Biomechanical improvements in gait following medial pivot knee implant surgery.

BACKGROUND: Total knee replacements are used to improve function and reduce pain in patients with advanced osteoarthritis. The medially stabilising implant is designed to mimic a healthy knee. This study aims to provide a comprehensive analysis of the kinematics and kinetics of a medially stabilising knee implant, comparing it to a healthy control group, as well as to its pre-operative state and the contralateral limb. METHODS: Sixteen total knee replacement patients and ten healthy participants were recruited. Patients underwent testing 4-6 weeks before surgery and repeated the same tests 12 months after surgery. Healthy participants completed the same tests at a single time point. All participants completed three walking trials: kinematics was captured with eight cameras; kinetics with in-ground force plates. Subject-specific musculoskeletal models were developed in OpenSim. Inverse kinematics and inverse dynamics were used to determine gait parameters. Joint angles and joint moments were evaluated using Statistical Parametric Mapping. Patient-reported outcome measures were also collected at both time points. FINDINGS: Spatiotemporal results indicate significant differences in velocity and step length between pre-operative patients and control participants. Differences are observed in the adduction angles between the contralateral and ipsilateral limbs pre-operatively. Postoperatively, there was an increase in the 1st peak flexion moment, reduced adduction moment and reduced internal rotation moment. In PROMs, patients all report improvements in pain levels and high satisfaction levels following surgery. INTERPRETATIONS: Following medial stabilising total knee arthroplasty, patients displayed improved clinical parameters and joint moments reflecting a shift towards more normal, healthy gait.

Potential of recombinant human growth hormone in HIV-associated adipose redistribution syndrome.

HIV infection recently has been complicated by the emergence of a rare metabolic dysmorphic disorder characterised by fat atrophy, redistribution and accumulation in the setting of hyperlipidaemia and, on occasion, hyperglycaemia. The disorder, sometimes referred to as HIV-associated Adipose Redistribution Syndrome (HARS), has a prevalence rate of about 50 to 60% and seems temporally related to the advent of highly active antiretroviral therapy, especially the usage of protease inhibitors. Various studies also implicate the nucleoside analogues stavudine, didanosine and lamivudine in the pathogenesis of HARS, especially fat atrophy. It is uncertain whether the changes described in HARS represent a single syndrome or a group of related syndromes. Reports have noted differences between morphologic and metabolic changes. More recently, it has been suggested that fat atrophy and fat accumulation may also be separate entities. There are several potential pathogenic theories for HARS that implicate both protease inhibitors and nucleoside analogues as causative agents. However, long term HIV infection rather than any specific agent or class of agent may be the source. Recombinant human growth hormone (rhGH) is a mammalian cell-derived product, which has been useful in a variety of human disorders ranging from pituitary dwarfism to septic shock. It has anabolic, immunological and metabolic properties that restore normal functioning to many aberrant disease pathways. The lipolytic properties of rhGH have been especially beneficial in the diminution of localised fat accumulation in the dorsocervical area (buffalo humps) and truncal region. This has been observed in various reports where rhGH has been administered at doses of 5 to 6 mg/day in patients with HARS for periods ranging from 3 months to >2 years. Relapses after discontinuation of rhGH occurred in most patients. Adverse effects included carpal tunnel syndrome, facial swelling, arthralgias and myalgias and worsening or onset of hyperglycaemia. The small uncontrolled studies conducted to date suggest that the most notable effect of rhGH treatment is the reduction of truncal adiposity and buffalo humps and that the agent has little effect on restoring the adiposity of the appendicular muscles, buttocks or face. Although most patients with HARS have associated hyperlipidaemia, rhGH has no notable effect on serum cholesterol and triglyceride levels. However, blood glucose levels can increase and pre-existent diabetes mellitus may worsen. A short term confirmatory placebo-controlled trial in patients with HARS is urgently needed, as are comparative trials using other anabolic agents such as oxandrolone and testosterone.

A computerised study on the results of in-vitro-fertilisation.

This project has been concerned with the comparison of children born as a result of fresh embryo transfer (IVF) with children conceived and born via the natural process. The former included children who were the single outcome of the birth (singletons) and children who were the result of a multiple birth (e.g. twins, triplets). A computer database was established into which was put 23 items of data on each child, making a total of 12,788 items overall. There were 278 "normally conceived" children (controls), 150 IVF Singletons, and 128 children from multiple births. The results show interesting differences in the gestational age at birth, the birth weight, the mode of delivery and the degrees of birth abnormalities and malformations.

A decision support system for cholinesterase genotyping.

Cholinesterase is a naturally occurring enzyme in the human body. Its importance became apparent when it was recognised that patients undergoing surgery and carrying abnormal genes for this enzyme were unable to recover from a dose of muscle-relaxant. It is therefore important to know the Genotype (the pair of genes) of a patient who might undergo surgery. The computer programme takes laboratory measurements and applies mathematical techniques and clinical judgements to determine the two genes present.

Strategies for preventing late-term vertical HIV transmission.

AIDS: The significant decrease in HIV transmission rates from mother to child (vertical transmission) in developed countries is due largely to the implementation of the three-part AZT protocol. An abbreviated, two-part course of AZT preventive therapy has reduced vertical transmission in developing countries. Cesarean sections (C-sections) performed before the rupture of uterine membranes has also reduced vertical transmission. When elective C-sections are combined with AZT treatment, the rate of transmission drops from 7.3 percent to 2 percent. The mode of infant feeding has played a significant role in vertical transmission in developing countries. Studies suggest breast feeding accounts for more than one-third of all HIV infections in infants. Alternatives to breast feeding may reduce these rates, but issues such as cultural acceptance, formula misuse, and replacement-feeding availability must be addressed.^ieng

Efavirenz pregnancy warning.

AIDS: A study conducted by DuPont Merck, manufacturer of efavirenz (DMP266, Sustiva), found severe birth defects occurred in an estimated one quarter of monkeys born to mothers taking the drug early in gestation. The company believes the abnormalities did not stem from genetic damage, but rather from the drug's effect on initial fetal growth. No pregnant women are included in the trial program, and women should not become pregnant while taking efavirenz. Participants will be required to use additional measures of contraception. DuPont Merck plans to request a category C pregnancy warning from the Food and Drug Administration (FDA) indicating safety in pregnancy is undetermined. The manufacturer also will conduct third trimester vertical transmission testing. Twenty percent of the 2,362 enrollees in the trial program are women.^ieng

Vertical transmission research at the Retrovirus Conference.

AIDS: Researchers have seen a dramatic drop in mother-to-child HIV transmissions due to medical breakthroughs and the role of AZT. ACTG protocols 076 and 185 provided further information on the association between maternal viral load and vertical transmission. Dr. Lynne Mofenson of the National Institute of Child Health and Human Development at the National Institutes of Health followed treatment-naive and treatment-experienced pregnant women through a three-part AZT regimen. The regimen was administered during the last two-thirds of pregnancy, during delivery, and to the newborn for six weeks. The studies showed that transmission took place across all levels, however, the women taking AZT reduced vertical transmission by two-thirds at each viral load level. Dr. Mofensen concluded that reducing viral load to low levels in pregnant women receiving AZT treatment will further reduce transmission. Other studies presented at the 5th Conference on Retroviruses and Opportunistic Infections concluded that predicting HIV transmission based on maternal viral load is more accurate for groups of untreated, rather than treated, mothers. In Thailand, a short-course treatment alternative of administering AZT near the end of gestation and during delivery, but not to the newborn, showed a 51 percent reduction in the rate of transmission. Although not proven, it is assumed that this is the period when most transmission occurs.^ieng

Looking down the drug pipeline.

AIDS: Reports at the 5th Conference on Retroviruses and Opportunistic Infections addressed new anti-HIV agents in primary phases of development that offer treatment alternatives to people with little or no treatment history and individuals with few treatment choices. FTC, a new nucleoside analog produced by Triangle Pharmaceuticals, is an alternative to 3TC. F-ddA (lodenosine), a nucleoside analog licensed by US Bioscience, is structurally similar to ddI and is reported to have good bioavailability, once-a-day dosing, and no bone marrow suppression. F-ddA has also shown in vitro activity against multidrug-resistant strains of HIV. Adult and pediatric studies are currently being conducted by the National Cancer Institute (NCI) and US Bioscience. Oral versus IV PMPA shows promising results as a possible alternative for 3TC- and AZT-experienced patients. Further testing is being done by Gilead Sciences and HIV Network for Prevention Trials (HIVNET). Abbott Laboratories is developing a second-generation protease inhibitor, ABT-378, which has a ten-fold greater antiviral activity in vitro than the original, ritonavir. It is administered with ritonavir to increase ABT-378 levels in the blood, but has no food requirements, and less severe side effects. Two trials are being conducted: one for patients who are treatment-naive and the second for patients who are failing other protease inhibitors. Immune-based therapies, such as Leukine (GM-CSF), are used to handle neutropenia and offset bone marrow toxicities from drugs. Concerns that GM-CSF may increase viral replication may be balanced by using highly active antiretroviral therapy. FP-21399, developed by Lexigen Pharmaceuticals, is being tested as an HIV fusion inhibitor.^ieng

The great salvage therapy drug juggle.

AIDS: Most patients on protease inhibitors who plateau at viral loads within quantifiable levels must switch to an alternative or salvage therapy to continue to decrease these loads and maintain some form of antiviral therapy. The Public Health Service Guidelines suggest using a different therapy if a particular therapy does not substantially lower viral loads to below quantifiable levels within four to six months. Physicians and researchers at the International Workshop on Salvage Therapy for HIV Infection advocated progressively switching patients to a more suppressive regimen to give them a better chance of long-term success. However, if a patient has a stable viral load or there is only a short-term benefit from switching early in therapy, then using a salvage therapy may not be warranted. Results from salvage therapies used for saquinavir failures are mixed. As with nelfinavir, subsequent regimens for patients failing indinavir have a better chance of success when implemented early in treatment. Saquinavir and nelfinavir combined seem to get better results when administered with two reverse transcriptase inhibitors. Use of new experimental drugs as a secondary therapy have mainly short-term benefits and conflicting side effects. Dr. Keith Henry of Regions Hospital in St. Paul treats each case individually. Dr. Henry cautions not to aim for short-term responses and avoid using alternative treatments too quickly, leaving little recourse after viral rebound. Further clinical trials are underway and more are planned to test additional salvage protocols.^ieng

Diarrhea drug rejection raises a ruckus.

AIDS: The Food and Drug Administration's (FDA) Advisory Committee has voted against approval of NTZ (Cryptaz) for treating cryptosporium-related diarrhea. The clinical data presented by the drug's sponsor, Unimed Pharmaceuticals, was found to be mediocre and incomplete. The company had only presented open-label data, which is not central to a drug's approval. Patients with CD4 counts above 180 are usually able to clear the parasite (Cryptosporidium parvum) from their intestines, unaided by other therapies. Now that HAART is available, the company may have lost their window of opportunity to get the data on NTZ and cryptosporidiosis that the FDA typically requires. Following the drug's rejection, the company says it plans to drop NTZ for treatment of cryptosporidiosis. As a result, the drug will only be available through the PWA Health Group in New York.^ieng

On the road with protease inhibitors.

AIDS: Recommendations are provided concerning protease inhibitor (PI) dosage schedules and how long distance traveling, across time zones, can affect these dosage schedules. Tables present guidelines for adjusting twice-daily (bid) regimens when traveling to and from Europe, as well as translating the indinavir schedule and nelfinavir and saquinavir dosing abroad. Other considerations include the need to refrigerate many PIs, which requires staying in hotels with refrigerators in the rooms, and using coolers or similar containers for transporting drugs. Beepers, timers, and programmable pillboxes can be useful for maintaining dosing schedules.^ieng

Working to improve pregnancy outcomes.

AIDS: Research to eliminate mother-to-child HIV transmission was a highlight at the 12th World AIDS Conference. ACTG 076 demonstrated that a three-part course of AZT can reduce the vertical transmission rate by 67 percent. Studies assessing the effectiveness of Cesarean section (C-section) deliveries are inconclusive, although it appears that surgical delivery, prior to the rupture of membranes, reduces transmission rates. Studies on HIV positive pregnant women, who did or did not receive drug treatment, and had elective C-sections, emergency C-sections, or vaginal deliveries are compared. Combination therapy may be the most effective treatment for the mother, but there is not enough data to judge the safety of these treatments on an infant. Treatment risks for newborns are addressed.^ieng

Debate widens over protease inhibitor side effects.

AIDS: Unusual abnormalities continue to be reported among HIV patients on highly active antiretroviral therapy (HAART), with many of these symptoms being reported worldwide. One of the most distressing symptoms is abnormal redistribution of body fat (lipodystrophy). There is no clear-cut cause identified with lipodystrophy, and the reported prevalence ranges from 5 percent to more than 60 percent. Australian studies forecast that nearly all protease inhibitor patients will experience metabolic abnormalities as a result of their treatment. Possible drug mechanisms that may lead to these abnormalities are described. Another study suggests that these metabolic abnormalities may be a form of post-traumatic stress syndrome, based on observing similar symptoms in survivors of leukemia and breast cancer. Possible treatments and prevention options for these abnormalities are discussed.^ieng

Ritonavir users put on liquid diet.

AIDS: Abbott Laboratories has announced that production problems are halting the manufacturing of the capsule formulation of Ritonavir (Norvir), although the oral formulation of the drug continues to be available. New batches of the capsule started crystallizing, and Ritonavir crystals slow down the rate at which the drug is dissolved and absorbed. Abbott Laboratories is currently working to remedy the manufacturing problem. The oral form of the drug can be easily substituted, but it has a bitter taste and a high alcohol content. Suggestions for making oral Ritonavir more palatable and guidelines for storing the drug are provided.^ieng

U.N. drug initiative hits the ground.

AIDS: The Joint United Nations Programme on HIV/AIDS (UNAIDS) announced its HIV Drug Access Initiative in November 1997. Advisory boards oversee the Initiative, set national policy, and determine criteria for eligible participants. The program also provides drugs for opportunistic infections and sexually transmitted diseases. The initial phase of the program includes Uganda, the Ivory Coast, Chile, and Vietnam, although funding remains a problem. UNAIDS is helping with medical training in each country, and uses a computerized system to track participants and drug distribution. UNAIDS is also negotiating with pharmaceutical companies to provide drugs at subsidized costs. Glaxo Wellcome and Hoffman-LaRoche have committed to making their drugs and diagnostic kits available via the program; others are considering joining the effort. A major effort is underway by the program to reduce vertical transmission of HIV.^ieng

A rocky road for nucleotide analogs.

AIDS: Nucleotide analogs, such as cidofovir (Vistide) and adefovir (Preveon) by Gilead Science, are a class of drugs that have demonstrated antiviral activity, but have been linked to some significant side effects. Impaired renal function, incidences of eye inflammation, and temporary hearing loss, have been associated with cidofovir. Gilead advises health practitioners to explicitly follow directions when administering cidofovir to minimize occurrence of these effects. Adefovir has been reported to cause gradual kidney damage, which may be managed by adjusting the dosage. Several trials are discussed, such as Protocol 417, which is still in process and is trying to determine the efficacy of adefovir at different dosages.^ieng

Set back for nerve growth factor.

AIDS: The Food and Drug Administration (FDA) has suspended Genentech, Inc.'s plan to file a new drug application for nerve growth factor (NGF), a genetically engineered substance developed to combat HIV-related neuropathy. The FDA found that the results from ACTG 291 were insufficient to determine the safety and efficacy of NGF. No further studies are planned for using NGF as a treatment for neuropathy in HIV patients, however, patients currently participating in ACTG 291 can continue to receive NGF for 48 weeks through a trial extension. A new application for NGF may be filed for the treatment of diabetic-related neuropathy. If NGF is approved under this application, it may be prescribed off-label for HIV populations. HIV activists are concerned that Genentech is not proactive enough in developing NGF for HIV. Contact information is provided.^ieng

NNRTIs: a neglected class.

AIDS: Non-nucleoside reverse transcriptase inhibitors (NNRTI) are a class of antiretrovirals that are effective in suppressing viral activity when used in combination with other antiretroviral agents. Nevirapine, Delavirdine, and efavirenz are all NNRTIs approved by the Food and Drug Administration. Researchers found that there is high cross resistance within NNRTIs, but cross resistance to drugs in other classes remains small. Studies indicate that treatment with protease inhibitors is possible after treatment failure with NNRTIs. Nevirapine was shown to be most effective in trials with triple combination regimens. Other studies looking at the effectiveness of Nevirapine are discussed. Delavirdine, taken three times a day, showed favorable results in triple combination therapy, and is considered a good option for primary therapy. Trials employing different levels of Delavirdine and protease inhibitors are reviewed, as is the use of Delavirdine and other NNRTIs in salvage therapy.^ieng