially better clinical scores at 5 years compared to baseline. Microfracture was more cost-effective when comparing all clinical scores.

Conclusion

Microfracture is associated with both lower costs and lower cost per point increase in patient reported outcome measures. There is a need of well-designed, high-quality randomized controlled trials before reliable conclusions regarding cost-effectiveness in the long run is possible.

Level of evidence

III.

     

No degeneration found in focal cartilage defects evaluated with dGEMRIC at 12-year follow-up

Background and purpose — The natural history of focal cartilage defects (FCDs) is still unresolved, as is the long-term cartilage quality after cartilage surgery. It has been suggested that delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) is a biomarker of early OA. We aimed to quantitatively evaluate the articular cartilage in knees with FCDs, 12 years after arthroscopic diagnosis.

Patients and methods — We included 21 patients from a cohort of patients with knee pain who underwent arthroscopy in 1999. Patients with a full-thickness cartilage defect, stable knees, and at least 50% of both their menisci intact at baseline were eligible. 10 patients had cartilage repair performed at baseline (microfracture or autologous chondrocyte implantation), whereas 11 patients had either no additional surgery or simple debridement performed. Mean follow-up time was 12 (10–13) years. The morphology and biochemical features were evaluated with dGEMRIC and T2 mapping. Standing radiographs for Kellgren and Lawrence (K&L) classification of osteoarthritis (OA) were obtained. Knee function was assessed with VAS, Tegner, Lysholm, and KOOS.

Results — The dGEMRIC showed varying results but, overall, no increased degeneration of the injured knees. Degenerative changes (K&L above 0) were, however, evident in 13 of the 21 knees.

Interpretation — The natural history of untreated FCDs shows large dGEMRIC variations, as does the knee articular cartilage of surgically treated patients. In this study, radiographic OA changes did not correlate with cartilage quality, as assessed with dGEMRIC.     

Relationships between Indoor Environments and Nasal Inflammation in Nursing Personnel

In this study, the authors sought to address the relationships between measured indoor environmental factors and nasal patency (i.e., minimum cross-sectional area) and volume and markers of nasal inflammation in nasal lavage fluid. Clinical data were obtained for 115 females who worked at 36 geriatric nursing departments. The indoor climates in the nursing departments were characterized by high room temperatures (median = 23 °C), low relative air humidities (median = 24%), and high air exchange rates indicated by low carbon dioxide levels (median = 570 ppm). Evidence of microbial amplification was observed in the ventilation unit in 3 of the departments. Decreased nasal patency was observed relative to microbial amplification in the ventilation units (minimum cross-sectional area 1 = 0.80 cm² vs. 0.64 cm², p = .003, minimum cross-sectional area 2 = 0.80 cm² vs. 0.67 cm², p = .02) and in relation to elevated indoor temperature (volume 1 = 3.46 cm³ vs. 3.22 cm³, p = .03). The authors concluded that the indoor environment may have affected the nasal mucosa of nursing personnel, thus causing nasal mucosal swelling. The results support the view that fungal contamination of air-supply ducts may be a source of microbial pollution, which can affect the nasal mucosa.     

Infections due to various atypical mycobacteria in a Norwegian multiplex family with dominant interferon-gamma receptor deficiency.

BACKGROUND: Atypical mycobacteria can cause systemic infections in patients with certain types of immunodeficiency. METHODS: Clinical samples were decontaminated and cultured to assess the presence of mycobacterial species. Gene sequencing was performed to reveal interferon-gamma receptor 1 (IFN-gamma R1) deficiency. RESULTS: The index patient received a diagnosis of dominant IFN-gamma R1 deficiency during treatment for a serious infection due to atypical mycobacteria. She belongs to a Norwegian multiplex family comprising 3 generations and 5 patients with dominant IFN-gamma R1 deficiency. Four of these patients have been treated with tuberculostatics because of extensive infection due to atypical mycobacteria, such as Mycobacterium avium-intracellulare, Mycobacterium scrofulaceum, Mycobacterium bovis (bacille Calmette-Guérin), Mycobacterium bohemicum, and Mycobacterium gordonae. Two of the patients have also received subcutaneous injections of IFN-gamma. One family member with the deficiency has not received treatment and is still healthy at 13 years of age. CONCLUSIONS: Serious infection due to atypical mycobacteria should initiate a search for primary immunodeficiencies, particularly IFN-gamma R1 deficiency. Treatment with IFN-gamma should be started when serious infection due to atypical mycobacteria is verified and dominant partial IFN-gamma R1 deficiency is suspected.