text:
Showing latest ads instead.
Member1£19,999Our Brokerage Service is FREE!FerndownWe are a dedicated local service operating a fair brokerage scheme for sellers looking to sell outright or part exchange against another leisure asset. We always ask sellers to discuss their options with us first, as you may be surprised how much we can help you achieve a...
Member10£22,999Elddis Sunseeker 140FerndownYear- 2007 Engine- 2.2L Mileage- 26,500 Berths- 4 This Elddis Sunseeker is most definitely in great shape for its age, making it an attractive buy for someone looking for something modern at a reasonable price. Its not surprising that this model is so popular, with such...
Featured7Immaculate camper vanBournemouth65,000 miles 2001 registration 2.7 litre petrol engine 5 seats A newly converted, Toyota 4 berth van with back kitchen installation, under mounted fridge/freezer, gas hob and sink. Electric hook up and battery for water, lights etc. Side storage cupboard and seating...
Featured9£24,5002012 VW T5 CAMPER VAN, MOTORHOME, AIR CON, CRUISE CONTROL, SAT NAV, BLUETOOTH, REAR PARKING SENSORS, SOLAR SYSTEM. 69KTewkesburyHI THANKS FOR LOOKING, THIS CAMPER IS NOW FINISHED AND READY FOR COLLECTION, I'm free this weekend for viewings It has a few extras over and above our standard conversion. 120W, 2 panel Solar system and barn door spoiler. Also has amazing spec on...
Featured9£24,9952012 VW T5 CAMPER VAN, MOTORHOME, 2.0 TDI, AIR CON, CRUISE CONTROL, BLUETOOTH, REAR PARKING SENSORS, 59K.TewkesburyHI THANKS FOR LOOKING, PLEASE NOTE PIC'S ARE OF A VAN WE HAVE JUST FINISHED. Price: £25,995 Model: Transporter T28 2.0 TDI T5 SWB Registration: PJ12 VEB Date of Reg: 13/07/2012 Colour: CANDY WHITE Mileage: 59,119 MILES Transmission: 5...
Member9£21,995Autocruise StarspiritFerndownYear- 2004 Mileage- 31,000 Engine- 2.8 The Autocruise Starspirit is one of the most popular models produced, making it a well sought after motorhome and Dorset Motorhomes is very proud to have one for sale. This particular one has the 2.8 litre HDI Peugeot engine...
Member9£22,995Autocruise StarblazerFerndownYear- 2004 Mileage- 52,000 Engine- 2.8 Oyster Satellite, Solar panel, Inverter, Habitation Air-Con, Cruise Control, Gaslow LPG refillable, Reversing Sensors, Autowatch Immobiliser and Awning. Autocruise really know how to make fantastic motorhomes, and non more so...
Member10£26,9952007 Bessacarr E425 31800 miles luxurious motorhome with 12 month warrantyHorshamCamper and Motorhome Centre have for sale this 2 owner from new Swift Bessacarr E520 4 berth motorhome. Full service history, new tyres, new batteries and 1 year extendable motorhome care warranty. 4 berth, 2 travel seats, canopy awning, bike rack, electric step, tow bar...
Member10£21,995FORD TRANSIT RIMOR KATAMARANO SOUND 2008 2.2 DIESEL 7 BERTH *WINTER SALE*ChesterThe Rimor Katamarano Sound is a spacious 7 berth motor home and is built on the Ford 2.2 TDCi 130BHP Chassis with a 6 speed gear box and includes Air-conditioning, Cruise Control and Auto headlights. It comes with a 12 months mot, 6 months warranty and a habitation...
8£36,995IH J220 MERCEDES AUTOMATIC (2010)Stroud2010 IH J220, 2 Berth Low Profile, Mercedes 2.2 Cd AUTOMATIC, Rm.44,000 Miles, Cab Air-Con, Multi-Media Bluetooth/Dvd/ radio/Sat-Nav, Rear Camera, Cruise Control, Rear Kitchen & Washroom, Half Leather upholstery, Microwave Combi Oven, Tv/Dvd, Dome...Posted Yesterday
7£15,995AUTOSLEEPER EXECUTIVE SX (2000)Stroud2000 AUTOSLEEPER EXECUTIVE SX, 2+2 Berth Coach Built, Peugeot 2.5 Td, Rm.57,000 Miles, Rear Kitchen/Washroom, 2 Singles or Large Double, Roll Out Awning, Bike Rack, Autosleepers Monocoque Body makes these highly sought after models...£15,995...Posted Yesterday
0Internal Silver Screens For MotorhomeWeston Super MareInternal Silver Screens suitable for FIAT DUCATO MAXI . MOTORHOME OR VAN ...AS NEW CONDITIONPosted Yesterday
3£100Mercedes Sprinter seat & baseBurnleyNewly upholstered in part leather/part fabric, no longer needed, cost over £500Posted Yesterday
9£6,250VW Transporter T4 2.5 tdiBridgendThe time has come to sell my beloved VW T4 2.5 TDI camper/day van. Its a 2003 model with 203000 miles on the clock. Don't let the mileage put you off, its a very strong and reliable engine and flew through its last MOT with no advisories. This van is ideal for people...Posted 1 day ago
8£1,095Day van / CamperIpswich1.9 Diesel 2004 model 160k miles 6 months MOT ('til April 2019) Starts no problem, runs really well Metalwork all good - couple of knocks and scuffs, but no rust-rot Sony Bluetooth/USB Stereo Reverse Parking Sensor Four good tyres and spare 3 belted seats Clean...Posted 1 day ago
8£4,500Cheve G20 dayvan camperWishaw1993 Chevy G20 fully loaded lots of history to much to list. Rock and roll bed power steering and windows. Air conditioning tow pack etc ## sound usebable investment ideal for cruise and days out classic car shows etc. Reason for selling I'll health and not getting enough...Posted 1 day ago
5£31,000Auto-sleeper Suffolk, 2008 (58 plate), Mercedes chassis, Automatic gearbox, Rear loungeFarehamWe are reluctantly selling our lovely Motorhome with lots of extras. Because of work & family commitments we are not getting the opportunity to use it. Mercedes chassis, Automatic Gearbox, Anniversary pack, Rear lounge, Cab air con/climate control, Cruise control...Posted 1 day ago
10£9,999Peugeot Boxer motorhome 4 berth camperNewton Abbot66000 miles Starts and drives very well All working as it should Toilet Shower Oven Hob Fridge Excellent mot history check online Part exchange considered Test drive welcome Call AndrewPosted 2 days ago
Member10£9,9951992 VW LT55 MOTORHOMELeeds1992 VW LT55 MOTORHOME (LOCATION LEEDS) 158,000 miles, 2400cc, 7 new tyres, MOT October 2018, 5 speed, most of the service history, reversing camera, TV/DVD, CD/radio, fridge/freezer, 2 hobs, £5000 on revamp all brand new inside painted silver and black...Posted 2 days ago
Member10£10,495Romahome Hylo Campervan (LOCATION ST ALBANS)St. AlbansRomahome Hylo Campervan (LOCATION ST ALBANS) 2006 Citroen Romahome Hylo 2 Berth Campervan (LOCATION ST ALBANS) MOT 24-08-19, Serviced 24-08-19, Only 29600 Miles, Drive away awning (2 meters sq) which attaches to the back of the vehicle, Safe to secure...Posted 2 days ago
10£12,495A lovely camper well looked after.ChesterfieldHere for sale is our Renault Trafic campervan professionally converted consists of 240v Hook up , 2 ring gas cooker, sink with 12v water pump and container, 12v electric fridge freezer, 3/4 Rock and roll bed, plenty of cupboard space and wardrobe. Leisure battery with...Posted 3 days ago
10£23,995EXCELLENT BARGAINTredegar2008 BESSACCAR E 425. FIAT DUCATO MULTI JET 2.3. 130 BHP. 6 SPEED GEAR BOX, POWER STEERING. ONE OWNER FROM NEW. FULL SERVICE HISTORY. 4 BERTH REAR L SHAPED LOUNGE, DOUBLE AT REAR, LARGE DOUBLE OVER...Posted 3 days ago
9£10,500Vw t4 transporter 2.5tdi campervanNeathExcellent condition sink hob fridge oven and grill swivel front seats rock and roll bed 12 volt + 240 hook up drive away awning .. 120.000 miles new rear brake pads and caliphersPosted 4 days ago
Member10£12,7502006 VW T5 (T30) CampervanThornton Cleveleys2006 VW T5 (T30) Campervan (LOCATION BLACKPOOL) 2.5 TDI, 5 Speed, 151k Miles, White with quirky blue leather seats make this little camper van stand out, Tinted Side Windows, Alloys, New Tyres, New brake Pads, Upgraded Speakers, Stereo/CD/MP3 Player, EVO...Posted 5 days ago
5£1,500Iveco not fordGlastonburyCamper/off grid conversion project, Was race day van, middle sleeps 2, rear is mechanics bay atm, fitted out with cooker, sink, electric points and hook up, no mot but just cosmetics to sort would suit off grid living, low mileage for year, I'm open to offers or PX, will...
10£39,999Burstner i 821 motorhome, 1 owner from newLincolnshireTop of the range Burstner i821 motorhome, with 6 new tyres, service history, 1 owner, Alde heating, cab aircon, 3 TV's and sound bar, 4 belted seats, reversing camera, tow bar, all round led lighting, cruise control, heated mirrors, electric step, 2 x 110 ah leisure...
6£6,2501996 2.5l turbo diesel automaticSleaford89000 miles In black Alloys Electric roof/blinds/windows and mirrors Seats 6 Dual gas hob Sink Plenty of storage Awning Bike rack (not fitted) Original wheels all with good tyres Comfy mattress topper in roof Cd radio MOT Dec 18 She drives well, is regularly serviced...
10£20,995VW T5 Camper Van Conversion - 2012 VOLKSWAGEN TRANSPORTER T30 140 TDI 6-speed manual DieselBristol2012 (12) -- Used -- 130,000 Miles -- 140 HP -- Manual -- 1968 cc -- Diesel -- Hi-Lo Roof -- Van Conversion -- 5 Travelling Seats -- 4 (adult) Berth -- Driveaway awning -- Right Hand Drive -- White -- Excellent Body Condition -- Excellent Mechanical Condition ...
9£5,700Mercedes Camper Van With Brand New MOTCardiffMercedes Vito camper van 2.2 automatic extra long CDI!. Brand New MOT until Nov 2019! Mileage 195,000 Fixtures & fittings include: - Fitted double rock and roll bed that converts into a sofa, one burner gas hob, sink with water container, curtains, thermal blinds for...
10£27,990SWIFT ESPRIT 412 MOTORHOME 2.3 FIAT DUCATO 130 BHP 6 SPEED MANUAL GEARBOX 2 BERTH 2 TRAVELLINGHaywards HeathFANTASTIC 2 BERTH MOTORHOME WITH FULL SERVICE HISTORY, SERVICED AT: 16K, 32K, 46K AND 59K, COMES WITH AWNING, CAB AIR CONDITIONING, REVERSE PARKING CAMERA, CRUISE CONTROL, CAB BLINDS...
1£50motorhomes / campervans bought for cash we pay more for your motorhome callOrmskirkall vans wanted nationwide collection by keen mature buyer top price paid call
10£19,500Vauxhall Vivaro 'Pop Top' campervan for sale. Yate nr BristolBristolVauxhall Vivaro Sportive CDTI SWB, 2012, 4 berth 'Pop Top' campervan, excellent condition, colour silver, alloy wheels, air conditioning, c/d radio, professionally converted in 2016, mileage 78000,Mot until May 2019, service history. 4 berth with rock and roll bed...
8£29,000Lunastar 800HD 6 Berth 2007 Motorhome £29000TorpointOctober 2007 Lunar Roadstar 800HD, with an Alko chassis and double floor construction, tow bar and rear cycle rack. It has been recently serviced, habitation checked and comes with 12 months MOT. There is a reversing camera, garage, island bed, large separate shower...
9£18,700BAILEY VIGO 2016 AS NEW CONDITIONSwanseaFOR SALE BAILEY UNICORN VIGO AS NEW CONDITION EVERY EXTRA ADD TO THIS VAN FROM NEW COMES WITH FULL AWNING DOUBLE MOTOR MOVER WATER BARRELS/WASTE WHALE PLUMBED IN WATER SUPPLY OVER £2000...
3Motorhome fordCallander130,000 km year 1993 gearbox machine Wheel Drive rear drive wheels effect 182 ch displacement 7.3 l Legal places 6 berths 6 length 848 cm width 250 cm Total weight 5,216 kg unloaded weight 4,590 kg payload 626 kg
6£18,500Fiat 2ltr motorhomeWorthing4 berth campervan vgc selling due go upgrade new curtains and covers.. .
Member10£8,9951995 Autoquest Elite 5 Berth MotorhomeCrediton1995 Autoquest Elite (LOCATION TAUNTON) Peugeot Autoquest Elite 350 D, 2400cc, 5 speed, New Habitation check May 2018, 11 months MOT, 119,634 miles, power steering, gas hobs and grill, NEW fridge with freezer compartment, hot water, heating, rear seatbelts...
10£9,950Timberland Voyager, Motor home camper van, panel van conversion fiat ducato basedBridgendTimberland Voyager 2 berth 2.8JTD, 2001, Fiat ducato, LWB - 5.7m, MOT July 2019, 70,000 genuine miles, part service history, Waxoyl chassis, rear travelling seat removed to give more living space and with swiveling side unit gives access to kitchen area when bed is...
6£1,500Mazda bongo 2.5 diesel tin topLiskeardSad sale of our Mazda bongo. 2.5 litre diesel tin top. Not converted so has 8 seats. P reg first registered in 1997. Two tone grey in colour. Has done 96,750 miles. Only owned for twelve months but work commits mean we just don't have the time to use it. Has now failed...
9£10,995Nissan Elgrand Elevating Roof Camper AUTOMATIC at Kent MotorhomesAylesfordDetails MakeNissan Elgrand ModelNissan Elevating Roof Camper Reg No."R" Reg Reg Date01-09-1997 Engine3.2 (Diesel) Gearbox4 Speed Automatic Mileage152,374 Miles Berths2 Seatbelts2 Dimensions Height7ft 2in (2.18m) Width (exc. mirrors)5ft 8in (1.73m) Length15ft 3in...
9£32,995HOBBY TOSCANA 650ES (2009)Stroud2009 HOBBY TOSCANA 650ES, 2+1 Berth Low Profile, Fiat 2.3 130 Multi-Jet, Rm. 17,000 Miles, 2 Single Beds, Rear Washroom with separate Shower, Cab Air-Con, Cruise Control, Tv/Dvd, Solar Panel, Rear Camera, Roll Out Awning, Bike Rack...£32,995...
7£39,995SWIFT BOLERO 630EW (2011)Stroud2011 SWIFT BOLERO 630EW,2 Berth Low Profile, Fiat 2.3 130 M-Jet, Rm. 12,000 Miles Only, Cab Air-Con,Cruise Ctl, Twin Rear Camera, Bluetooth Radio, Large Rear Washroom with Separate Shower, Fridge-Freezer, Microwave, Alde Combi Boiler System, Roll Out...


text:
March 2012
Boceprevir (Victrelis) and telaprevir (Incivek) are newly licensed treatments for hepatitis C virus (HCV) mono-infection (HCV infection only). Clinical trials are planned or underway testing these drugs in people who are co-infected with HCV and HIV. These drugs are meant to be used in combination with interferon-alpha and ribavirin.
The goal of anti-HCV therapy is to maximize the chances of curing HCV infection. Bearing this in mind, physicians are likely to continue therapy in the face of drug side effects provided that they are not life-threatening.
As with all new drugs, the full range of side effects and drug interactions may not be known for several years. Based on an analysis of Phase III trials of boceprevir and telaprevir, French liver specialist Dr. Christophe Hézode (Université Paris Est) has provided guidance for physicians caring for people who develop side effects while taking these new drugs. We encourage readers to note that while side effects with anti-HCV therapy are common, those caused by boceprevir and telaprevir are generally manageable.
Common side effects with this drug include the following:
Common side effects with this drug include the following:
Red blood cells (RBCs) help to carry oxygen to tissues and remove the waste product carbon dioxide. When RBC levels fall below normal, people can become tired easily. In more severe cases, fatigue, shortness of breath, dizziness and headache can develop. Anemia can occur because the anti-HCV drug ribavirin can cause these cells to prematurely die. In clinical trials, about 20% of people who received boceprevir or telaprevir developed anemia.
RBCs carry an iron-containing protein called hemoglobin, which gives blood cells (and blood) its characteristic deep red colour. To assess anemia, hemoglobin levels in blood samples are measured -- levels less than 10 g/dl indicate anemia.
Anemia did not apparently have an effect on recovery from HCV among telaprevir users. However, among participants who received boceprevir, recovery from HCV was more likely if participants developed anemia. The reason for this link between recovery and anemia on boceprevir is unclear.
Depending on the severity of anemia that occurs, doctors have several options:
In the past two decades researchers have become aware that HCV infection can be associated with skin problems. A large French study with 1,614 participants (56% men, 46% women) found that the following skin problems occurred even before patients received treatment:
The reasons for this are not clear but this link with HCV infection and skin problems is important to bear in mind.
Before the approval of specific anti-HCV drugs such as boceprevir and telaprevir, standard therapy for HCV consisted of a combination of interferon-alpha and ribavirin. These two drugs can also cause skin problems, such as generalized itchy rash or dry skin or sometimes a combination of both. In some cases, the affected skin may develop temporary red lesions. In most cases, these can be managed with prescription anti-inflammatory creams containing corticosteroids. As the rash subsides, patients can switch to using moisturizers.
Data from clinical trials suggests that telaprevir can affect the skin -- causing rash and other skin-related problems in about 50% of participants. The vast majority of rashes were of mild-to-moderate intensity, involving less than 30% of the skin. Generally such rashes did not become worse. The rash seen with telaprevir was generally similar to rash seen with interferon and ribavirin, however, telaprevir-associated rash tended to be more frequent and more severe.
Rash related to telaprevir can occur at any time while the drug is being used. Researchers have found that 50% of telaprevir-related rash occurred during the first four weeks of use. Even if therapy is stopped, it may take several weeks before rashes completely resolve.
Dr. Hézode has suggested the following staging system for mild-to-moderate rash associated with telaprevir:
According to Europe-based HCV researchers, in cases of mild-to-moderate rash, corticosteroid-containing creams and certain antihistamines, including the following, may be used:
|How to Use Moisturizer
Moisturizing creams rather than lotions or ointments "may be effective in relieving [very red, itchy and swollen skin]," says Dr. Hézode. He and other leading HCV researchers recommend the following regimen: "Cream should be applied for at least 15 minutes, beginning with areas around the hands, feet and the skin around the large joints" ... "And progressing with broad strokes across the rest of the skin. This should begin 15 minutes after showering or bathing and should be applied daily." Other rash-relieving tips: Limit exposure to sun and heat. Take baking soda or oatmeal baths. Wear loose-fitting clothes.
No comments have been made.
The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.
|Sex and the HIV Reservoir: New Research Points to the Powerful Effect of Estrogen
|First U.S. Failure of Truvada as PrEP Is Reported at IDWeek
|Post-AIDS 2018 Updates on HIV Cure Research
|On-Demand PrEP Is Great. Now, What About Women?
|High Rates of Anal HPV Infection in Gay Men Using PrEP in IPERGAY: The Role of Vaccination

subset: commoncrawl


text:
The other day I took note of the fact that, as I have long predicted, the media is losing interest in climate change in large part because the climate campaign long ago became an unimaginative crashing bore. Moreover, as also long expected, we're starting to see the "counter-intuitive" narrative start to appear—namely, that moderate warming might have net benefits. (Actually the IPCC reports have implied this all along, but the notorious Summary for Policy Makers, which is all most journalists and politicians ever bothered to read, always leaves this out or obscures it.)
And so here's another one. Remember how the polar bear became the charismatic megafauna of the threat of global warming (even though there are credible claims that polar bear numbers have increased in recent decades)? Well, there a new article in the scientific journal PlosOne that concludes most arctic species will benefit from global warming. Here's the abstract:
Arctic and subarctic (i.e., [sub]arctic) ecosystems are predicted to be particularly susceptible to climate change. The area of tundra is expected to decrease and temperate climates will extend further north, affecting species inhabiting northern environments. Consequently, species at high latitudes should be especially susceptible to climate change, likely experiencing significant range contractions. Contrary to these expectations, our modelling of species distributions suggests that predicted climate change up to 2080 will favour most mammals presently inhabiting (sub)arctic Europe. Assuming full dispersal ability, most species will benefit from climate change, except for a few cold-climate specialists. However, most resident species will contract their ranges if they are not able to track their climatic niches, but no species is predicted to go extinct. If climate would change far beyond current predictions, however, species might disappear. The reason for the relative stability of mammalian presence might be that arctic regions have experienced large climatic shifts in the past, filtering out sensitive and range-restricted taxa. We also provide evidence that for most (sub)arctic mammals it is not climate change per se that will threaten them, but possible constraints on their dispersal ability and changes in community composition. Such impacts of future changes in species communities should receive more attention in literature. (Underline added.)
To me the most important part of this article is the late underlined bit, which makes the point I've been trying to make for a long time—the main driver of species contraction is not climate but changes in habitat and/or habitat fragmentation. But to climate fanatics, everything gets reduced to climate.


text:
& Raritan Canal
State Park
Central New Jersey
Burlington, Hunterdon, Mercer, Middlesex and Somerset
Mailing Address:
145 Mapleton Road
Princeton, NJ 08540
GPS Coordinates
View map for Bull's island Office and DnR Canal office
Size: 6,595
Fees: No entrance fee.
Link to the Related
Fees page
Parking is available in designated parking lots
along the canal towpath. The main canal runs from
Trenton to New Brunswick with a break at the Route
1 crossing. The feeder canal stretches from Trenton
north to Frenchtown along the Delaware River.
The park office is located at 145 Mapleton Road.
From Route 1
Exit at Route 522 east (Ridge Road) heading towards the town of Kingston for approximately 1 mile. Make a left turn onto Division Street. At the stop sign turn left onto Academy Street (Academy Street becomes Mapleton road). The park office and Mapleton Preserve is located .2 miles on the left side of the road across from the Mapleton Nurseries.
From Route 27:
Turn onto Academy Street at the traffic light in Kingston (across from the Kingston Cemetery). Academy Street becomes Mapleton road as it heads towards route 1. The park office and Mapleton Preserve is located .3 miles on the left side of the road across from the Mapleton Nurseries.
Facilities & Activities:
Nearby Attractions:
The Delaware and
Raritan Canal State Park is one of central New Jersey's
most popular recreational corridors for canoeing, jogging,
hiking, bicycling, fishing and horseback riding. The canal
and towpath are part of the National Recreational Trail System.
The 70-mile linear park is a valuable wildlife corridor connecting
fields and forests.
With its 19th-century bridges, bridgetender
houses, past and present locks, cobblestone spillways and
hand-built stone-arched culverts, the canal is a tremendous
attraction for history lovers. The upper reach of the feeder
canal wanders through quaint New Jersey towns along the Delaware
River such as Stockton and Lambertville. The main canal passes
the Port Mercer canal house, through the charming village
of Griggstown to Blackwells Mills, ending up in New Brunswick.
Canoes can be rented at Griggstown and Princeton from private
Most of the canal system remains intact
today and is a reminder of the days when the delivery of freight
depended upon a team of mules or steam tugboats. Nearly 36
miles of the main canal and 22 miles of the feeder canal still
exist, with many historic structures along the canal.
Following Governor Phil Murphy's Executive Order No. 34 (pdf), DEP Commissioner Catherine R. McCabe has issued Administrative Order No. 2018-24 closing all DEP owned, managed or otherwise controlled lands to bear hunting during the October and December 2018 season segments. The closure includes, but is not limited to, the following: state forests, parks, recreation areas and natural areas; and wildlife management areas.
Administrative Order 2018-24 (pdf)
Through the Carry-In/Carry-Out Program you can help us keep your parks clean
and beautiful by carrying out the trash you carry in. Bags are provided
throughout the site. Thank you for your cooperation and remember to recycle.
The towpath and recreational facilities at D&R Canal state park are partially accessible for persons with disabilities. Please contact the park office for further information regarding disability access needs. Text telephone (TT) users, call the New Jersey Relay Service at (800) 852-7899.
Open daily sunrise to sunset
Office hours:Monday - Saturday 8:30 am to 4:30 pm
Tree Stands and Blinds Policy
BE ADVISED: A dredging project is planned for the D & R Canal from Kingston to Amwell Road at East Millstone. This extensive project (administered by NJ Water Supply Authority), is slated to begin in the JULY 9, 2018 and may take up to three years to complete. For more information about this project, go to:
Hydrilla was discovered in the Washington Crossing section of the Canal in July 2016. Hydrilla is an extremely aggressive invasive aquatic plant that spreads very rapidly and forms dense mats that can choke the flow of water through the canal. A lake management firm was hired in September, 2016 to survey, assess, and map the extent of hydrilla and other problem weeds in the high-priority segments of the Delaware & Raritan Canal. The survey report indicates that, for the 18.31 miles surveyed, submerged aquatic vegetation was collected at 96 percent of the sites, confirming the spatial extent and diversity of vegetation in the Canal. Hydrilla was observed at 56 percent of the survey sites.
On May 31, 2017, the Authority began a low-dose (<4 ppb) herbicide injection of Sonar Genesis for up to 120 days targeting the hydrilla and other nuisance aquatic vegetation. At these low rates, there are no restrictions on fish/fish consumption, human/animal water consumption or contact. There are some recommended water irrigation usage restrictions that have been posted along the tred areas of the canal. All Canal water customers have been engaged in the management planning process and continue to be updated on the status of treatment. The herbicide application is showing promising signs of effectively controlling the Hydrilla and other nuisance aquatic plants. The Authority and consulting firm are monitoring the status of plants and the herbicide concentrations at several points along the Canal. For monitoring and project information, please visit http://www.njwsa.org/hydrilla.html
Emerald Ash Borer Tree removal project
UPDATE EMERALD ASH BORER TREE REMOVAL PROJECT: Be advised -Ash removal project currently shut down for timing restrictions.
The Department of Environmental Protection (DEP) is in the process of developing a comprehensive management plan for the Bull's Island Recreation Area upper river camping section, which includes hazardous tree removal and reforestation. The upper river campground/low lying area campsites are closed for public access until the area can be reopened for passive recreational use. The down river campsites are closed for the 2012 camping season pending a second phase tree assessment which will be conducted over the summer. Day use activities in the lower river section, including the boat ramp and picnic area remain open.
The DEP conducted a tree assessment of the entire upper river campground as a result of a large sycamore falling in 2011. The assessment provided evidence of hazardous trees due to root decay from silt buildup related to repeated floods. Most of the trees in the area were found to have compromised root systems.
As a result, the DEP closed all camping areas to protect the public. For the upper river campground which consists of a 5 acre parcel with more than 200 large trees, a management plan is in development to mitigate the public safety hazards with the goal of eventually reopening the area to the public for passive recreation. The management plan will include the removal of trees in the upper river camping area and replanting of the area with smaller growing trees, shrubs and other native vegetation. To adequately refine this management plan and to ensure that impacts of the tree removal to the natural resources, including migratory and nesting birds and other wildlife, are minimized, a coordinated team representing the various technical programs within the DEP are providing input to ensure concerns are addressed and any necessary reviews are conducted and appropriate permits obtained. Plant material that will thrive in this type of environment and not create hazards for public access will be the focus of the plan, with attention to monitoring for, and controlling invasive species. The area will ultimately reopen for passive recreational use. The DEP will make a decision on the lower river camping section once the tree assessment is completed.
The Department will continue to update its website message on Bull's Island Recreation Area as information becomes available. Thank you.
Please call the park office at 609-924-5896 before visiting.
D&R Canal Dredging Project
Park Map
High resolution for printing purposes; Print Size: 8.5 x 14
File Size: 2067KB
D&R Canal State Park Path
in Trenton NJ
D&R Canal State Park map through Duck Island - Lock 1 and Lock 2
Six Mile Run Trail Map
Horseshoe Bend Preserve map
APPLICATION for INDIVIDUAL APPROVAL and WAIVER
2013 Annual Report
This charming 19th-century
mill complex contains both grist and linseed oil mills. The
site is leased and operated by the Delaware River Mill Society,
which sponsors concerts and other programs on site. For information
about programs, call (609) 397-3586.
The wooden canal bridge, the Mule tender's
Barracks, the Bridge tender's House and station and
the site of the Griggstown Mill are situated along the canal.
Canoes can be rented at a private canoe rental concession
on the canal. The Griggstown Lock is less than a mile south
on the towpath. A short walk brings you to grassy fields with
picnic tables and grills.
The Bridge tender's House, wooden bridge
and mill site are reminders of the area's active past. Several
annual events are held at the house. Picnic tables and grills
are located around a large field with views of the river.
This historic site provides access to the canal, towpath and
Griggstown and Blackwells Mills are located
between the Millstone River and the D&R Canal and can
be reached off Route 533, Millstone River Road in Hillsborough
or from Canal Road in Franklin Township. Both historic sites
provide access to the Millstone River as well as the canal
and towpath.
Trail heads for Six Mile
Run Reservoir are nearby. Horse trailer parking is
This area displays a deciduous lowland hardwood
forest adjacent to the Heathcote Brook in Kingston. A short
trail takes visitors to the forest and small ponds.
Kingston Trails Map
The Six Mile Run Reservoir Site, is
one of Central New Jersey's most hidden recreational resources
for hiking, biking, horseback riding and Hunting. The 3000 acre reservoir
site, rich in cultural and historic significance, is also
a valuable oasis of wetlands, forests, farmlands and old fields.
Six Mile Run Reservoir Site Trail Map
(High resolution for downloading/printing purposes)
File Size: 724KB
The Park staff offer a variety of historical and natural interpretive programs throughout the year. Contact the park office for a schedule of programs. Program fees may apply.
The towpath and multi-use trails are great for all ages and physical abilities. Both the Main Canal Trail, which runs 34 miles in length, and the Feeder Canal Trail at 31.5 miles are ADA accessible.
Kingston Trails of D&R Canal State Park
D&R Canal Towpath Trail in Abbott Marshlands
Feeder Canal Near the Trenton Battle Monument
Picnic table and grills are located at some of the access points and near a few of the historic sites. Informal picnicking is allowed along the canal. Open fires are not permitted. Charcoal fires are restricted to the grill in the picnic areas.
The historic towpath found along the feeder and main canal is suitable for hiking, jogging and biking. Horseback riding is permitted on the main canal only. Motorized vehicles or ATV's are not permitted on trails in the park. In addition to the canal trail, patrons can access trails at the Six Mile Run Reservoir Site, Kingston greenway and Cook Natural Area Trails from the park office located in Kingston as well as one trail found within the Bull's Island Natural Area.
Fishing is permitted the entire length of
the canal. Anglers can find bass, sunfish, catfish, perch
and pickerel within the canal as well as trout, which the
Division of Fish
and Wildlife stocks the canal with each spring. Fishing
is also permitted in the Delaware River. All canal and river
fishing is subject to the New Jersey Division of Fish and
Wildlife regulations.
The D&R Canal State Park offers five boat launches into the Delaware River. Launches are located at:
Kingwood Township, Hunterdon County
Byram, Hunterdon County
Bulls Island, Stockton, Hunterdon County
Lambertville, Free
Fireman's Eddy, Hopewell Township, Mercer County
Boat Launches are available from sunrise to sunset year round.
A Launch Ramp fee is in effect from Memorial Day to Labor Day. Canoes, kayaks, boats, vessels and personal watercraft (e.g. jet-skis) that are transported in any manner are subject to launch ramp fees. Required daily or annual permits can be purchased at the Bulls Island Main Office at 2185 Daniel Bray Highway, Stockton, NJ 08859. For further information, call 609-397-2949.
There are no motor
restrictions on the river, but all the New Jersey boating
regulations apply.
There are restrictions on boating and canoeing on
the canal. Only electric motors, car top launch, and canoes
are permitted, which, can be rented from private concessionaires
in Griggstown and Princeton.
Launch Ramp Permit Information Sheet
• Bull's
Island Recreation Area
• Delaware and
Raritan Canal State Park and Canal Commission
• Delaware
Canal State Park
• D&R Greenway Land Trust
• Delaware River Scenic Byway Map
regarding our parks and forests can be directed
Michele Buckley of the State Park Service.
Department: NJDEP Home | About DEP | Index by Topic | Programs/Units | DEP Online
Statewide: NJ Home | Services A to Z | Departments/Agencies | FAQs
Copyright © State of New
Jersey, 1996-2018
Last Updated:
September 18, 2018


text:
The rare type of hick, redneck, and hillbilly located in the northern U.S.A. They have very close family ties to the soutern united states. They don't have much of a southern accent, but can fluently speak and comprehend it. They do not hang a confederate flag in fear of being shot or arrested. Most northern hicks are located in the states of washington, oregon, and idaho. They live in cities with a population or about 20,000. The cities are usually mostly composed of these northern hicks, so most people around there are wearing plaid and overalls. Northern Hicks do not own a rusty old truck that they drive around, they have the biggest truck you can buy, but it has to be very clean. Northern Hicks are truly the same as the original hick, redneck, and hillbilly, at heart, but their ways are set back by the cruelty of the city life...
by Hick at heart April 30, 2006
Usually someone with the name Sam, lives anywhere above georgia. Likes black people
Sam is a northern hick, says emmitt
by Reptar eater of ozones May 05, 2011
Basically someone who wants to be a "hick" or from the south. Some who have actually came from the south and kepted their southern ways. They are mainly located in Iowa, Oregon, or Idaho, living in a small town. Try really hard to be a hick, A lot of the time over dose things, just to look like a hick, like be racist, when most of them down south loves black people. I dont believe in a hick unless they are truly southern!!
northern hick
by dixy123 September 10, 2011


text:
December 2002
The orthographic plum was a sensible shift in the alphabetic ordering of ICAAC abstracts. For years HIV abstracts got grouped under I. This year the HIV crowd suffered a small jolt when flipping to the abstract book's familiar I section and finding -- nothing. What? No HIV abstracts this year? Hardly. HIV jumped one rung up the abecedarian ladder to H, replacing "Virology (other than HIV)," which tumbled to V.
But that wasn't the only HIV difference between ICAAC 42 and most every other ICAAC for the past decade. HIV attendees endured another little shock when they scanned the program for the opening night session, long devoted to the notorious retrovirus. Not this year. Instead the keynote session considered vaccines, with one HIV talk by Lawrence Corey, a CDC foray into "the impact of global immunization programs," and -- perhaps inevitably -- a talk on "vaccines for agents of bioterrorism."
Well, at least Tony Fauci is back with plenary lecture to update his take on HIV pathogenesis. What's this? Fauci is talking about what? Right. Bioterrorism. Perhaps the HIV set should be happy that the keynote session didn't focus entirely on treacherous plagues like West Nile virus or -- an epidemic still limited to the U.S. West, apparently -- mad deer disease.
But HIV hasn't gone away. Globally, no one needs convincing, though patterns may be mutating if we can believe the U.S. Central Intelligence Agency. The agency's National Intelligence Council predicts a watershed shift in the epidemic's course.1 The devastation of southern and eastern Africa will continue, according to CIA seers, but eight years from now most infected people will live in China, Ethiopia, India, Nigeria, and Russia. Things aren't so great in the United States either, where -- year after dreary year -- another 40,000 people open their lymph nodes to HIV, and reports of risky escapades by already at-risk people appear in the paper weekly. But teaching abstinence without promoting needle exchange will make things better, we hear.
It's easy to get cranky about this state of affairs. So far bioterrorism has killed fewer people in the U.S. -- five -- than Michael Gottlieb (four), Henry Masur (11), and Frederick Siegal (four) reported in their seminal AIDS case series of 1981.2-4 West Nile virus has sent 198 Americans to their graves since 1999,5 compared with 233 CDC-reported AIDS deaths in the epidemic's first three years here, 1979 through 1981.6 (And the counting wasn't so good back then, since no one knew the disease existed.)
Despite such gripes, ICAAC has served HIV well, and HIV researchers from near and far observe the yearly haj to showcase their studies there. ICAAC's 2002 edition featured 152 reports of new HIV research, not counting studies summarized in five symposia and three caffeine-fueled Meet-the-Experts exegeses. And there's plenty of room on ICAAC's sumptuous program for topics great and small. But any hints of drift from a stern focus on the retrovirus rouse concern.
The reasons for that are simple. One, HIV continues its largely unimpeded global stampede. And two, for all the superb science HIV has inspired, it still guards key secrets as closely as thick steel once secured lock boxes at the San Diego Trust and Savings Bank (at top). When newly wealthy San Diegans lined up to lock down necklaces and notes of credit in William Templeton Johnson's nouveau Renaissance cathedral of finance, they could not suspect those notes might be worthless a year later, when the 1929 crash ignited the Great Depression. The secrets HIV guards seem more likely to retain their value, and to resist turnkey attempts to retrieve them from their safe-deposit security.
Who would have thought that Jay Levy's CD8 antiviral factor (CAF), first described in Science7 only five years after Gottlieb et al. described AIDS, would elude discovery -- and even agreement about its existence8 -- for at least 16 years? Who would have imagined that in 2002 a good HIV vaccine might lie as far in the future as Gottlieb's report lies in the past?
Yet, as ICAAC showed, neither ugly possibility can be erased with confidence.
Who would have predicted, once puissant regimens rescued people from the grave's lip, that stopping successful therapy would be considered a reasonable -- even a wise -- option? Who could have foreseen, when a single protease inhibitor (PI) seemed destined to extract HIV from every T cell that mattered, that so much work would explore combining two of them, or three of them? Who would have guessed, once drug labs started spewing potent antiretrovirals, that bright clinicians who treat a deadly infectious disease would still have to debate when to start?
Yet in the Year of the Plague 2002, as ICAACers learned, those issues remain very much in play. Start with the starting debate, ably argued by Diane Havlir (University of California, San Francisco) at an ICAAC interactive session:
ICAAC has spotlighted some skilled educators at these sessions, none more skilled than Diane Havlir, who bravely dusted off that shopworn snarler -- when to start antiretroviral therapy -- and showed that it remains a vibrant and critical question. She zeroed in on the group's zeitgeist by posing a simple case and modifying it twice.
* Combivir combines zidovudine (AZT) and lamivudine (3TC).
+ Trizivir entwines AZT, 3TC, and abacavir.
Vote, then see how your colleagues answered in Table 1.
If you're like seven of 10 people in the ICAAC audience, you don't treat a newly diagnosed 47-year-old woman whose CD4 count and viral load lie outside the GO box drawn by most current guidelines. Nearly the same proportion starts scribbling scrips -- usually for three drugs -- if that woman's viral load tops 100,000 copies/mL. And, even if her viral load is low (26,000 copies/mL), but her CD4 count precarious (205 cells/mm3), almost everyone starts treating.
Maybe the most surprising result of this survey is that nearly one third of respondents do start HAART when the T-cell tally still stands above 350 cells/mm3 and the RNA assay measures a mere 30,000 copies/mL. Maybe the woman's age, 47 years, has something to do with it. Or maybe this quick-trigger 31 percent doesn't buy the advice that discretion is the better part of antiviral prescribing.
Havlir doesn't.
Showing a cartoon depicting a woman pushing the when-to-start pendulum back toward earlier intervention, Havlir explains that the woman is she.
Diane Havlir's chief concern lies with the endpoints tallied in big cohort studies that find little advantage to starting treatment above 350 cells/mm3 versus starting between 200 and 350 cells/mm3. The much-sifted data from Robert Hogg,9 Timothy Sterling,10 and Matthias Egger11 all reckon descents to AIDS or death -- the endpoints -- then fix their compass on the same foreboding polestar -- 200 cells/mm3. On the one hand, using AIDS and death as endpoints makes sense because those are the two "outcomes" everyone hopes most to outlast. But Havlir argues that a blinkered focus on these two dire denouements overlooks other benefits earlier treatment may bring:
At the same time, as authors of cohort studies themselves observe, the typical two- or three-year follow-up will miss a longer-term advantage of earlier treatment, if such an advantage were to emerge. But perhaps history is the factor that most dilutes the reliability of the when-to-start cohort studies presented so far. They involve cohorts first treated from 1996 to 1999,9 1996 to 2001,10 and at a median date of December 1997 (interquartile range June 1997 to July 1998).11 Although Sterling10 tracked people into 2001, the median follow-up of 24 months means most of them started HAART in 1999 or earlier. So a large majority in all three studies began treatment with a musty 20th century regimen, not the more potent therapies prescribed up front today. As Havlir observed, 21st century first-line combos are also typically simpler and often more tolerable than 1998 standbys like stavudine (d4T), 3TC, and solo indinavir.
Havlir is not alone in making this point. In a long interview on antiretroviral strategies, veteran HIV clinician Howard Grossman observed that potent, simple, and safe regimens -- 3TC, abacavir, and tenofovir, for example -- should encourage a closer look at hit-hard-but-later fiat.12
At ICAAC Michael Saag (University of Alabama, Birmingham) accented the increasing potency of newer combinations in a slide comparing this year's standards of care with those of the late 1990s [abstract LB1]. The elder antiretroviral mixes came from a 2001 meta-analysis of 23 clinical trials completed in the second half of the last decade.13 This year's crop came from Saag's study of didanosine (ddI), emtricitabine (FTC), and efavirenz [abstract LB1] and a trial of d4T versus tenofovir plus 3TC and efavirenz [abstract LB2]. The simpler 2002 triple therapies won in a walk (Table 2).
Havlir's final pendulum push borrowed some muscle from two studies showing that HIV DNA -- a measure of virus at its ease in resting T cells -- offers another way to predict disease progression.14,15 In 130 people not treated with combination antiretrovirals, every 10-fold higher HIV DNA level in peripheral blood mononuclear cells raised the risk of AIDS 2.62 times and death 1.84 times, independently of age at seroconversion, baseline CD4 count, viral load, and T-cell-receptor excision circles.14 In 292 people evaluated before the HAART era, HIV DNA predicted disease progression and death independently of RNA load and CD4 count, and more robustly than either of those more familiar sibyls.15 More and perhaps better tools to predict progression, Havlir proposed, could justify earlier therapy in people who need it.
One oft-cited argument that Havlir mentioned only tangentially is the possibility that delayed therapy may allow ongoing immune wrack and ruin that treatment will not reverse. An enlightening study by Timothy Schacker and Ashley Haase, published after ICAAC, shows that one facet of immune decay can appear in the earliest days of infection.16 By this measure, treatment started at 355 instead of 205 cells/mm3 would make little difference. But the study bolsters Havlir's point that sturdy progression predictors remain to be discovered.
Scrutinizing lymph node biopsies from 11 people before they started potent antiretrovirals, Schacker found that baseline lymph tissue fibrosis predicted lymphoid CD4 levels and response to therapy. With collagen as a marker of fibrosis, he showed that the more collagen a person had before treatment, the fewer CD4 cells that person had in the paracortical T-cell zone, where 98 percent of T cells lie (r2 = 0.72, P < 0.0001). The amount of collagen did not correlate with pretreatment peripheral CD4 count, pretreatment viral load, or duration or stage of HIV infection. One person had acute HIV infection, three had been infected six months or fewer, six had CD4 counts over 200 cells/mm3 and no AIDS diagnoses, and one had AIDS. Lower pretreatment collagen also predicted bigger peripheral CD4 gains after six months of therapy in seven people who started antiretrovirals (r2 = 0.91, P < 0.0001).
Schacker and colleagues believe this lymph tissue fibrosis with HIV infection "is analogous to the pathogenesis of cirrhosis in chronic active hepatitis B and C infection, wherein ongoing viral replication in hepatocytes leads to a state of chronic inflammation and fibrosis." They suggest that a pretreatment lymph node biopsy could help clinicians stage HIV disease and "provide useful information on when to initiate therapy." The researchers also think their findings suggest the need to study adjunctive anti-inflammatory therapy as a way to limit, or even reverse, damage to the paracortical T-cell zone.
The study serves as a reminder that research can pry loose HIV's secrets, but that many others remain. It also hints that the standard of care in 2006 will differ more from today's standard than today's differs from 1998's.
The early group started with an average CD4 count of 506 cells/mm3, compared with 275 cells/mm3 in the later-starting group (P < 0.001). No one had an AIDS diagnosis before treatment. Although early and later starters did not differ in age (34 versus 35 years), viral load (4.8 versus 4.7 logs), or relative use of PIs and nonnucleosides (NNRTIs), the later group had three nearly significant and possibly related disadvantages:
After 12 weeks of antiretroviral therapy, 89 percent in both groups had at least a 1-log drop in circulating virus or fewer than 400 RNA copies/mL. After one year, 86 percent in the early group and 88 percent in the later group had a sub-400 viral load. The "clinical event" rate was higher in the delayed group, but not significantly so, and that group had a trend to more frequent immune reconstitution disease than the early group (50 versus 16.7 percent, P = 0.171).
The critical outcome difference proved to be the rate and reasons for regimen switching. In the early group, 57 percent switched their regimen over 18 months of follow-up, compared with 67 percent in the later group, a nonsignificant trend (P = 0.157). But nearly three times more later starters (36 percent) than early starters (13 percent) switched because of virologic failure (P = 0.005). In a multivariate analysis adjusted for the three variables bulleted above, a later start independently upped the odds of switching for failure by a factor of 5 (P = 0.003). But injection drug use, adherence below 90 percent, and HCV coinfection each raised that risk much more, at respective odds ratios of 50 (P = 0.016), 37 (P = 0.02), and 40 (P = 0.014).
Because of their lower pretreatment CD4 count, the later group also trailed the early starters in CD4 count three, six, nine, 12, 15, and 18 months after starting therapy (P < 0.0001 at every point). But at 18 months they had a good average count of 525 cells/mm3, compared with 786 cells/mm3 in the early group.
Reasonable people can disagree about what this study means. Perez-Elias and colleagues offered a binocular view. "It seems safe to delay initial [antiretroviral therapy] in non-AIDS patients until the CD4 count reaches a number between 350 and 200 cells/mm3, in terms of clinical outcomes," they concluded. "However, the higher risk of changes due to failure complicates further antiretroviral therapy management" in later starters. Indeed, the study slices some sinew from the stock argument that people who start treatment at high T-cell counts will expend their antiretroviral options faster than waiters. In this cohort, at least, the exact opposite could prove true.
Reasonable people can also turn the table and ask, if someone started treatment with a high CD4 count, as Perez-Elias's early group did, is it safe to stop if treatment keeps HIV under wraps? Before ICAAC two studies suggested that people can stop safely if they launched their antiretroviral argosy at CD4 and RNA sums no longer deemed grounds for intervention by the guideline givers -- generally, above 350 cells/mm3 or below 55,000 copies/mL.17,18 An ICAAC study reached the same conclusion.
Another Madrid group, represented by Manuel Fernández-Guerrero (Fundación Jiménez Díaz), tracked 49 people averaging 34 years of age who took their first antiretroviral with 300 to 500 CD4 cells/mm3 or 10,000 to 70,000 RNA copies/mL, and usually both [abstract H-1082]. The plan of this ongoing study calls for renewed treatment if CD4 cells tumble under the 300 line, if the viral load tops 70,000 copies/mL twice in a row, if an opportunistic disease develops, or if a person withdraws consent.
The group's average CD4 count when they stopped treatment stood at a robust 730 cells/mm3. That average dropped rapidly in the drug holiday's first four months, to 544 cells/mm3, then drifted to 525 cells/mm3 at month eight, 496 cells/mm3 at month 12, and 481 cells/mm3 at month 16. So far 12 people (24 percent) have resumed treatment, four in the first eight months, and eight during months nine through 20. But all restarters regained virologic control with the regimen they had stopped. Only one person endured a disease suggesting compromised immunity, herpes zoster.
Elena Seminari and colleagues at the Policlinico San Matteo in Pavia have nearly completed a one-year study that randomized people with viral loads below 50 copies/mL on treatment to continue therapy or to switch between treatment and no treatment every month. A subanalysis presented at ICAAC tried to figure why five people met the protocol criterion for leaving the study -- a CD4 count below 200 cells/mm3 after a full month on treatment following a break [abstract H-1745]. One person failed to climb back to 200 cells/mm3 at month two, two at month four, one at month six, and one at month eight. All five shared one trait, a T-cell nadir below 50 cells/mm3. But that deficit alone did not explain their poor CD4 recovery while on treatment, because 12 other study participants had nadirs under 50 and did not have to leave the study.
Comparing the five dropouts, the 12 others with sub-50 nadirs, and 45 study participants with nadirs above 50 cells/mm3, Seminari found no differences in age, gender, duration of treatment, duration of viral control below 50 copies/mL, or antiretroviral regimen. The CD4 nadirs in the 17 with sub-50 nadirs averaged 23 cells/mm3, compared with a nadir of 256 cells/mm3 in the other 45 (P < 0.001). Having a nadir under 50 cells/mm3 raised by 18 times the risk of failing to attain a count above 200 cells/mm3 after a full on-treatment month.
The first on-treatment month after the first holiday month held the clue to protocol-defined CD4 failure. Everyone in the 45-person comparison group regained all the CD4 cells lost during the first break during their first month back on treatment. The 12 people with nadirs under 50 cells/mm3 who did not have to leave the study regained 70 percent of their T cells in the first on-treatment month. And the five people who failed to climb back to 200 cells/mm3 at some point in the study regained only 37 percent of their T cells in the first on-treatment month. Seminari proposed that this "flattened regain curve" in the first treatment month after the first treatment break may predict later CD4 failure.
Not surprisingly, a CD4 count under 200 cells/mm3 emerged as one of eight predictors of death in a retrospective analysis of 67 people who died in a population of 639 with HIV infection [abstract H-1145]. But statistical analysis by Chiu-Bin Hsiao (State University of New York, Buffalo) rated a sub-200 CD4 sum as only a "minor" factor. The two major factors were a small surprise: thrombocytopenia and hyperglycemia (Table 3).
Hsiao's record review involved 417 males and 222 females seen between December 1998 and September 2001. The group included 292 African Americans, 229 Caucasians, and 90 Hispanics; 253 had HCV coinfection. After a median follow-up of two years, 47 males and 20 females had died. Forty-three of those who died (64 percent) had a CD4 count under 200 cells/mm3, and 42 (63 percent) had a viral load above 10,000 copies/mL.
A multivariate analysis determined that a platelet level below 130 x 103/µL inflated the risk of death 5.3 times, followed by hyperglycemia, a viral load above 10,000 copies/mL, anemia, high lactate dehydrogenase, HCV coinfection, a CD4 count under 200 cells/mm3, and age over 39 years (Table 3). Assigning a numeric value to each of the eight risk factors, Hsiao fashioned two schemes to reckon the risk of death.
A person with none of the risk factors has a 0.6 percent risk of death. Someone with all the risk factors has a 98 percent risk. Risk rates reflect the median follow-up of two years (range 12 to 1,245 days) for the cohort. In the 67 cohort members who died, a median of 360 days (range 12 to 904 days) elapsed between the date of data collection and death.
This kind of analysis comes with built-in limits. Although the cohort's make-up is diverse, it is relatively small and includes only 67 deaths. Substantial subsets were taking no antiretrovirals (151 or 24 percent) or only two NRTIs (66 or 10 percent). Hsiao did not report how many in those groups died, but he reported that different regimens did not influence mortality. Still, the surprise finding on thrombocytopenia and the high risk with hyperglycemia -- a PI side effect -- stress the value of tracking these lab values and should inspire further research.
The study involved treatment-naive people in Asia, Africa, Europe, and North and Central America with a median baseline viral load around 4.9 logs (about 80,000 copies/mL). More than 40 percent had a viral load over 100,000 copies/mL. The median starting CD4 count measured 286 cells/mm3 in the atazanavir arm and 280 cells/mm3 in the efavirenz arm. The cohort was young, with a median age of 34 years. About one third of study participants were women.
The noncompleter-equals-failure analysis counted failure as stopping the assigned treatment for any reason, an AIDS diagnosis, or a confirmed rebound above 50 copies/mL after a response. More than 80 percent in both groups finished 48 weeks of treatment. But at that point only one third of study participants had a viral load under 50 copies/mL by the intent-to-treat analysis and only half had a sub-50 load in an on-treatment analysis (Table 4). The small differences between treatment arms did not reach statistical significance. Although the atazanavir group gained significantly more CD4 cells than the efavirenz group, Squires reasonably proposed that the modest difference probably has no clinical relevance.
One third in the atazanavir group had hyperbilirubinemia, but only 5 percent had to lower their atazanavir dose and fewer than 1 percent left the trial as a result. As in other atazanavir trials, fasting lipids changed little with the drug over 48 weeks. People taking efavirenz had bigger lipid jumps, but few people crossed National Cholesterol Education Program (NCEP) thresholds for antilipid therapy.
Some factor or factors clearly sabotaged the virologic response to both drugs in this study. Although research has yet to establish the potency of atazanavir, efavirenz has an unblemished record in head-to-head trials that enroll treatment-naive people. In a study of efavirenz plus 3TC with either tenofovir or d4T, for example, 48-week proportions with viral loads under 50 copies/mL measured over 80 percent in a missing-data-equal-failure analysis [see abstract LB2 below]. Reason dictates that efavirenz did not suddenly become a rotten drug.
A few factors could contribute to the dreadful virologic results. The protocol forbade dose reductions with AZT or 3TC or switches to different nucleosides. Those dictates may have spawned spotty adherence reflected in emergence of the 3TC-related M184V mutation in more than half of the study participants genotyped so far. Poor adherence seems even more likely when one considers that the nonnucleoside-linked K103N mutation cropped up in 65 percent of those genotyped, a rate that drew stunned murmurs from the crowd. Atazanavir's apparent signature mutation, I50L, appeared in only 16 percent so far. But, as much research shows, resistance will emerge first against 3TC and nonnucleosides when a regimen begins failing.
Poor adherence apparently followed a regional pattern. Squires told IAPAC Monthly that virologic responses in some regions considerably lagged those in others. European participants did worse than those in Asia and Africa, she noted, surmising that a higher proportion of injection drug users in the European population may partly explain those differences. At the same time, Squires added, the relative unavailability of antiretrovirals in Africa and Asia could inspire stricter adherence among people lucky enough to get into trials.
Finally, the trial used a tougher than usual definition of failure prescribed by the Food and Drug Administration. It counts any drug switch for any reason or two consecutive viral loads above 50 copies/mL as a failure. The AIDS Clinical Trials Group, for example, requires consecutive rebounds above 200 copies/mL to signal failure, figuring that touchy ultrasensitive assays could record some 50+ readings that do not signal abiding rebounds.
Clearer answers should emerge as the researchers analyze region-specific response and resistance patterns. (The trial did not include a formal adherence measure.) Even if poor adherence and a draconian failure definition explain this downfall of atazanavir and efavirenz, clinicians will likely want fresh proof of atazanavir's antiviral punch in the wake of this study. Few are likely to demand the same for efavirenz.
If atazanavir turns out to be a notch or two feebler than hoped, a ritonavir boost could be a fallback strategy. At this point atazanavir's maker still positions the drug as an unboosted first-line agent, but Bristol researchers did study the impact of a 100-mg ritonavir prod in 30 healthy volunteers [abstract H-1716]. S. Agarwala and colleagues gave them 300 mg of atazanavir once daily for 10 days, then added ritonavir on days 11 through 20. Atazanavir's geometric mean peak concentration jumped from 3,288 ng/mL on day 10 to 6,129 ng/mL on day 20, an 86 percent gain. The area under the concentration-time curve (AUC) for atazanavir vaulted from 16,875 ng · h/mL on day 10 to 57,039 ng · h/mL on day 20, more than a threefold surge. The trough concentration climbed about 10-fold. Ritonavir levels varied little over the course of the study.
As with any drug, the danger of increased exposure is increased toxicity. In earlier studies that used 400 or 600 mg of atazanavir daily, more people taking the higher dose had bilirubin elevations. And, as Bristol's Edward O'Mara reported in an analysis of 202 people enrolled in phase I studies of the PI, higher AUCs raised the risk of billowing bilirubin regardless of whether a person has a genotype favoring hyperbilirubinemia [abstract A-1253]. At the same time, a 7/7 genotype in the UGT 1A1 gene independently raised the risk that total bilirubin would exceed 2.5 mg/dL. (UGT 1A1 glucuronidates unconjugated bilirubin.) Eleven of 13 people (85 percent) with the 7/7 genotype had a total bilirubin topping 2.5 mg/dL, compared with 17 of 49 (35 percent) with a 6/7 genotype and eight of 62 (13 percent) with a 6/6 genotype.
Analyzing 950 isolates from people with PI experience but naive to atazanavir, Bristol's Richard Colonno found that most isolates resistant to one or two PIs remained susceptible to atazanavir when he used an arbitrary 3-fold drop in susceptibility to indicate resistance [abstract H-2049]. But most isolates resistant to three or more PIs also proved resistant to atazanavir. The analysis broke down like this:
Colonno also figured which mutations in these isolates conferred resistance to atazanavir. No single mutation did, but any five from the following familiar 14 did: (see Diagram 1)
An intent-to-treat analysis at week 48 considered all study participants who took their assigned drugs and had at least one on-drug RNA rating. By that measure, 51 percent taking saquinavir and 71 percent taking efavirenz notched a viral load below 50 copies/mL. The saquinavir group did better in an on-treatment analysis, but still lagged the efavirenz group, with 73 versus 93 percent under 50 copies/mL. The study tested the hypothesis that saquinavir/ritonavir is "noninferior" to efavirenz in pushing viral loads under 50 copies/mL. "Noninferiority criteria," Montaner reported, "were not met."
Gastrointestinal (GI) side effects proved the PIs' undoing in the intent-to-treat analysis. One third of the 81 people assigned to saquinavir/ritonavir had nausea, vomiting, or diarrhea, compared with 4 percent of the 80 people randomized to efavirenz. Twelve people (15 percent) stopped saquinavir/ritonavir because of side effects and 11 (14 percent) withdrew their consent to continue. Respective numbers in the efavirenz group were five (6 percent) and three (4 percent).
Total cholesterol rose from an average 171 mg/dL at baseline to 206 mg/dL in the PI group and from 167 to 204 mg/dL with efavirenz. Triglycerides climbed from 124 to 175 mg/dL with saquinavir/ritonavir and from 139 to 210 mg/dL with efavirenz. Because research shows that d4T boosts lipids [see abstract LB2 below], knowing which NRTIs people were taking may have enlightened this lipid analysis.
Montaner proposed that the saquinavir group's GI troubles may be traced to an ingredient in saquinavir's soft-gel capsule. He suggested that the venerable hard-gel formulation may be easier to stomach with a ritonavir boost.
Another study of saquinavir/ritonavir, this time at 1,000/100 mg twice daily in people with or without PI experience, pitted those PIs against indinavir/ritonavir at 800/100 mg twice daily [abstract H-172]. The regimens yielded similar virologic responses, but more people had to switch from the indinavir arm than from the saquinavir arm, and more taking indinavir suffered disease progression. Two features of the MaxCmin 1 trial design complicate interpretation of the results: First, as in the FOCUS study, individual clinicians picked the NRTIs to give with the PIs; they could also add an NNRTI if deemed necessary. But chief investigator Jan Gerstoft (University of Copenhagen) did not report the non-PI treatment assignments. Second, the study population can safely be called mixed. About 40 percent in each treatment arm had no PI experience. Among those who had tried a PI, about 60 percent had a viral load under 400 copies/mL when they entered the study.
After 48 weeks of follow-up, an intent-to-treat analysis involving study participants who took at least one assigned dose rated 20 percent taking indinavir and 18 percent taking saquinavir as virologic failures. But 41 percent randomized to indinavir/ritonavir had to stop taking those PIs compared with 27 percent randomized to saquinavir/ritonavir (P = 0.018). Gerstoft recorded clinical progression in 28 percent of the indinavir group and 15 percent of the saquinavir group (P = 0.006), with no deaths in either arm. Total cholesterol, low-density lipoprotein cholesterol, and triglycerides each rose about 20 percent with indinavir/ritonavir, but less than 10 percent with saquinavir/ritonavir (P < 0.05).
Another study by Jan Gerstoft appraised one familiar combination (saquinavir/ritonavir at 400/400 mg twice daily plus AZT/3TC) and two rarer hybrids (ddI/d4T/abacavir and AZT/3TC plus nelfinavir at 1,250 mg twice daily and nevirapine at 400 mg twice daily) in 178 treatment-naive people [abstract H-164]. The rationale offered for the triple-nuke regimen was that it may be less prone to cross-resistance than abacavir plus AZT and 3TC. The main outcome of the trial seems to be that half the people in each treatment arm bailed out of the study before week 48. With 60 people in each group, 33 stopped saquinavir/ritonavir, 24 nelfinavir/nevirapine, and 35 the three nucleosides.
Neurologic toxicity -- presumably neuropathy -- felled 16 people (27 percent) in the NRTI group compared with three taking saquinavir/ritonavir and two taking nelfinavir/nevirapine (P < 0.001). When compared by grade 4 toxicity rates, saquinavir/ritonavir proved the most tolerable regimen (four people), followed by nelfinavir/nevirapine (seven), and the triple nukes (eight). The NRTI regimen also lagged the others in a missing-data-equal-failure analysis of sub-20-copy viral loads at 48 weeks, with about 41 percent under that mark compared with 55 percent taking saquinavir/ritonavir and 62 percent taking nelfinavir/nevirapine. Few would contest Gerstoft's conclusion that "this triple NRTI regime cannot be recommended."
FTC trounced d4T by numerous measures of efficacy in a double-blind, placebo-controlled trial involving treatment-naive people also beginning once-daily ddI plus efavirenz [abstract LB1]. FTC -- a cytosine analog like 3TC -- needs only one 200-mg dose daily. Michael Saag (University of Alabama, Birmingham) reported that the 286 people randomized to FTC and the 285 randomized to d4T matched closely in pretreatment viral load (4.9 logs in both groups) and CD4 count (280 cells/mm3 in the FTC group and 300 cells/mm3 in the d4T group).
After 24 weeks of treatment, 81 percent taking FTC and 70 percent taking d4T had a viral load under 50 copies/mL (P = 0.002). FTC bettered d4T in 52-week Kaplan-Meier probabilities of efficacy, tolerability, and effectiveness, defined in Table 5. By week 52, people taking FTC had gained significantly more CD4 cells than those taking d4T.
If licensed, FTC would join ddI, 3TC, and tenofovir as nucleosides (or -tides) that can be taken once daily. Also like 3TC and tenofovir, it stifles hepatitis B virus as well as HIV. A 48-week interim analysis of another placebo-controlled trial showed similar potency with tenofovir or d4T in antiretroviral-naive people, but significantly fewer side effects with tenofovir [abstract LB2]. The 600 study participants had an average starting viral load of 4.9 logs and an average CD4 count of 279 cells/mm3. Everyone also took 3TC and efavirenz.
Joel Gallant (Johns Hopkins University) reported similar RNA and CD4 responses with tenofovir and d4T after 48 weeks. In a missing-data-equal-failure analysis, 82 percent taking tenofovir and 81 percent taking d4T had a viral load under 50 copies/mL. Responses did not differ in subgroups starting treatment with fewer or more than 100,000 RNA copies/mL. The tenofovir group gained an average 169 cells/mm3, compared with 167 cells/mm3 with d4T.
Rates of grade 3 or 4 side effects proved similar in the two groups -- bedeviling 19 percent taking tenofovir and 17 percent taking d4T. But the d4T group lagged tenofovir takers in three key lab measures and in peripheral neuropathy. Triglycerides rose an average 74 mg/dL in the d4T group but did not change in the tenofovir group (P < 0.001). Total cholesterol climbed by 53 mg/dL with d4T versus 25 mg/dL with tenofovir (P < 0.001). Whereas 7 percent taking tenofovir reached lactate levels above 2.1 mmol/L, 36 percent taking d4T did (P < 0.001). Peripheral neuropathy affected 2 percent taking tenofovir and 7 percent taking d4T (P < 0.001).
Among people starting tenofovir with a thymidine analog mutation (the TAMs are M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E), only 11 percent attained a sub-50 viral load, whereas 49 percent without TAMs did so. Having the 3TC-induced M184V mutation also favored a good virologic response with add-on tenofovir; 49 percent with M184V at baseline got their viral load under 50 copies/mL.
In a multivariate analysis, Miller calculated the following odds ratios (OR) for a sub-50 copy reading according to baseline viral load or mutation array:
Intensification of a floundering regimen can be risky. If adding a new drug doesn't stop the slide, mutations can pile up, as Miller also demonstrated in this analysis. His findings give clinicians a few tools to help decide whether adding tenofovir is worth the risk. When tenofovir regimens did fail in this population, added TAMs proved the biggest culprit. The tenofovir-linked K65R mutation popped up in only 3 percent (eight people), and none suffered a virologic rebound.
Because T-20 is hard to make, it will cost a lot, almost certainly more than any current antiretroviral. It has to be mixed carefully a half-hour before each dose (see "T-20" in reference 12), and it must be injected under the skin twice daily. Almost everyone who uses T-20 gets injection site reactions, 98 percent in the two big randomized trials.20,21 Although only 3 percent in those studies quit as a result, more will almost certainly abandon the drug in practice. In the European-Australian trial,20 the overall 24-week dropout rate was 11 percent in both the T-20 group and the non-T-20 group. But in the North American-Brazilian trial,21 17 percent quit the T-20 arm compared with 5 percent in the control arm.
At ICAAC Julio Montaner reviewed results from the North American-Brazilian trial, looking at potential subgroup differences and at predictors of antiviral vim [abstract H-1074]. Compared with the optimized regimen alone, T-20 plus optimized background yielded a better virologic response in males and females, whites and nonwhites, people under and over 40 years old, people with baseline viral loads below or above 100,000 copies/mL, and people with starting CD4 counts below or above 100 cells/mm3. People with phenotypic or genotypic sensitivity to zero, one to two, or three to four antiretrovirals did significantly better with T-20 than with optimized background alone (P < 0.05). Those with phenotypic or genotypic sensitivity to five or more antiretrovirals got a better response with T-20, but not a significantly better response.
In a multiple regression analysis estimating the log change in viral load at 24 weeks, six variables mattered:
Replacing the phenotypic sensitivity score with a genotypic sensitivity score yielded similar results. Baseline viral load did not figure in the response to T-20. The interesting findings with lopinavir/ritonavir clearly indicate that T-20 does much better when it teams with a potent ally. Montaner noted, though, that the T-20 group did not differ from the control group in proportions pretreated with lopinavir or getting lopinavir in the salvage regimen.
The one randomized study of the three involved 37 people taking lopinavir and amprenavir with 100 or 200 mg of ritonavir twice daily [abstract H-1078]. Everyone in the study had used at least two PIs and one NNRTI. Median baseline numbers included seven protease mutations, 207 CD4 cells/mm3, and 4.7 log copies/mL (about 50,000 copies/mL). After 26 weeks, reported Gilles Raguin (Bichat Hospital, Paris), the median viral load had dropped 2.5 logs in the 200-mg ritonavir group and 1.4 logs in the 100-mg group (P = 0.02). Eleven people (61 percent) taking 200 mg twice daily and six (32 percent) taking 100 mg twice daily reached a viral load below 50 copies/mL (P = 0.07). CD4 counts rose about 120 cells/mm3 in both groups.
The extra ritonavir did not compromise tolerability in this trial. Four in each study arm had to stop treatment. Seven (39 percent) in the 200-mg group and 10 (53 percent) in the 100-mg group had a grade 4 side effect. In a multivariate analysis, the extra ritonavir (P = 0.007) and fewer baseline protease mutations (P = 0.02) predicted virologic success. Baseline resistance phenotype did not predict success.
A larger, noncomparative study in people with shorter antiretroviral résumés and less advanced disease documented a reasonable six-month response to indinavir/ritonavir at a dose of 800/200 mg twice daily [abstract H-173]. Pompeyo Viciana and colleagues in Madrid and Barcelona gave doubly boosted indinavir plus two NRTIs to 105 people who had already tried an average of 2.2 PIs. Their baseline viral load averaged 4.3 logs (about 20,000 copies/mL) and their starting CD4 count 284 cells/mm3.
After six months of indinavir/ritonavir, 41.9 percent had a viral load under 200 copies/mL in a noncompleter-equals-failure analysis. An on-treatment analysis showed that 54.4 percent had a sub-200 viral load. The average CD4 count climbed to 370 cells/mm3. Baseline detection of mutations conferring resistance to indinavir and ritonavir (V82A and L90M) did not rule out a good response to the salvage regimen. But fewer people with the nelfinavir-linked D30N mutation responded.
Ritonavir-induced gastrointestinal (GI) problems proved the most frequent grade 3 or 4 toxicity, vexing 16 people (15 percent). In all, clinicians reported a toxicity of any grade in 38 people (36 percent).
A second noncomparative study in people with even better baseline barometers did not record a better response to the same dose of indinavir/ritonavir than did Viciana [abstract H-175]. David Parr from the University of Texas Medical Branch at Galveston, and coworkers in Georgia and Florida, treated 63 people with a mean CD4 count of 360 cells/mm3 and a mean viral load of 3.85 logs (about 7,000 copies/mL). Forty-eight of them (76 percent) were taking their first failing single-PI regimen, while 15 (24 percent) were on their second PI or their first dual PI combo.
The initial study lasted 24 weeks, during which 16 people dropped out (seven because of toxicity). Of the 47 people who finished 24 weeks, 20 did not enroll in a 24-week extension because of the timing of the extension approval. Of the 27 who did continue, eight dropped out before week 48 (five because of toxicity).
In a 24-week noncompleter-equals-failure analysis, 35 people (56.5 percent) had a viral load under 400 copies/mL and 23 (37.1 percent) were under 50 copies/mL. In the 48-week analysis excluding the 20 people who could not re-enroll, 10 (23.3 percent) were under 400 copies/mL and nine (20.9 percent) under 50 copies/mL. A last-observation-carried-forward analysis charted mean CD4 gains of 96 cells/mm3 at week 24 and 131 cells/mm3 at week 48.
Not counting those unable to sign up for the 24-week extension, 24 people dropped out of the study at some point. Nine of the 24 (37.5 percent) quit because of side effects. But some of the other reasons for bowing out could reflect poor tolerance, such as withdrawn consent (five people) and loss to follow-up (three people). Eight of the toxicity-related dropouts (representing 13 percent of the original study group) involved GI intolerance, a possible consequence of the doubled ritonavir dose.
Clinicians considering the extra ritonavir boost have to weigh the virologic benefits recorded in studies like these against the risk of increased toxicity. And toxicity rates will surely vary depending on disease stage and other variables. In a case series at the Lipodystrophy Workshop a week before ICAAC, Düsseldorf clinician Stefan Mauss reported that eight of 11 people could not tolerate 200 mg of ritonavir twice daily with lopinavir (400 mg twice daily) and amprenavir (600 mg twice daily).22 In an earlier study of lopinavir plus amprenavir with 100 mg of ritonavir twice daily, Mauss reported only one discontinuation among nine people because of GI toxicity.23
Alice Tseng (Toronto General Hospital) measured fasting lipids in 21 people starting a lopinavir salvage combination [abstract H-1916]. After a median nine months of follow-up, the median total cholesterol rose from 4.46 to 5.60 mmol/L (172 to 217 mg/dL, P < 0.001) and median triglycerides from 2.22 to 4.71 mmol/L (197 to 417 mg/dL, P < 0.09). The median lopinavir trough concentration measured 4.13 µg/mL in people with high triglycerides and 2.64 µg/mL in people with low triglycerides (P = 0.05). Among people with high total cholesterol, the median lopinavir trough stood at 4.08 µg/mL versus 2.87 µg/mL in people with low total cholesterol, but that difference was not significant. Lopinavir peak concentrations did not correlate with hyperlipidemia in Tseng's analysis.
Studying 22 people taking lopinavir in salvage, Sergio Padilla (University Hospital, Elche, Spain) figured a mean lopinavir plasma level for each person based on three to nine troughs [abstract H-1915]. Percent increases in cholesterol and triglycerides from baseline to weeks 12 and 24 correlated positively with mean lopinavir levels (r = 0.55, P = 0.008, for triglycerides at week 12; r = 0.55, P = 0.007, for cholesterol at week 24). At week 48 cholesterol was significantly higher in people with higher lopinavir troughs (8.88 versus 5.67 mmol/L [343 versus 219 mg/dL], P = 0.017). Subcutaneous and adipose abdominal tissue measured by CT increased over 48 weeks. But fat changes did not correlate with lopinavir concentration.
How much PI experience a person has when starting lopinavir could make a difference. Among 70 of 100 people who took lopinavir/ritonavir for 204 weeks as part of their first antiretroviral regimen, 12 (17 percent) had cholesterol levels between 240 and 300 mg/dL and one (1 percent) had between 300 and 400 mg/dL [abstract H-165]. Robert Murphy (Northwestern University, Chicago) reported that nonfasting triglycerides stood between 400 and 750 mg/dL in 18 (26 percent) and above 750 mg/dL in four (6 percent). One of 100 study participants dropped out because of high lipids.
A group of Spanish clinicians not affiliated with Virco found that Virco's VirtualPhenotype did better than standard phenotyping in picking more potent rescue regimens [abstract H-1079]. (The Virtual-Phenotype matches a submitted isolate's genotype with phenotypes of database viruses that have the same genotype.) This double-blind trial randomized 276 people from five outpatient clinics to have VirtualPhenotyping or standard phenotyping as a guide for their clinicians to pick new regimens. Most people (60 percent) had tried drugs from all three classes, and the average viral load hovered around 10,000 copies/mL.
Maria Jesus Perez-Elias reported that people in the Virtual arm got an average of 2.9 drugs rated "active," while those in the phenotyping arm got an average of 2.8. The 24-week missing-data-equal-failure analysis defined failure as a regimen switch because of virologic failure -- but not because of intolerance. By that standard, the median viral load dropped 1.3 logs in the Virtual arm and 0.92 log in the phenotyping arm (P = 0.008). Respective proportions with a viral load below 400 copies/mL were 56.5 percent and 46.5 percent (P = 0.01).
At the 2002 Resistance Workshop, Neil Parkin plumbed ViroLogic's vast viral database to propose novel genotypic pathways promoting resistance to lopinavir.24 At ICAAC he did the same favor for amprenavir. Analyzing more than 4,000 isolates, he found frequent discordance between genotypic resistance or sensitivity determined by four rule sets and phenotypic sensitivity or resistance determined with a conservative fold-change susceptibility cutoff of 2.5. For example, according to the ANRS algorithm, 15 percent of isolates called genotypically sensitive proved phenotypically resistant, and 7 percent called genotypically resistant proved phenotypically sensitive, for a total discordance score of 22 percent. All the rule sets yielded total discordance rates between 22 and 25 percent.
Because the genotypic rules relied on defined amprenavir mutations -- V32I, I50V, I54L/M, and I84V -- Parkin figured that genetic pathways not including amprenavir-selected mutations must contribute to slumping susceptibility. To scout out the mutational milestones on these shadowy pathways, he analyzed mutations at all protease positions that turned up in more than 1 percent of his samples. Then he used a univariate analysis to pick mutations that may contribute to reduced susceptibility to amprenavir, and he tested those mutations for resistance when combined with each other and with a second list of canonical protease mutations. This exercise yielded a suite of mutations and mutation sets that shave susceptibility to amprenavir:
If Parkin added the first set listed above to the mutations in current algorithms, total phenotypic-genotypic discordance dropped from 24.5 percent to 20.6 percent. If he then tossed in 33F + 82A, total discordance dwindled to 17.9 percent. Piling on the third set narrowed total discordance to 15.1 percent. Finally, Parkin verified the refurbished algorithm against a validation set of 1,634 resistant isolates not included in the set used to track down the newly implicated mutations. Along the way to these findings, he also showed that resistance conferred by amprenavir's signature mutation, I50V, can be reversed by the N88S substitution.
Retroviral researchers of every stripe have now stalked HIV through dusky forests for 20 years. And some did frame fearful symmetries -- X4 and R5 viruses, unraveling error-prone RNA strands, and life-saving two-target therapies come to mind. But the talk of HIV research as this year's ICAAC unfolded was whether Linqi Zhang and David Ho (Aaron Diamond AIDS Research Center, New York) had managed to frame another symmetry by completing a coup with CAF -- Jay Levy's long-since discovered, but never defined, CD8 antiviral factor. As Fate's immortal hand would have it, ICAAC organizers had already slated Ho to talk during a pathogenesis plenary. And by the time he took the stage, everyone knew the "Host factors that suppress HIV replication" in his talk's title were alpha-defensins [presentation 1192].
Never mind that few -- if any -- attendees had ever heard of these pint-sized proteins before Zhang and Ho's paper went online.26 Many could appreciate the neat symmetries here. Levy published his CAF discovery in Science in 1986,7 but diligent work in his lab never managed to nab the culprit molecule. Over the years Levy emerged as an outspoken critic of Ho's eradication essays,27 not to mention his hit-hard-hit-early tenet.28 Now, 16 years after CAF's first sighting, Zhang and Ho's paper, again in Science, claims their findings "show that alpha-defensins-1, -2, and -3 collectively account for the anti-HIV-1 activity of CAF that is not attributable to beta-chemokines."26
Alpha-defensins, which Zhang identified with a novel gene chip, turned up in CD8 cells from three of three nonprogressors, none of four rapid progressors, and 11 of 15 volunteers without HIV infection. Zhang showed that antibodies against alpha-defensins eliminate CAF activity, and that adding synthetic alpha-defensins to HIV-infected cells inhibits HIV replication.
Although the discoverer of alpha-defensins called this work "very convincing,"8 not everyone buys the conclusion that they account for the tiger's share of CAF's anti-HIV action. The study population was small; the antiviral activity weak; and no one could explain how alpha-defensins, which breach the walls of noxious bacteria, also bring down HIV. (For more detailed reviews of Zhang's study, see references 8 and 29.)
But there's a bigger question about this research: What does it mean for the millions of people with HIV who are not long-term nonprogressors? The most optimistic answer is that -- if Zhang and Ho are right about alpha-defensins' antiviral role -- this work could lead to novel antiviral strategies. But, appropriately, Ho himself downplayed that possibility in press interviews. Whether synthetic alpha-defensins could be turned into a tolerable drug, and -- if they can -- whether they would stop HIV in humans without unhinging healthful doings, remain weighty riddles.
No. The talk that preceded Ho's framed a symmetry that means more to people destined to become long-, short-, or mid-term progressors. Back when CAF came to light in Levy's lab, virologists thought about two types of HIV-1 -- the type found in North America, and the type found in Africa, explained Thomas Quinn of Johns Hopkins University [presentation 1191]. A scant six years later, viral orthographers had named five subtypes -- or clades -- of the retrovirus, A through E.30 That was only the beginning.
Now we are up to subtype K, and there is talk of L. But wait. It gets more complicated. Some of the original subtype designations turned out to be wrong. Today's subtype E, for example, really represents a circulating recombinant form (CRF) of A and some older E. Subtype I actually denotes a CRF that recombines four parental strains. So far researchers have tallied 14 CRFs, and they haven't stopped to catch their breath.
IAVI Report goes on to explain why this case of superinfection may not spell doom for vaccine research. The index case had HIV to begin with, and even minimally compromised immunity could make him more susceptible to reinfection than a freshly vaccinated, uninfected person. His immune response to the new virus was cell based, and no one expects a CTL-based vaccine to block infection. But, to tell the truth, everyone would be happier if this man's immune system had fought off the new virus.
As Quinn noted, leaders in this field disagree when estimating the impact of viral diversity on vaccine development. Andrew McMichael (Oxford) thinks vaccine developers have to trek from region to region, sample the locally prevalent virus, then use it to brew a local vaccine. Bette Korber (Los Alamos National Laboratory) believes they must time-travel all the way back to the parental HIV-1 -- via computer calculations -- if they want to make a vaccine that works. Quinn himself proposed that a vaccine derived from subtypes A, B, C, and D, plus CRF01 and CRF02, which account for 85 percent of worldwide infections, holds the most promise.
So far, of course, no one seems close to a single-subtype vaccine.
Those fearfully symmetric correlates of protection, which a potent vaccine would mimic, remain unframed.
Mark Mascolini writes about HIV infection (email@example.com).
Back to the December 2002 issue of IAPAC Monthly.
The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.


text:
Connected Degree
Information Security
to B.S. Information Technology - Network Administration
An opportunity to gain an associate degree from Delaware Tech and a bachelor's degree from Western Governors University.
Delaware Tech has established agreements with four-year colleges and universities that connect Delaware Tech associate degree programs with bachelor's degree programs to create smooth transfer opportunities for you. These Connected Degree programs enable you to complete your associate degree and then transfer to a four-year degree program as a junior.
Delaware Tech's Information Security program addresses local, regional, and national workforce needs following the National Security Telecommunications and Information Systems Security standards. Students will learn how to build and maintain secure networks, diagnose and resolve vulnerabilities, implement security policies, and manage operating systems. Graduates will be prepared to protect personal and networked computing devices from various kinds of cyber attacks and will be qualified for entry-level positions such as computer network technician, network specialist, computer support specialist, database administrator, and network administrator. Western Governors University's Bachelor of Science in Information Technology (IT) - Network Administration will prepare students with the cutting-edge network server administration skills in demand by employers. This program incorporates 14 industry recognized IT certifications as part of the degree program including Microsoft Certified Solutions Associate (MCSA). The cost of required certifications is provided at no additional cost to the student. They are covered by the term tuition fee. This online program is flexible and adaptable to the student's schedule. Graduates are prepared to become effective, marketable network server administrators.
By completing your associate degree at Delaware Tech, you'll receive excellent instruction in small classes at a campus close to home. Delaware Tech's affordable tuition can reduce the overall cost of your college education, making the completion of your bachelor's degree more manageable.
Refer to the Connected Degree curriculum (on the reverse side of this page) for the sequence of courses needed to complete this program. Call Delaware Tech and let us help you follow the path to your bachelor's degree.
Suggested Course Sequence
Information Security
B.S. Information Technology - Network Administration
|The Bachelor of Science program in Information Technology - Network Administration requires a minimum of 120 credits. Course sequencing may vary by semester. See your advisor. RDG 120, Critical Reading and Thinking, is a required DTCC course unless the student is exempt.
|For more information contact:
|Delaware Tech
Dover, DE: (302) 857-1836 Georgetown, DE: (302) 259-6490 Wilmington, Delaware: (302) 573-5475
|Western Governors University
Online University: (239) 980-2263
|This articulation agreement is subject to change based on Delaware Tech and senior institution curriculum changes. 11/2012
- Programs of Study
- Accounting
- Advertising Design
- Agribusiness Management
- Architectural Engineering Technology
- Associate of Science
- Automotive
- Automotive Technician Studies
- Aviation Maintenance Technology
- Bachelor of Science in Nursing
- Baking and Pastry Skills Certificate
- Baking and Pastry Skills Studies
- Biological Sciences
- Biotechnology
- Building Automation Systems Option
- Business Administration Transfer Option
- Cardiovascular Sonography
- Chemical Process Operator
- Chemical Process Operator Certificate
- Chemical Process Operator Studies
- Chemistry
- Chemistry Math Concentration
- Civil Engineering Technology
- Civil Transfer Option
- Commercial Transportation Certificate
- Commercial Transportation Studies
- Communications
- Computer Aided Drafting Design Technology
- Computer Engineering Tcy Option
- Computing and Information Science
- Construction Management
- Cooking Certificate
- Correctional Officer Certificate I
- Criminal Justice
- Culinary Arts
- Dental Hygiene
- Design Engineering Mechanical
- Developmental Math
- Developmental Reading
- Developmental Writing
- Diagnostic Medical Sonography
- Direct Support Professional Certificate
- Drug Alcohol Counseling
- Drug Alcohol Counseling Certificate
- Early Care and Education Birth to Second Grade
- Early Childhood Development
- Early Childhood Studies
- Electrical and Computer Engineering Transfer Option
- Electromechanical
- Electronics Engineering Tcy
- Electronics Engineering Technology Biomedical Option
- Electronics Engineering Technology Instrumentation Certificate
- Electronics Engineering Technology Instrumentation Option
- Electronics Engineering Technology Transfer Option
- Elementary Education
- Emergency Medical Technician Paramedic
- Emergency Medical Technician Paramedic Certificate
- Energy Management
- English
- English as a Second Language Certificate
- Entrepreneurship
- Entrepreneurship Certificate
- Environmental Engineering Technology
- Exercise Science
- Food Safety
- Food Safety Certificate
- General Airframe Maintenance Certificate
- General Business
- General Powerplant Maintenance Certificate
- Geographic Information Systems Technology
- Health Information Management
- Histotechnician
- Homeland Security and Emergency Management
- Hospitality Management
- Human Services
- Information Technology and Networking
- Instruction, Design, and Technology Certificate
- Kitchen Skills Studies
- Landscape and Ornamental Horticulture
- Law Enforcement Option
- Logistics, Supply Chain, and Operations Management
- Machinist Training Level 1 Certificate
- Machinist Training Level 2 Certificate
- Management
- Marketing
- Math Secondary Education
- Mathematics
- Mechanical Engineering Technology
- Medical Assistant
- Medical Coding Studies
- Medical Laboratory Technician
- Middle-Level Math Education
- Multimedia
- Nuclear Medicine
- Nursing
- Occupational Therapy Assistant
- Office Administration
- Paraeducator
- Paralegal
- Paralegal Certificate
- Photo Imaging
- Physical Therapist Assistant
- Practical Nursing Studies
- Production Agriculture
- Radiologic Technology
- Refrigeration Heating AC
- Refrigeration Heating AC Studies
- Renewable Energy Solar
- Respiratory Care
- Science
- Science Education Chemistry Physics
- Social Science
- Surgical Technology
- Surveying and Geomatics Engineering Technology
- Turf Management
- Veterinary Technology
- Registration Information
- Academic Calendar
- Transfer Options
- International Education
- Instructional Technology & CCIT
- Learning Options
- Student Handbook
- College Catalog
- An Equal Opportunity Institution
- A Message From The President
- Board of Trustees
- General Information
- Services for Students
- Financial Information
- Academic Policies and Procedures
- Campuses
- Programs of Study
- Bachelor of Science Degree (B.S.) Programs
- Associate in Applied Science Degree (A.A.S.) Programs
- Associate of Arts in Teaching Degree (A.A.T.) Programs
- Associate of Science (A.S.) Programs
- Diploma Programs
- Certificate Programs
- Course Descriptions
- Administrative, Instructional, and Student Affairs Personnel


text:
Eureka! That's probably the wrong word to use, but we've done it! Thanks to Stefan Roos of Trier in Germany, we've achieved a major breakthrough in our researches. Victor's missing siblings have been traced.
Now we know that Victor's parents Lazarus and Jeanette had six children: Raphael Louis (1818) and his twin sister who was stillborn; Salomon (1822); Joseph (1824); Victor (1827) and another stillborn daughter (1829) – all born in Luxembourg. Perhaps these siblings were not discovered during our researches at the Grand Duchy's National Archives because Lazarus was registered in Luxembourg as Cahen, the French spelling of Kahn. I can feel another visit to Luxembourg coming on.
As a result of the email from Stefan, we also know that Lazarus and his wife (Jeanette Isaac Lazard) were first cousins, Jeanette being the daughter of Lazarus's mother's brother. This was an unsuspected link.
Furthermore, we now know that Lazarus died in Luxembourg in 1873. Perhaps we missed the record of his death because it was recorded under the name of Cahen while we were concentrating on Kahns. In fact, Lazarus appears to have used both spellings of his name, as evinced in the on-line listings of recipients of St Helena medals, the Napoleonic (and hence French) campaign award for those fighting as part of the Grand Armee. (www.stehelene.org/php/accueil.php?page=4&lang=en).
And yet more information: Stefan introduced us to an entirely new family: that of Elisabeth Alexander. She married Ralph Louis Kahn (Victor's brother) in 1859 in Saarlouis. They had three surviving children: George (1861), Paul (1863) and Henriette (1864), all registered under the name of Cahen and born in Luxembourg. Elisabeth's father was Lazard Alexander and her mother was born Fleurette Aron.
Finally, here is that elusive Welschbillig connection: Lazarus's brother Levy and sister Johanetta both settled there with their respective families. So our last year's speculative trip to that pleasant part of rural Germany was relevant after all.
When time permits, we'll add this new data to the biographies section. In the meantime, we are very grateful to Stefan for this invaluable information. Of course, the search continues and we'd be delighted to hear from any descendants of Victor's brothers, no matter how distant.